Utah toddler one of first to receive groundbreaking gene replacement therapy – KSL.com

MORONI A Utah toddler is one of the first in the U.S. to receive a potentially groundbreaking therapy, and his father is doing everything he can to give his son the strength to win his fight.

Deep in the farm country of central Utah, a family is counting their blessings.

Yes, I would call it living the dream, yes maam, said Alex Wight, who lives with his family in Moroni.

Four years ago, while riding in the high country, Wight and his horse went off a cliff. The fall shattered Wights foot. Far from help, I was definitely going into some shock and I thought, Man, Im never going to get out of here,' Wight said.

Wight climbed back on that horse and rode for 20 miles. If I would have quit, I would have never made it out, he said.

Never was that toughness more vital than when his wife gave birth to their son, Cinch. I was pretty torn up. I cried a lot. Not gonna lie, Wight said.

Newborn screenings showed Cinch has spinal muscular atrophy, or SMA.

I cried. I was working at the sawmill, didnt even tell anyone I was leaving, (I) just put my machine away and left, Wight said.

The neuromuscular disorder paralyzes a baby in the first few weeks or months of life.

My first thought was that my son will never be able to ride broncs, rope, or just be a cowboy in general, Wight said.

Many babies with SMA dont survive to their second birthday, but the day after Cinch was born, the U.S. Food & Drug Administration approved a new therapy. We felt like our prayers were answered, Wight said.

In a single infusion, a virus delivers a new copy of the gene into the babys nerves, said Dr. Russell Butterfield, a pediatric neurologist with University of Utah Health and Intermountain Primary Childrens Hospital.

Only this time, its not delivering a diseased gene that just causes more virus to be made, but a gene that we care about, Butterfield said.

Its a $2.1 million treatment.

I was thinking, Man, theres no way Ill ever pay for it, Wight said.

Wight was determined. We just stayed on top of it. I wasnt going be the one to not get it, he said.

With help from insurance and Primary Childrens Hospital, Cinch got the gene replacement therapy through the Primary Childrens Center for Personalized Medicine.

The Wights wouldnt know for months if it worked. Amber Wight, Cinchs mother, said, Every days a waiting game, we have no idea.

Alex wrote a book to teach children they can do hard things, even when theyre hurt or discouraged.

Early one morning, a cowboy stepped out of his camp and into the corral, Wight said, reading the book to his son.

He held his breath the day Cinch took his first steps. He just cruises, Wight said.

It just brings a tear to your eye, to be honest, Butterfield said.

Time will tell if the gene replacement therapy is indeed a breakthrough. I just hope he never quits, Wight said.

With love wider than a prairie I guess on a scale of one to 10, Id call it a 12, Wight said and with the wonders of medical science, Cinch has a shot at a bright future, full of promise.

You can get Alex Wights book at Amazon.com.

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Utah toddler one of first to receive groundbreaking gene replacement therapy - KSL.com

Here’s Why Shares of Editas Medicine and Beam Therapeutics Are Soaring Today – Motley Fool

What happened

Shares of Editas Medicine (NASDAQ:EDIT) and Beam Therapeutics (NASDAQ:BEAM) rose as much as 23% and 29%, respectively, today after the pair were rumored to be considering a merger. Although investors shouldn't invest based on speculation, a merger would make sense on multiple fronts.

The duo already have an agreement in place to collaborate on genetic medicines, but the struggling pipeline of Editas Medicine could receive a significant boost from Beam Therapeutics. It would also allow Editas shareholders to avoid many of the technical pitfalls of first-generation CRISPR gene-editing tools, which have yet to be adequately reflected in stock prices. Of course, the flip side is that the merger doesn't make as much sense for Beam Therapeutics.

As of 12:50 p.m. EDT, both small-cap stocks had settled to gains of about 14%.

Image source: Getty Images.

There are multiple reasons a merger makes sense. Consider that:

There's not much to the report that Editas Medicine and Beam Therapeutics are considering a merger. Only one digital publication mentions "chatter" without providing any follow-up details. The rumors are at least plausible given the ties to the Broad Institute and overlap of the scientific founders, but investors simply don't have much to go on. That said, a merger would make more sense for Editas Medicine than Beam Therapeutics, as the latter has a much stronger technical foundation to lean on for the long haul.

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Here's Why Shares of Editas Medicine and Beam Therapeutics Are Soaring Today - Motley Fool

Image of the Month: Locating molecular players in Batten disease – Baylor College of Medicine News

Mutations in either protein CLN6 or CLN8 result in two forms of Batten disease with remarkably similar clinical features. It turns out, as recently shown by the laboratory of Dr. Marco Sardiello, that both proteins work together to equip lysosomes, the waste-disposal hubs of the cell, of the much needed enzymes that process cellular waste.

Batten disease is a family of 13 rare, genetically distinct conditions. Collectively, they are the most prevalent cause of neurodegenerative disease in children, affecting 1 in 12,500 live births in the U.S. One of the Batten disease genes is CLN6. How mutations in this gene lead to the disease has been a mystery, but a study led by researchers at Baylor College of Medicine and published in the Journal of Clinical Investigation reveals how defective CLN6 can result in Batten disease.

People with Batten disease have problems with their cells ability to clear cellular waste, which then accumulates to toxic levels, said first author Dr. Lakshya Bajaj, who was working on this project while a doctorate student in the Sardiello lab at Baylor. Bajaj is currently a post-doctoral associate at Harvard Medical School.

In cells, lysosomes process cellular waste. They are sacs containing enzymes, a type of proteins that break down waste products into its constituent components that the cell can recycle or discard. In Batten disease caused by mutations in CLN6, the lysosomes do not process waste effectively for unknown reasons. This results in waste accumulation. Batten disease is a type of lysosomal storage disorder. Although all types of cells can be affected by defects in lysosomal waste management, brain cells, neurons, are particularly susceptible.

Waste accumulation in neurons perturbs many cellular processes and eventually results in cell death. This leads to the progressive degeneration of motor, physical and intellectual abilities observed in Batten disease patients, Bajaj said.

The connection of CLN6 with Batten disease was a bit of a mystery. This protein is not found in lysosomes, but in the endoplasmic reticulum, a structure inside cells where proteins, including lysosomal enzymes, are made. The endoplasmic reticulum is separate from the lysosomes. So, how do defects in a protein located outside of the lysosomes interfere with lysosomal function?

The Sardiello lab had previously solved a similar mystery involving CLN8, another protein located in the endoplasmic reticulum and whose mutations also cause a type of Batten disease.

We showed that CNL8 assists on the exit of lysosomal enzymes from the endoplasmic reticulum en route to the lysosomes. When CLN8 is defective, the transport of enzymes from their place of synthesis to the final destination is deficient and the lysosomes end up having fewer enzymes to work with, said Sardiello, associate professor of molecular and human genetics at Baylor and corresponding author of this work.

The clinical manifestations of Batten disease caused by CLN8 mutations and those of Batten disease due to defective CLN6 are remarkably similar. This and other evidence led the researchers to suspect that CLN6 and CLN8 might be working together.

Their investigations revealed that CLN6 and CLN8 do interact with each other forming a molecular complex that collects lysosomal enzymes at the endoplasmic reticulum and mediates their trafficking towards the lysosomes.

We propose that CLN8 and CLN6 together herd the enzymes into a hub, a sort of bus stop. Then, CLN8 escorts the enzymes on the bus en route to the lysosomes, while CLN6 remains at the bus stop. CLN8 returns to the bus stop after delivering the enzymes, and they repeat the process, Bajaj said. When CLN6 is defective, the enzymes are not effectively herded into the bus stop and fewer are transported to the lysosomes.

The researchers are interested in finding whether other factors are involved in transporting enzymes to the lysosomes. For instance, whether there are other bus conductors or herders of lysosomal enzymes involved that, if defective, may also contribute to Batten disease.

Other contributors to this work include Jaiprakash Sharma, Alberto di Ronza, Pengcheng Zhang, Aiden Eblimit, Rituraj Pal, Dany Roman, John R. Collette, Clarissa Booth, Kevin T. Chang, Richard N. Sifers, Sung Y. Jung, Jill M. Weimer, Rui Chen and Randy W. Schekman. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; Texas Childrens Hospital; University of California, Berkeley; Sanford Research, Sioux Falls, South Dakota; and Sanford School of Medicine at the University of South Dakota.

This work was supported by NIH grants NS079618 and GM127492 and grants from the Gwenyth Gray Foundation, Beyond Batten Disease Foundation and NCL-Stiftung. This project was supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Integrated Microscopy Core and the Proteomics Core at Baylor College of Medicine with funding from NIH (DK56338, and CA125123), CPRIT (RP150578, RP170719), the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

By Ana Mara Rodrguez, Ph.D.

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Image of the Month: Locating molecular players in Batten disease - Baylor College of Medicine News

Genetic Modification Therapies Market 2020: Challenges, Growth, Types, Applications, Revenue, Insights, Growth Analysis, Competitive Landscape,…

The global Genetic Modification Therapies market is expected to exceed more than US$ 3.5 Billion by 2024 at a CAGR of 34% in the given forecast period.

FYI, You will get latest updated report as per the COVID-19 Impact on this industry. Our updated reports will now feature detailed analysis that will help you make critical decisions.

Browse Full Report: https://www.marketresearchengine.com/genetic-modification-therapies-market

The global Genetic Modification Therapies market report provides geographic analysis covering regions, such as North America, Europe, Asia-Pacific, and Rest of the World. The Genetic Modification Therapies market for each region is further segmented for major countries including the U.S., Canada, Germany, the U.K., France, Italy, China, India, Japan, Brazil, South Africa, and others.

Genetic modification therapies, significantly gene therapy and RNA therapy, have existed for many years, with very little clinical success. However, recent enhancements in these therapies, together with higher delivery systems, additional economical and sturdy gene expression constructs, precise polymer editing tools, have brought this industry to the forefront, and its currently poised for explosive growth within the coming back years.

Because of the potentially curative nature of those medicines theres monumental potential in several applications, starting from cancer to neurology to rare diseases. Genetic modification therapies represent consecutive wave of medicines with monumental potential for treating and curing draining and high diseases. As a result of its wide scope, genetic modification therapy can play a vital role within the future world medical economy.

Continuing advances in key technologies like DNA editing, viral design and production, and gene expression, further as a pressing medical want in several serious and enervating disorders, are driving the expansion of the marketplace for genetic modification therapies. Developments in these multidisciplinary fields promise to advance the genetic modification therapies trade and build distinctive market opportunities.

The overall market is anticipated to witness important growth in opportunities for a spread of stakeholders within the returning decade. its necessary to spotlight that many technology suppliers, reaching to develop and / or support the event of gene therapies, with improved effectiveness and safety, have designed and already introduced advanced platforms for the engineering of vectors. Innovation during this domain has additionally semiconductor diode to the invention of novel molecular targets and strong the analysis pipelines of corporations targeted during this house. the potential to focus on numerous therapeutic areas is taken into account to be amongst the foremost outstanding growth drivers of this market.

Market Insights

The global Genetic Modification Therapies market is segregated on the basis of Platform Technology as Gene editing, Gene Therapies, Genetically Modified Cell Therapies, and RNA Therapies. Based on Delivery Technologies the global Genetic Modification Therapies market is segmented in AAV, Adenovirus, Lentivirus, Retrovirus, Other Viral, and Nonviral Based on End-User Industry the global Genetic Modification Therapies market is segmented in Hospitals, Diagnostics and Testing Laboratories, Academic and Research Organizations, and Others.

Based on Disease, the global Genetic Modification Therapies market is segmented in Cardiology, Oncology, Ophthalmology, Hematology, Musculoskeletal, Neurology, Rare Diseases, Other Indications.

Competitive Rivalry

4D Molecular Therapeutics, Abeona Therapeutics, Beam Therapeutics, Casebia Therapeutics, Editas Medicine, Fate Therapeutics, GE Healthcare, Hitachi Chemical Advanced Therapeutics, Immunocore, Jivana Biotechnology, and others are among the major players in the global Genetic Modification Therapies market. The companies are involved in several growth and expansion strategies to gain a competitive advantage. Industry participants also follow value chain integration with business operations in multiple stages of the value chain.

The Genetic Modification Therapies Market has been segmented as below:

The Genetic Modification Therapies Market is segmented on the lines of Genetic Modification Therapies Market, By Platform Technology, Genetic Modification Therapies Market, By Delivery Technologies, Genetic Modification Therapies Market, By End-User Industry, Genetic Modification Therapies Market, By Disease, Genetic Modification Therapies Market, By Region and Genetic Modification Therapies Market, By Company.

Genetic Modification Therapies Market, By Platform Technology this market is segmented on the basis of Gene editing, Gene Therapies, Genetically Modified Cell Therapies and RNA Therapies. Genetic Modification Therapies Market, By Delivery Technologies this market is segmented on the basis of AAV, Adenovirus, Lentivirus, Retrovirus, Other Viral and Nonviral. Genetic Modification Therapies Market, By End-User Industry this market is segmented on the basis of Hospitals, Diagnostics and Testing Laboratories, Academic and Research Organizations and Others. Genetic Modification Therapies Market, By Disease this market is segmented on the basis of Cardiology, Oncology, Ophthalmology, Hematology, Musculoskeletal, Neurology, Rare Diseases and Other Indications. Genetic Modification Therapies Market, By Region this market is segmented on the basis of North America, Europe, Asia-Pacific and Rest of the World. Genetic Modification Therapies Market, By Company this market is segmented on the basis of 4D Molecular Therapeutics, Abeona Therapeutics, Beam Therapeutics, Casebia Therapeutics, Editas Medicine, Fate Therapeutics, GE Healthcare, Hitachi Chemical Advanced Therapeutics, Immunocore and Jivana Biotechnology.

The report covers:

Report Scope:

The global Genetic Modification Therapies market report scope includes detailed study covering underlying factors influencing the industry trends.

The report covers analysis on regional and country level market dynamics. The scope also covers competitive overview providing company market shares along with company profiles for major revenue contributing companies.

The report scope includes detailed competitive outlook covering market shares and profiles key participants in the global Genetic Modification Therapies market share. Major industry players with significant revenue share include 4D Molecular Therapeutics, Abeona Therapeutics, Beam Therapeutics, Casebia Therapeutics, Editas Medicine, Fate Therapeutics, GE Healthcare, Hitachi Chemical Advanced Therapeutics, Immunocore, Jivana Biotechnology, and others.

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Researchers identify environmental components that affect gene expression in cardiovascular disease – The South End

A research team led by Francesca Luca, Ph.D., associate professor of Wayne State Universitys Center for Molecular Medicine and Genetics, has published a study that annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes that could exacerbate or buffer the genetic risk for cardiovascular disease. Their results highlight the importance of evaluating genetic risk in the context of gene-environment interactions to improve precision medicine.

Interpreting Coronary Artery Disease Risk Through GeneEnvironment Interactions in Gene Regulation was published in Genetics, the journal of the Genetics Society of America.

The study, said Dr. Luca, also of the WSU Department of Obstetrics and Gynecology, illustrates that combining genome-wide molecular data with large-scale population-based studies is a powerful approach to investigate how genes and the environment interact to influence risk of cardiovascular disease.

By identifying regions of DNA important for endothelial cell response to different common environmental exposures, the researchers discovered that caffeine can influence the risk of cardiovascular disease. The study demonstrates the potentially beneficial and/or detrimental effects of certain environmental exposures on the cardiovascular disease risk differ depending on individual DNA sequence.

The study focused on cardiovascular disease, Dr. Luca said, because it is the leading cause of death, both in the United States and worldwide. Also, the disease is highly multifactorial, with large contributions from both environmental and genetic risk factors. By treating endothelial cells under a controlled environment, we can discover how these genetic and environmental risk factors influence each other at the molecular level, she said. Our lab has developed expertise in cardiovascular research, with additional projects using endothelial cells to develop new assays to test the regulatory activity of genetic variants. The approach outlined in this paper can be applied to many different diseases; for example, our lab has also focused on how bacteria in the human gut affect gene expression in the colon, and also on the effect of psychosocial stress on asthma.

While the work identified regions of the genome important for how endothelial cells respond to the environment and can influence the risk of cardiovascular disease, the researchers do not yet know exactly which genetic variants are directly responsible. A former graduate student, Cynthia Kalita, developed an assay to test thousands of genetic variants for gene regulatory activity. The researchers can test the variants discovered in their study using that assay to validate and explore the mechanisms by which they exert their effects, Dr. Luca said. They also are developing computational/statistical methods that can yield better personalized risk scores.

We have extended our approach to study cardiomyocytes, which are the muscle cells of the heart. Healthy heart tissue is difficult to obtain, so we have collaborated with researchers at the University of Chicago to derive cardiomyocytes from stem cells, Dr. Luca said. This will allow us to shift our focus from the vasculature to the heart itself, where we can study diseases like cardiomyopathies and arrhythmias.

As the cost of DNA sequencing continues to decrease, Dr. Luca expects that genetic testing will play a greater role in preventive health care. To fully realize the potential of precision medicine, we need to consider both genetic and environmental risk factors of disease, and how they interact. While there are already direct-to-consumer tests that prescribe an individualized diet based on DNA, these products currently offer no demonstrated clinical value. However, with very large numbers of individuals for whom we have both DNA sequencing and information on diet and lifestyle, we may one day be able to offer better recommendations.

Others involved in the study included Anthony Findley, an M.D./Ph.D. student; Allison Richards, Ph.D., a research scientist; Cristiano Petrini, of the Center for Molecular Medicine and Genetics; Adnan Alazizi, lab manager; Elizabeth Doman, of the Center for Molecular Medicine and Genetics; Alexander Shanku, Ph.D., research scientist; Gordon Davis, of the Center for Molecular Medicine and Genetics; Nancy Hauff, Department of Obstetrics and Gynecology; Yoram Sorokin, M.D., professor of Obstetrics and Gynecology; Xiaoquan Wen, of the Department of Biostatistics at the University of Michigan; and Roger Pique-Regi, Ph.D., associate professor of the Center for Molecular Medicine and Genetics, and of the Department of Obstetrics and Gynecology.

Continued here:
Researchers identify environmental components that affect gene expression in cardiovascular disease - The South End

The ultimate COVID-19 mystery: Why does it spare some and kill others? – Seattle Times

The novel coronavirus can be a killer or no big deal. It can put a person in the intensive care unit on a ventilator, isolated from family, facing a lonely death or it can come and go without leaving a mark, a ghost pathogen, more rumor than reality.

Six months into a pandemic that has killed more than 400,000 people globally, scientists are still trying to understand the wildly variable nature of COVID-19, the disease caused by the virus.

Among their lines of inquiry: Are distinct strains of the coronavirus more dangerous? Does a patients blood type affect the severity of the illness? Do other genetic factors play a role? Are some people partially protected from COVID-19 because theyve had recent exposure to other coronaviruses?

Much of the research remains provisional or ambiguous, and for now scientists cant do much better than say that COVID-19 is more likely to be worse for older people often described as over the age of 60 and for those with chronic conditions such as hypertension, diabetes, lung disease and heart disease.

That describes tens of millions of people in the United States alone. It also isnt much of an explanation: The link between chronic disease and the severity of COVID-19 is more in the category of correlation than causation. The why of the matter remains unclear.

The issue of disease variability is the most critical question about COVID, said Edward Behrens, chief of the rheumatology division at Childrens Hospital of Philadelphia.

Why do some people get sick? Why do some people have no problem at all? he said.

Social and demographic factors, including sex, race, ethnicity, income and access to quality health care, play major roles in how this pandemic affects people and who suffers the most. The ultimate goal of many researchers is to develop a personalized risk score so that a person who has COVID-19, or remains vulnerable to catching the disease, would have some idea of how to navigate the pandemic.

One potential breakthrough was highlighted recently by National Institutes of Health Director Francis Collinson his blog: Scientists developed an artificial intelligence tool that sorted the blood of COVID-19 patients and found 22 proteins that consistently appear among the patients who are severely ill.

At this point, such a blood marker only tells doctors what they can already see with their own eyes a very sick patient. But if such a blood test and analysis could be rolled out early in the course of the disease, it could help doctors decide which patients are most vulnerable.

Blood-type research is also intriguing. This month, European scientists posted online a study not yet peer-reviewed that found strong links between variations on two places in the genome and respiratory failure in COVID-19 patients in Italy and Spain.

One, the ABO gene, determines blood type. The researchers found that patients who had Type A blood had a 50% higher risk of needing oxygen or a ventilator. Type O blood seemed to have a partial protective effect.

Why that gene matters remains unknown, according to co-author Andre Franke, a professor of molecular medicine at the University of Kiel in Germany. The genetic variant may cause the risk by being associated with inflammation.

Another possibility is that Type A blood is associated with small blood clots that characterize some severe COVID-19 cases. And there may be other things cooking in that region of the genome, Franke said.

The consumer genetics giants Ancestry.com and 23andMe are getting involved. 23andMe recently released preliminary findings showing that people with Type O blood are 9 to 18% less likely to test positive for COVID-19 than people with other blood types. The company is still exploring links between blood type and disease severity.

More than 750,000 of the companys customers have completed a web-based survey about their experiences with COVID-19, and 2,000 of them said theyd been hospitalized from the disease. The company is now recruiting 10,000 non-customers who have been hospitalized with COVID-19.

It would be very nice if there was a single gene that we could understand as conferring different levels of risk for COVID-19, said Adam Auton, 23andMes principal scientist. In reality, dozens or hundreds or even thousands of genes are all making very small contributions toward disease risk.

Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University, is co-leading an international team searching the genomes of outliers patients younger than 50 who had no known preexisting conditions, but were hospitalized with life-threatening cases of COVID-19. Theyre looking for unusual gene variants that these patients have in common.

Casanova and his colleagues have previously found genetic mutations that increase a persons susceptibility to infectious diseases, such as severe pneumonia caused by influenza.

There are many, many infectious diseases for which genetic variations have been shown to be causal, Casanova said. So when COVID occurred, if I may say, its business as usual.

Numerous papers have explored whether different strains of the virus are more transmissible or lethal. One strain has become dominant in much of Europe and the United States. That strain has a genetic mutation affecting what is called the spike protein the structure that lets the virus bind to receptor cells in humans.

So far, there is no consensus that this or other mutations are significant from a clinical standpoint. Francis Collins, director of the U.S. National Institutes of Health, says of the different strains, I think theyre all acting the same.

Another possibility frequently discussed by researchers is that the mode of transmission is key to understanding the severity of the disease. Many scientists argue that, contrary to what the World Health Organization and the Centers for Disease Control and Prevention have repeatedly stated, the virus sometimes spreads through tiny aerosol particles, not simply through large respiratory droplets.

That leads some scientists to think the aerosol transmission could enable the virus to penetrate deep into the lungs and trigger a more severe infection.

The body has an innate immune system that includes physical obstacles for any invading viruses. But tiny particles can go with the air flow and potentially reach the deepest regions of the lungs, said Raymond Tellier, a microbiologist at McGill University Health Center.

For Tellier, thats a sign that this virus must be spreading in part through aerosols.

How else would the virus go down the lower respiratory tract where the cells can be infected? he asks.

The amount of virus initially transmitted from one person to another could play a role in determining the course of illness: more virus, sicker patients. Albert Ko, an infectious-disease epidemiologist at the Yale School of Public Health, said, If I spew out a lot of virus at you and youre one foot away, youre going to get a higher inoculum than if youre six feet away.

Even with all the focus on the virus, and its potential mutations and dosages, the most critical factor is the person getting infected the host. Not everyone hosts the virus the same way. The human immune system is a complicated tangle of pathways and partners, as Collins puts it.

Its conceivable, Collins said, that some people have immune systems that are better primed for this new invader because of previous exposure to genetically related coronaviruses. Thats still highly conjectural.

The immune system not only can be protective, it can also go haywire and make an illness catastrophically worse. If the immune system is an army that attacks infections, molecules called cytokines are the messengers that tell the troops what to do to beat back the invader. Too few cytokines, and the defense will be too weak, allowing the infection to progress. Too many, and the commands become a cacophony that causes an erratic and overreactive immune response a cytokine storm.

The army goes crazy and just sort of does more damage than they would intend to do, said Behrens, of Childrens Hospital of Philadelphia.

You start making too many cytokines all at the same time. Now your immune cells are confused. Theyre trying to do everything all at once, he said. Now its no longer the virus thats killing you, its the immune system thats killing you.

Some children infected with the coronavirus have a severe, sometimes fatal Kawasaki-like syndrome. It affects multiple organs the gut, the heart, the skin, the eyes, Behrens said and research by his team suggests it is a cytokine storm. Behrens hopes the teams study of children with COVID-19 will also shed light on why some adults get so sick.

Quickly identifying a storm of cytokines, which can be detected in blood tests, is key, he said. In March, CHOP developed a rapid diagnostic test, which delivers patients results in a day. But theres much more to learn.

What is their particular storm? Where in the process are they? Which drug should we pull off the shelf? Behrens said. That kind of personalized precision medicine is the holy grail for all this.

In the United Kingdom, health officials have released two different measures of risk. One developed by the National Health Service looks at age, gender and very granular medical factors such as whether you have preexisting conditions such as high blood pressure or diabetes.

Those at low risk are asked to social distance as the economy reopens. Those at higher risk are asked to shield, which means staying inside as much as possible and avoiding contact with others.

Jennifer Lighter, a hospital epidemiologist at NYU Langone, found that obesity was the No. 1 risk factor in her hospital system among those younger than 60. Patients with a body mass index between 30 and 34 obese under CDC definitions were two times as likely to be admitted to the ICU than patients with a BMI under 30. Those with a BMI of 35 and over were three times more likely to die than those with a healthy BMI.

As we are opening up the nation, one idea is to consider opening up by risk groups, Lighter said.

As we are opening up the nation, one idea is to consider opening up by risk groups. Jennifer Lighter, hospital epidemiologist

In the broadest sense, the risk of a bad outcome is pretty clear. Its better to be young and healthy if the coronavirus pays a visit.

Among the 238 sailors aboard the aircraft carrier USS Theodore Roosevelt who tested positive for the virus after an outbreak on the ship, only two required hospitalization, according to a new study from the CDC. One out of 5 reported no symptoms at all.

Older people suffer from immunosenescence. Their immune systems become dysregulated. Casanova describes this as the inevitable descending slope of life from about the age of 18 or 19.

The median age of people who died in virus-ravaged northern Italy was 81.

The difference between catching COVID and dying is so stark the older you get, its important to recognize that, said Carl Heneghan, director of the Center for Evidence-Based Medicine at Oxford University. In the U.K., theres been virtually no excess death for people under age 45 since the pandemic began, he said.

Another wrinkle: People who have little history of viral infections tend to have more severe reactions when they get infected later in life.

You have to try and stay healthy, get fit, Heneghan said. If youve got diabetes, youve got to lose weight and moderate that. If you do all those things, your risk of dying is small, or very small.

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The ultimate COVID-19 mystery: Why does it spare some and kill others? - Seattle Times

$14M Federal Grant to Research CAR-T Gene Therapy to Cure HIV – POZ

A group of collaborating scientists received a $13.65 million federal grant to study and develop a CAR-T therapy that will genetically modify immune cells and potentially cure HIV, according to a press release from the University of California, Los Angeles (UCLA).

The National Institutes of Health (NIH) funds the five-year grant as part of its effort to support HIV cure research. Participating researchers are affiliated with UCLA, the University of WashingtonFred Hutchinson Cancer Research Center and CSL-Behring, a biotech company based in the United States and Australia.

The overarching goal of our proposed studies is to identify a newgene therapy strategy to safely and effectively modify a patients own stem cells to resist HIV infection andsimultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection, said UCLAs Scott Kitchen, PhD, an associate professor of medicine in the division of hematology and oncology, in the press release. Kitchen will colead the research with Irvin Chen, PhD, director of the UCLA AIDS Institute at the David Geffen School of Medicine.

Transplantation ofHIV-resistant stem cells is the only approach that has ever led to a known cure for HIV(andlikely a second such cure). But stem cell transplants are risky and can only be done in people with HIVwho need them for cancer treatment. Using gene therapy tomodify an individuals own stem cells might be a safer way toachieve the same result.

The Food and Drug Administration first approved CAR-T therapywhich stands for chimeric antigen receptor T-cell therapyin 2017. Its used to treat some forms of cancer, but as POZs sister publication Cancer Health has reported, it hasnt been commonly used because it is expensive and must be custom made for each patient.

In the case of cancer treatment, CAR-T therapy involves taking a patients T cells and sending them to alab where they are genetically modified to recognize and attack the cancer. The resulting cells are then infused back into the individual after the person has received strong chemotherapy to kill off some of their existing immune cells to make room for the new ones.

In CAR-T therapy for HIV, blood-forming stem cells would be genetically engineered togive rise to T cells that would seek out and destroy cells infected with HIV.

In a recent early study of the approach, the UCLA scientists found that engineered CAR T cells destroyed HIV-infected cellsand lived for more than two years.

Our work under the NIH grant will provide a great deal of insight into ways the immune response can be modified to better fight HIV infection, said Chen, a professor of medicine and of microbiology, immunology and molecular genetics at the Geffen School of Medicine. The development of this unique strategy that allows the body to develop multiple ways to attack HIV could have an impact on other diseases as well, including the development of similar approaches targeting other types of chronic viral infections and cancers.

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$14M Federal Grant to Research CAR-T Gene Therapy to Cure HIV - POZ

COVID-19-Related Genes Have Higher Expression in Certain Patients With Asthma – Pulmonology Advisor

In patients with coronavirus disease 2019 (COVID-19), higher sputum cell expression of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) was observed in certain patients with asthma while lower expression was found in patients who used inhaled corticosteroids (ICS), according to study results published in the American Journal of Respiratory and Critical Care Medicine.

COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may be more severe in patients with chronic lung disease, including patients with asthma, and it appears that demographic or biological factors influence susceptibility to the infection or severity of disease. Because ACE2 and TMPRSS2 mediate viral infection of host cells, researchers reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells in patients with asthma may identify subgroups at risk for COVID-19 morbidity.

By analyzing gene expression for ACE2 and TMPRSS2 as well as intercellular adhesion molecule 1 (ICAM-1) in sputum cells from 330 participants and 79 healthy control individuals, researchers found that gene expression of ACE2 was lower than TMPRSS2, and that expression levels of both genes were similar in patients with asthma and healthy individuals. In patients with asthma, however, men, African Americans, and people with diabetes had higher expression of ACE2 and TMPRSS2. In patients with asthma, ICAM-1 expression increased and there were fewer consistent differences related to sex, race, and ICS use. Use of ICS was associated with lower expression of ACE2 and TMPRSS2, while treatment with triamcinolone acetonide did not decrease expression of either gene or ICAM-1.

Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes, the study authors wrote. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.

Reference

Peters MC, Sajuthi S, Deford P, et al; for the National Heart, Lung, and Blood Institute Severe Asthma Research Program-3 Investigators. COVID-19 related genes in sputum cells in asthma: Relationship to demographic features and corticosteroids [published online April 29, 2020]. Am J Respir Crit Care Med. doi:10.1164/rccm.202003-0821OC

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COVID-19-Related Genes Have Higher Expression in Certain Patients With Asthma - Pulmonology Advisor

New HHT Center Gives Hope to Father and Son with Rare Genetic Disease – Michigan Medicine

Arthur Gutowski and his son, Arthur Jr., share not only a name, but a rare hereditary blood vessel disorder that can cause severe nosebleeds, costing them as much as a cup of blood at a time.

My mom and uncle had nosebleeds, my grandma had nosebleeds, I have nosebleeds, says Gutowski, 72, of Dearborn, Mich. All three of his sons, including the eldest, who goes by AJ, have or had experienced them as well. (Chris the middle son, passed away in 2012.)

The Gutowskis have hereditary hemorrhagic telangiectasia (HHT), a disorder characterized by nosebleeds and fragile blood vessels. Its also known as Osler-Weber-Rendu disease.

Not a lot of physicians know about HHT, says their mutual doctor, Jeffrey Terrell, M.D., a professor of otolaryngology (also known as an ENT, for ear, nose and throat) at Michigan Medicine, so an estimated 90% of people with it go undiagnosed.

Terrell hopes to change that as Michigan Medicine becomes the states first designated HHT Treatment Center. The honor comes from Cure HHT, a nonprofit dedicated to finding a cure for the disease, and the CDC.

It means an integrated team of HHT experts including genetic counselors, ENTs, hematologists and interventional radiologists work together to provide the highest level of care to help patients manage their HHT.

Patients used to drive to Cleveland or Minnesota to go to such a Center but they have one much closer now, Terrell says.

The designation came with the help of a research grant Michigan Medicine hematologist Suman Sood, M.D. received from the Department of Defense and the CDC that combines treating people with HHT and hemophilia, an inherited disorder where the blood cant clot because of missing proteins in the blood.

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HHT is a gene mutation that causes blood vessels to form abnormally. While the cure remains elusive, it affects about 1 in 5,000 to 1 in 10,000 people. For the Gutowski family, it had a 100% frequency rate.

The nosebleeds experienced by the Gutowski family and others with the disorder frequently causes their hemoglobin numbers to plummet from a healthy adult male range of 12-18 to 4-6, making them tired, dizzy, short of breath and anemic. Before they started seeing Terrell, simple triggers for bleeds were yawning, sneezing and bending over to tie their shoes.

I learned to sneeze with my mouth, AJ says. So does his father.

AJ was in sixth grade taking a quiz when he believes he got his first nose bleed, which is a typical age for the disease to emerge. I knew at the time something was off but I knew my dad and grandma had nose bleeds, too, says AJ, 51, also of Dearborn. It was his normal.

HHT patients tend to have two types of blood vessel abnormalities. The smaller ones emerge on the skin, appearing as red or purple dots the size of a pinhead or elaborate spider veins. Theyre called telangiectasia and are found on the hands, face, mouth lips or inside the nose. The larger blood vessel abnormalities, arteriovenous malformation (AVMs), hide elsewhere in the body, but favor the nose, lungs, gastrointestinal tract, brain and liver. They can be life threatening. The brain AVM, for instance, can cause a stroke. The Gutowskis have liver and gastrointestinal AVMs, along with telangiectasia.

HHT evolves through the years. At first, the elder Gutowskis only symptom was nosebleeds and another spot on his liver, but when he started getting tired all the time, Terrell and his Michigan Medicine colleagues, including Sood and gastroenterologist Neil Sheth, M.D., looked closer. Gutowski had new AVMS in his gastrointestinal tract and they were bleeding.

Sheth used laser treatments to stop the flow and Sood gave Gutowski iron transfusions so he could resume his active life. For his nose vessels, he is on Avastin, a chemotherapy drug thats a vascular growth inhibitor.

For a while there he quit doing everything and was mostly housebound because he was out of breath and extremely fatigued by his anemia, Terrell explains. This past summer he went Up North to fish and travel around. His treatment was life changing.

Gutowski agrees. The U of M doctors are great, he says.

AJ likes having access to the HHT team of doctors, too. He recently had a procedure to blast a kidney stone and they monitored him with extra vigilance because of his tendency to bleed.

Of all the Gutowskis, AJ has long been the most proactive about his care. He keeps up on advancements and raises funds through his volunteer involvement with Cure HHT. He also drives to Washington University in St. Louis where they have an HHT Center for Excellence. Because he has a long relationship with them, he believes hell continue to drive eight hours to get his suggested three year scans to make sure his AVMs have remained the same or that no new ones have emerged. In fact, theyre the ones who noticed his kidney stone during an abdominal scan.

But having an HHT Center closer to home is comforting, too.

Dr. Terrell approached me about the new treatments and we talk about the risks and benefits, AJ says. I think actually over time, I've gotten more effective treatments with much less side effects under Dr. Terrells care, something he expects to continue as Terrell and the Centers team explore newer, emerging treatments.

Having the same doctor as his father is an advantage, too, AJ says.

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Were able to talk to each other about our care and sometimes we go in together, AJ says.

It's probably been helpful for the doctors to some extent, too, because they see how the disease is working in both of us. And they're able to connect dots a little bit easier, which translates to better care for both of them.

If you suspect HHT or have been diagnosed with HHT and want to meet with a Michigan Medicine specialist, contact a patient care coordinator at (734) 936-6393.

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New HHT Center Gives Hope to Father and Son with Rare Genetic Disease - Michigan Medicine

Low-cost, low-tech health care options often work best – Midland Reporter-Telegram

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UPDATE Amicus Therapeutics Announces Upcoming Presentations at the American Society of Gene & Cell Therapy 23rd Annual Meeting – GlobeNewswire

CRANBURY, N.J., May 06, 2020 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD) a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel medicines for rare diseases today announced the acceptance of several abstracts for presentation at the American Society of Gene & Cell Therapy 23rd Annual Meeting being held virtually on May 12 15. Preclinical data from its Pompe gene therapy program, which Amicus is developing with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania, will be presented as an oral presentation. Preclinical data related to the CLN6 and CLN8 Batten disease programs, with our partners at Sanford Research and Nationwide Childrens Hospital, will be presented in respective posters.

Oral Platform Presentation: Thursday, May 14, 2020,4:45-5:00p.m. ET

Pompe Disease:

Poster Session: Tuesday, May 12, 2020, 5:30-6:30 p.m. ET

CLN6 Batten Disease:

Poster Session: Wednesday, May 13, 2020, 5:30-6:30 p.m. ET

CLN8 Batten Disease:

All abstracts for the American Society of Gene & Cell Therapy 23rd Annual Meeting are now available online.

About Pompe DiseasePompe disease is an inherited lysosomal disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Reduced or absent levels of GAA leads to accumulation of glycogen in cells, which results in the clinical manifestations of Pompe disease. The disease can be debilitating and is characterized by severe muscle weakness that worsens over time. Pompe disease ranges from a rapidly fatal infantile form with significant impacts to heart function to a more slowly progressive, late-onset form primarily affecting skeletal muscle. It is estimated that Pompe disease affects approximately 5,000 to 10,000 people worldwide.

About Batten DiseaseBatten disease is the common name for a broad class of rare, fatal, inherited disorders of the nervous system also known as neuronal ceroid lipofuscinoses, or NCLs. In these diseases, a defect in a specific gene triggers a cascade of problems that interferes with a cells ability to recycle certain molecules. Each gene is called CLN (ceroid lipofuscinosis, neuronal) and given a different number designation as its subtype. There are 13 known forms of Batten disease often referred to as CLN1-8; 10-14. The various types of Batten disease have similar features and symptoms but vary in severity and age of onset.

Most forms of Batten disease/NCLs usually begin during childhood. The clinical course often involves progressive loss of independent adaptive skills such as mobility, feeding, and communication. Patients may also experience vision loss, personality changes, behavioral problems, learning impairment, and seizures. Patients typically experience progressive loss of motor function and eventually become wheelchair-bound, are then bedridden, and die prematurely.

About Amicus Therapeutics Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow us on Twitter and LinkedIn.

Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans or projections will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding results of preclinical studies and clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2019. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this press release to reflect events or circumstances after the date hereof.

CONTACTS:

Investors/Media:Amicus TherapeuticsAndrew FaughnanDirector, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

FOLDG

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UPDATE Amicus Therapeutics Announces Upcoming Presentations at the American Society of Gene & Cell Therapy 23rd Annual Meeting - GlobeNewswire

Complement genes add to sex-based vulnerability in lupus and schizophrenia – Newswise

Newswise BIRMINGHAM, Ala. Variants in a gene of the human immune system cause men and women to have different vulnerabilities to the autoimmune diseases lupus and Sjgrens syndrome, according to findings published in the journal Nature. This extends recent work that showed the gene variants could increase risk for schizophrenia.

The gene variants are a member of the complement system, a cascade of proteins that help antibodies and phagocytic cells remove damaged cells of a persons own body, as well as an infection defense that promotes inflammation and attacks pathogens. Normally the complement system keeps a person healthy in the face of pathogens; it also helps cart away the debris of damaged human cells before the body can mount an autoimmune attack. Now complement gene variants apparently play a contributing role in the diseases systemic lupus erythematosus, Sjgrens syndrome and schizophrenia.

It had been known that all three illnesses had common genetic associations with a section of the human chromosome called the major histocompatibility complex, or MHC. This region on chromosome 6 includes many genes that regulate the immune system. However, making an association with a specific gene or with the mutational variants of a specific gene that are called alleles has been difficult, partly because the MHC on human chromosome 6 spans three million base-pairs of DNA.

The Nature paper is a collaboration of 22 authors at 10 institutions in the United States and one in England, along with many members of a schizophrenia working group. Robert Kimberly, M.D., professor of medicine at the University of Alabama at Birmingham and director of the UAB Center for Clinical and Translational Science, is a co-author of the research, which was led by corresponding author Steven McCarroll, Ph.D., assistant professor of genetics at Harvard Medical School.

The identified alleles are complement component 4A and 4B, known as C4A and C4B.

The research showed that different combinations of C4A and C4B copy numbers generate a sevenfold variation in risk for lupus and 16-fold variation in risk for Sjgrens syndrome among people with common C4 genotypes. Paradoxically, the same C4 alleles that previously were shown to increase risk for schizophrenia had a different impact for lupus and Sjgrens syndrome they greatly reduced risk in those diseases. In all three illnesses, the C4 alleles acted more strongly in men than in women.

For the complement proteins that are encoded by the genes for C4 and for complement component 3, or C3, both C4 protein and its effector C3 protein were present at greater levels in men than in women in cerebrospinal fluid and blood plasma among adults ages 20-50. Intriguingly, that is the age range when the three diseases differentially affect men and women for unknown reasons. Lupus and Sjgrens syndrome affect women of childbearing age nine times more than they do men of similar age. In contrast, in schizophrenia, women exhibit less severe symptoms, more frequent remission of symptoms, lower relapse rates and lower overall incidence than men, who are affected more frequently and more severely.

Both men and women have an age-dependent elevation of C4 and C3 protein levels in blood plasma. In men, this occurs early in adulthood, ages 20-30. In women, the elevation is closer to menopause, ages 40-50. Thus, differences in complement protein levels in men and women occur mostly during the reproductive years, ages 20-50.

The researchers say sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, the greater risk of women for lupus and Sjgrens, and the greater vulnerability of men for schizophrenia.

The ages of pronounced sex differences in complement levels correspond to the ages when men and women differ in disease incidence. In schizophrenia cases, men outnumber women in early adulthood; but that disparity of onset lessens after age 40. In lupus, female cases greatly outnumber male cases during childbearing years; but that difference is much less for disease onset after age 50 or during childhood. In Sjgrens syndrome, women are more vulnerable than are men before age 50.

The researchers say the differing effect of C4 alleles in schizophrenia versus lupus and Sjgrens syndrome will be important to consider in any therapeutic effort to engage the complement system. They also said, Why and how biology has come to create this sexual dimorphism in the complement system in humans presents interesting questions for immune and evolutionary biology.

Co-authors with McCarroll and Kimberly for the paper, Complement genes contribute sex-biased vulnerability in diverse illnesses, are Nolan Kamitaki, Aswin Sekar, Heather de Rivera, Katherine Tooley and Christine Seidman, Harvard Medical School, Massachusetts; Robert Handsaker and Christopher Whelan, Broad Institute of Massachusetts Institute of Technology; David Morris, Philip Tombleson and Timothy Vyse, Kings College London, London, United Kingdom; Kimberly Taylor and Lindsey Criswell, University of California-San Francisco School of Medicine; Loes Olde Loohuis and Roel Ophoff, University of California-Los Angeles; Michael Boehnke, University of Michigan; Kenneth Kaufman and John Harley, Cincinnati Childrens Hospital Medical Center, Ohio; Carl Langefeld, Wake Forest School of Medicine, North Carolina; Michele Pato and Carlos Pato, State University of New York, Downstate Medical Center; and Robert Graham, Genentech Inc., South San Francisco, California.

Support came from National Institutes of Health grants HG006855, MH112491, MH105641 and MH105653; and from the Stanley Center for Psychiatric Research.

At UAB, Kimberly holds the Howard L. Holley Research Chair in Rheumatology.

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Complement genes add to sex-based vulnerability in lupus and schizophrenia - Newswise

Immunicum AB (publ) Receives Regenerative Medicine Advanced Therapy Designation from FDA for Ilixadencel in Kidney Cancer – GlobeNewswire

Press Release

6 May 2020

Immunicum AB (publ) Receives Regenerative Medicine Advanced Therapy Designation from FDA for Ilixadencel in Kidney Cancer

Immunicum AB (publ; IMMU.ST) announced today that it has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA) for the Companys lead candidate, ilixadencel, a cell-based, off-the-shelf immune primer for the treatment of metastatic Renal Cell Carcinoma (mRCC). The FDAs decision was made based on the previously communicated results from the Phase II MERECA clinical trial that evaluated the safety and efficacy of ilixadencel in combination with Sutent (sunitinib) in patients with newly diagnosed mRCC. Advantages of the RMAT designation include all the benefits of the Fast Track and Breakthrough Therapy Designation programs including guidance and early interactions with the FDA to discuss potential surrogate or intermediate endpoints to support accelerated approval as well as potential ways to satisfy post-approval requirements.

We are very excited to have received the RMAT designation for ilixadencel in kidney cancer as it recognizes both the potential of our novel therapeutic approach as well as the clear need for viable therapies to address this difficult-to treat disease. As a designation similar to the FDAs Breakthrough Therapy Designation, we will now also have the opportunity to receive direct guidance from the FDA which will inform key development decisions and ultimately bring us closer to delivering ilixadencel to patients in need, commented Alex Karlsson-Parra, CEO of Immunicum.

Established in 2017 under the 21st Century Cures Act in the United States, RMAT designation is an expedited program designed to facilitate the development and review of regenerative medicine therapies intended to address an unmet medical need in patients with serious conditions. An investigational regenerative medicine therapy (e.g. cell or gene therapy) is eligible for RMAT designation if it is intended to treat, modify, reverse or cure a serious condition and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such a disease or condition. As a cell therapy medicinal product, ilixadencel falls within the definition of a regenerative medicine therapy.

The latest results of the Phase II MERECA trial were presented in February at the ASCO-SITC Clinical Immuno-Oncology Symposium 2020 in Orlando, Florida. As of December 2019, the patient follow up data indicates a separation in Kaplan-Meier survival curves in favor of the ilixadencel treatment group in line with the projected separation based on the data from July 2019. The median OS value could not be calculated yet in either group as the data is not mature. The confirmed ORR for the ilixadencel treatment group was 42.2% (19/45) versus 24.0% (6/25) for the sunitinib control group.

Refer to the following link for more information on Regenerative Medicine Advanced Therapy Designation: https://bit.ly/3c7bFah

About MERECAMERECA is an exploratory, international, randomized, controlled and open-label Phase II clinical trial in which a total of 88 newly diagnosed, intermediate and poor-prognosis metastatic renal cancer patients were enrolled. Based on a 2-to-1 randomization, patients received either two intratumoral doses of ilixadencel before nephrectomy (surgical removal of the tumor-affected kidney) and subsequent treatment with sunitinib or sunitinib therapy alone post-nephrectomy. The primary objectives of the study are to evaluate median OS and 18-month survival rates. Secondary objectives include evaluation of safety and tolerability, tumor response and immunological profiling including T cell infiltration.

About renal cell cancer / carcinomaThere are approximately 273,000 new cases of Renal Cell Cancer diagnosed worldwide each year, representing approximately two percent of all cancers. The therapeutic effect of existing treatments, called targeted therapies, is often of short duration, with limited survival gain. With no alternatives to these therapies, there exists a relatively large unsatisfied medical need for new treatments that are effective, more cost-efficient and have less unwanted side effects.

About ilixadencelIlixadencel is an off-the-shelf cell-based cancer immunotherapy developed for the treatment of solid tumors. Its active ingredient is activated allogeneic dendritic cells, derived from healthy blood donors. Injection of these cells in the patients tumor generates an inflammatory response which in turns leads to tumor-specific activation of the patients cytotoxic T cells. To-date ilixadencel has been tested in a range of clinical trials in various solid tumor indications including metastatic Renal Cell Carcinoma (mRCC), hepatocellular carcinoma (HCC) and gastrointestinal stromal tumors (GIST) and in combination with several standard-of-care cancer therapies such as the tyrosine kinase inhibitors Sutent (sunitinib) and Stivarga (regorafenib), and the checkpoint inhibitor Keytruda (pembrolizumab). Ilixadencel has consistently maintained a positive safety and tolerability profile and demonstrated initial signs of efficacy as seen in the randomized Phase II MERECA trial. Ilixadencel is currently moving towards late-stage clinical development.

The information is such information that Immunicum is obliged to make public pursuant to EU Market Abuse Regulation. The information was released for public disclosure through the contact persons detailed below on 6 May 2020 at 8:00 am CET.

For more information, please contact:

Alex Karlsson-Parra, CSO and Interim CEO, ImmunicumTelephone: +46 8 732 8400E-mail: info@immunicum.com

Sijme Zeilemaker, COO, ImmunicumTelephone: +46 8 732 8400E-mail: info@immunicum.com

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Immunicum AB (publ) Receives Regenerative Medicine Advanced Therapy Designation from FDA for Ilixadencel in Kidney Cancer - GlobeNewswire

Unraveling the use of CBD in veterinary medicine – Jill Lopez

It was about the 3rd week into Bastions recovery from his TPLO surgery and he was already having a rough time. Bastion was a gregarious yellow Labrador who had his injured stifle about 25 days ago. Fortunately, his family elected for him to have his stifle surgically reconstructed. Initially, he had recovered well from surgery. But one day in particular, he presented to the hospital because he had a brief setback. He was limping far more severely than what would be normally expected at this stage of recovery.

The osteotomy from his surgery had not yet completely healed and he was still in the middle of his prescribed 5 weeks of exercise strict restriction. His family was trying their best but Bastion wasnt having it. He was too active at home and his humans were growing frustrated. Anti-anxiety medications had been dispensed but they were not given. Instead, his family had decided to give him CBD oil at home. When I asked why the prescribed medications had not been given, the client responded, I found CBD oil at the local farmers market and I figured it would work just as well.

Like Bastion, an increasing number of pets are receiving cannabidiol (CBD) supplements. The popularity of CBD continues to rise and many clients are incorporating CBD as part of the medication protocol for their pets, either as an adjunct or, as alternative treatment option.

Perhaps the initial interest in the benefits of CBD can be traced back to 1998, or possibly earlier, when scientists at the National Institutes of Health discovered that CBD could protect cells from oxidative stress. These findings fueled interest in the human medical field and, in large part, that appeal has been transmuted into veterinary medicine. The regard for this molecule has risen to such levels that in many homes, CBD is being used as the sole treatment option for a variety of medical conditions.

Veterinarians are becoming more fluent in the fascinating pharmacology regarding the use of this phytocannabinoid. A recent survey indicated that most veterinarians (61.5%) felt comfortable discussing the use of CBD with their colleagues, but only 45.5% felt comfortable discussing this topic with clients.1 Furthermore, veterinarians and clients in states with legalized recreational marijuana were more likely to talk about the use of CBD products to treat canine ailments than those in other states.2 Lastly, CBD was most frequently discussed as a potential treatment for pain management, anxiety and seizures.1 At first glance, the use of CBD has tangential or limited relevance in the world of veterinary surgery. However, as one takes a closer look at the putative, and proven benefits, it is clear that we are just scratching the surface of its therapeutic benefits. This article takes a brief dive into the world of CBD and its promise in the field of veterinary surgery.

Pain

Whether you perform surgery within a specialty discipline (oncology, orthopedics, neurology, soft tissue surgery, mixed animal, oral/dental, etc), or surgery is only a small part of your general practice, every veterinarian endeavors to aggressively manage pain. The first choice for pain relief among many clinicians are the medications that have been more extensively studied including, but not limited to, anti-inflammatories, gabapentinoids, opioids, local anesthetics, and other analgesics (acetaminophen, amantadine, cerenia etc). These medications or a combination thereof, have been prescribed to treat pain from orthopedic surgery, soft tissue surgery, surgical neuropathic conditions, pain from intestinal surgery, to name just a few. In the most basic schema, pain is divided into four categories: nociceptive pain (a response to damaged tissue), neuropathic pain (a response to directly-damaged sensory or spinal nerves), centralized pain (the result of pain signals being improperly amplified), and inflammatory pain.1 Cannabinoids may have a role to play in mediating all four of these types of pain states. When tissue is damaged, histamine, serotonin, TNF-alpha, IL-1-beta, IL-6, and Il -17 6, and interleukin 17 are released.2 Cannabinoids bind to the CB1 receptors and attenuate the pain signal by slowing down the release of those neurotransmitters.3 This process can take place locally or in the central nervous system.3 Cannabinoids have also been shown to inhibit the release of GABA, a well known neurotransmitter associated with pain.3 Although there is a paucity of clinical research on the use of CBD to treat postoperative pain in the veterinary medical setting, there has been heartening research conducted in humans. Indeed, National Academies of Sciences, Engineering, and Medicine concluded that there is, substantial evidence that cannabis is an effective treatment for chronic pain in adults.

Opioids have long been the go to option, or cornerstone of pain management, however, the potential for the adverse events associated with the use of opioids in veterinary patients is universally accepted.38 I have seen how distressing it can be for a family to see their pet experiencing any of the unpleasurable side effects of opioids including urine retention, delayed bowel movements, whining, panting, disorientation, or other manifestations of dysphoria. Those are just some of the challenges that clinicians face when using opioids for chronic pain management. Considering the ongoing consequences of the opioid epidemic, there is a search for pain management solutions that are innovative, prone to less adverse events, and are more effective. As the scientific community begins to evaluate the evidence for use of CBD , it is clear that more research is needed.

Anecdotal reports of CBDs efficacy as a pain reliever are ubiquitous but more are turning to scientific data for evidence of CBDs efficacy. A study in 2020 evaluating effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients found that over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens.5 Almost all CBD users (94%) reported quality of life improvements.5 And in a recent study evaluating orally consumed cannabinoids for long-lasting relief of allodynia in a mouse model, found that cannabinoids reduced hyperalgesia and a similar effect was not found with morphine.4 Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine.4 The study demonstrated that cannabinoids provide long-term relief of chronic pain states.4 If research shows that use of cannabinoids in animals, specifically, CBD, can help to decrease the use of opioids for pain management, that would help make more animals comfortable and potentially help to fight the tragic epidemic of human prescription opioid abuse. Further research is needed in a variety of species, specifically, both the canine and feline species.

Bone Healing

Both general veterinary practitioners and veterinary surgeons commonly diagnose and treat fractures. A large retrospective study of fracture incidence in dogs in North America has not been published since 1994; however, the findings from that study are still informative regarding the frequency of bone injuries. That study demonstrated that approximately 24% of all patients in the population studied over a 10 year period were affected by a disorder of the musculoskeletal system, with fractures contributing the largest proportion (over 29%) of all of the diagnosis of the appendicular skeletal system.7 Although that research is dated, the conclusions from this study - at the very least, indicate that fractures are commonplace in the clinical veterinary setting.7 Fracture repair has gradually become more straightforward due to improvements in technology. Because of these innovations, speciality surgeons and general practitioners who repair fractures have begun to see better surgical outcomes. So whether you primarily stabilize fractures with implants, or if external coaptation of fractures with the intention to refer (or perhaps as the primary means of fixation) is your treatment of choice, all veterinary practitioners aim to help fractured bones heal quickly. Despite these technological improvements, bone healing can be protracted or non existent with some fractures. There are a variety of options at a veterinarians disposal to kick-start the healing process but perhaps in the near future, CBD may be added to that armamentarium. The effect of CBD in fracture healing has been investigated evaluating bone callus formation in femur fractures in a rat model.8 The findings demonstrated enhanced biomechanical properties of healing fractures in those given CBD compared with a control group.8 This effect was not found in those only given 9-THC. Moreover, the bone forming effects (osteogenic) of CBD were weakened when test subjects were given equal amounts of CBD and 9-THC.6 Another in vivo research study indicated that when CBD is incorporated into a surface that promotes bone growth (osteoconductive scaffold) it can stimulate stem cell migration and osteogenic differentiation.9 Further studies are needed to better evaluate the role of CBD in healing and bone metabolism of companion animals so that these findings can be applied in the clinical setting.

Additionally, cannabis has been shown to be a useful addition in treatment plans optimized to improve bone health in laboratory studies. A study endeavored to more closely understand the role of CB2 receptors in maintaining bone health. CB2 receptors in bone cells have been linked to maintaining bone density and stimulating growth, and may therefore have a part in reversing the effects of osteoporosis.10 One study evaluating role of CB2 receptors, found that in mice whose genes had been altered to remove the CB1 or CB2 receptors, those that developed signs of bone weakness that were far more pronounced than those in the control group.12 Another study in 2009, investigated the relationship between CB2 expression and bone disease in humans. The study found that people with dysfunctional CB2 receptors to have significantly weaker hand bones.11

Arthritis

Osteoarthritis (OA) affects many dogs, large and small. Most often, OA is the consequence of a developmental orthopedic disease that often affects a single joint or a pair of joints, and, less often, affects multiple joints. It is axiomatic that Mother Nature likes symmetry thus developmental orthopedic diseases frequently affect both left and right joints. For example, hip dysplasia is reportedly bilateral in >60% of affected dog,s13 and elbow dysplasia is bilateral in approximately 50% of affected dogs.14 Osteoarthritis occurs secondary to a myriad of primary orthopedic conditions that affect a variety of joints including: the hip (most common causes of OA in the hip: hip dysplasia, Perthes disease); stifle (patellar luxation, cranial cruciate ligament disease, osteochondritis dissecans [OCD]); elbow (elbow dysplasia, elbow OCD, fragmentation of the medial coronoid process, incomplete ossification of the humeral condyle); shoulder (shoulder OCD, developmental shoulder subluxation); tarsus (OCD of the talus), and carpus (carpal laxity, carpal subluxation secondary to chondrodystrophy); and metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joint degenerative osteoarthritis (digital osteoarthritis) .

Cannabinoids were found to treat pain secondary to inflammation in a variety of studies on humans. Some of the most compelling research has shown that cannabis can reduce the inflammation in the joint caused in human patients diagnosed with immune mediated arthritis.15 One study found that cannabinoids could simultaneously reduce the secretion of cytokines involved in inflammation from one type of TH immune cells, which were being under-produced, while also increasing their numbers to correct their scarcity.15 Furthermore in a study in 2003, researchers found that plant-based cannabinoids could suppress the expression of interleukin-1betaone of the most prominent markers for inflammation in patients with rheumatoid arthritisby as much as 50%.16 And finally, in 2006, transdermal applications of CBD were shown to decrease biomarkers that can contribute to neurogenic inflammation in a sample of arthritic rats. 17

A report published in the journal of PAIN, lead by researchers at Baylor College of Medicine revealed the results of a large, double blinded, placebo controlled study on the positive effects CBD had in the fight against osteoarthritis.18 The study was designed with two main goals: The first portion of the research studied the effect CBD had on the inflammatory molecules and cells in mice.18 The second portion of the study, investigated whether CBD improved the quality of life in dogs diagnosed with osteoarthritis. In lab tests and in mouse models, CBD significantly decreased the production of natural chemicals that promote inflammation and it increased the natural chemicals that fight inflammation.18 Essentially, what they saw was a drop in proinflammatory cytokines and an increase in anti-inflammatory cytokines. 18 For dogs with osteoarthritis, CBD significantly decreased pain and increased mobility in a dose-dependent fashion. Importantly, A lower dose of liposomal CBD was as effective as the highest dose of nonliposomal CBD, indicating that the effect of CBD was quicker and more effective when CBD was delivered encapsulated in liposomes than without.18 Blood samples indicated no significant harmful side effects, or adverse events, over the 4-week analysis period.18 Although this study is very promising and it supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain in dogs, it is important to consult with your pets veterinarian before giving any supplement or medication.

In the veterinary population, use of cannabidiol and other alternative treatments may have the potential to obviate the need for other medications, and thus spare patients from adverse effects associated with their use. More likely, the use of cannabinoids could be additive or synergistic in a multimodal treatment strategy and could increase quality-of-life issues associated with painful arthritic conditions.

Intervertebral Disk Disease

As our patients age, discs in the spine also undergo degenerative changes. Thus, degeneration of intervertebral discs is evitable. This process of degeneration is multifactorial process and it involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content.39 The magnitude and severity of disc degeneration can vary widely between patients. The most common locations of clinically relevant disc disease are located in the cervical spine, thoracolumbar spine, and the lumbosacral spine.40 Although there are various manifestations of disc disease, broad classifications of Hansen Type I and Type II are typically used to describe the condition. In short, disc material may either extrude (acute herniations) or protrude (chronic herniations), both of which compress the spinal cord which ultimately can cause pain, paresis, paralysis and other neurological deficits.40 The prevalence of thoracolumbar disc disease dogs has been estimated at 3.5%.40 Depending on the neurologic examination, diagnosis, severity, prognosis, and other factors, surgery may be recommended to decompress the spinal cord.

After surgical decompression, there are a host of challenges that the the patient, the family, and the surgeon, may have to work through including a potentially protracted recovery, recurrence of neurological signs, post surgical pain, spinal instability, urinary disorders, (cystitis, urinary tract infection, urinary retention, micturition disorders), ascending myelomalacia, and others.41 Could CBD play a part in helping to improve those affected by disc disease pre-, intra-, or post-operatively and what types of spinal disorders could benefit from CBD? A study conducted on the use of CBD in mice with degenerative disc disease showed promise in mitigating the effect of disc damage and wear.19 Instead of being ingested orally, CBD was injected at the site of the disc. Researchers investigated the effects of cannabidiol intradiscal injection using a combination of MRI and histological analyses.19 A puncture was created in the disc and then CBD was injected into the disc (30, 60 or 120 nmol) shortly after.19 The effects of intradiscal injection of cannabidiol were analyzed within 2 days by MRI.17 Fifteen days later, the group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses after the cannabidiol injection.19 What they found was that cannabidiol significantly decreased the effects of disc injury induced by the needle puncture.19 These results suggest that this compound could be useful in the treatment of intervertebral disc degeneration perhaps using a novel route of administration.

Unfortunately, the exact mechanism for how CBD oil helped protect disc damage is still being investigated. The hope is that the neuroprotective properties of cannabidiol can also be found in the study of canine and feline disc disease to ultimately improve functional recovery.

References:

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Abd-Elsayed A., Deer T.R. (2019) Different Types of Pain. In: Abd-Elsayed A. (eds) Pain. Springer, Cham. https://doi.org/10.1007/978-3-319-99124-5_3

Manzanares J, Julian MD, Carrascosa A. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes Curr Neuropharmacol. 2006 Jul; 4(3): 239257.

Abraham AD, Leung EJ, Brenden A, Wong BA, Rivera ZM, Kruse LC, et al. Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain. 2020 Jun;45(7):1105-1114. doi: 10.1038/s41386-019-0585-3. Epub 2019 Dec 7.

Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020 Jan;132(1):56-61. doi:10.1080/00325481.2019.1685298. Epub 2019 Nov 12.

Abraham AD, Leung EJ, Wong BA, Rivera ZM, Kruse LC, Clark JJ, Land BB. Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain. Neuropsychopharmacology. 2020: 45:11051114.

Johnson, J., Austin, C., & Breur, G. Incidence of Canine Appendicular Musculoskeletal Disorders in 16 Veterinary Teaching Hospitals from 1980 through 1989. Veterinary and Comparative Orthopaedics and Traumatology, 07(02), 5669. (1994). doi:10.1055/s-0038-1633097

Kogan NM, Melamed E, Wasserman E. Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts J Bone Miner Re. 2015 Oct;30(10):1905-13. doi: 10.1002/jbmr.2513. Epub 2015 May 10.

Kamali, A., Oryan, A., Hosseini, S., Ghanian, M. H., Alizadeh, M., Baghaban Eslaminejad, M., & Baharvand, H. Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects. Materials Science and Engineering: (2019). C, 101, 6475. doi:10.1016/j.msec.2019.03.070

Bab I, Zimmer A. Cannabinoid Receptors and the Regulation of Bone Mass. British Journal of Pharmacology. 2007 153:182-188 doi:10.1038/sj.bjp.0707593

I. Idris, A. Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies. Current Neuropharmacology. 2010. 8(3), 243253. doi:10.2174/157015910792246173

Meliha Karsak et al. The Cannabinoid Receptor Type 2 (CNR2) Gene Is Associated with Hand Bone Strength Phenotypes in an Ethnically Homogeneous Family Sample. Human Genetics. 2009. 5:629-36 doi:10.1007/s00439-009-0708-8.

Loder, R. T., & Todhunter, R. J. The Demographics of Canine Hip Dysplasia in the United States and Canada. Journal of Veterinary Medicine. 2017 115. doi:10.1155/2017/5723476

ONeill DG, Brodbelt DC, Hodge R,. Church DB, Meeson RL. Epidemiology and clinical management of elbow joint disease in dogs under primary veterinary care in the UK. Canine Medicine and Genetics. 2020 volume 7:1

Susan H. Pross et al. Differential Suppression of T-cell Subpopulations by THC (delta-9- tetrahydrocannabinol). International Journal of Immunopharmacology 12, no. 5 (1990): 539-44. doi:10.1016/0192-0561(90)90118-7

Robert B. Zurier et al. Suppression of Human Monocyte Interleukin-1 Production by Ajulemic Acid, a Nonpsychoactive Cannabinoid. Biochemical Pharmacology. 2003 4:649-55. doi:10.1016/s0006-2952(02)01604-0.

D.c. Hammell et al. Transdermal Cannabidiol Reduces Inflammation and Pain-related Behaviours in a Rat Model of Arthritis. European Journal of Pain. 2015 6:936-48. doi:10.1002/ejp.818

Verrico, C. D., Wesson, S., Konduri, V., Hofferek, C. J., Vazquez-Perez, J., Blair, E., Halpert, M. M. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. 2020. Pain. doi:10.1097/j.pain.0000000000001896

Silveira, J. W., Issy, A. C., Castania, V. A., Salmon, C. E. G., Nogueira-Barbosa, M. H., Guimares, et al. Protective Effects of Cannabidiol on Lesion-Induced Intervertebral Disc Degeneration. 2014. PLoS ONE 9:12 doi:10.1371/journal.pone.0113161

Yam, M., Loh, Y., Tan, C., Khadijah Adam, S., Abdul Manan, N., & Basir, R. . General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation. International Journal of Molecular Sciences. 2018 19(8), 2164. doi:10.3390/ijms19082164

Costigan, M., Scholz, J., & Woolf, C. J. Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage. Annual Review of Neuroscience. 2009 32(1), 132. doi:10.1146/annurev.neuro.051508.135531

Arora A, Taliyan R, Sharma PL. Ameliorative Potential of Cannabis Sativa Extract on Diabetes Induced Neuropathic Pain in Rats. International Journal of Pharmaceutical Sciences and Research 1. 2010 https://www.researchgate.net/publication/216536386_Ameliorative_potential_of_cannabis_sativa_extract_

Mark S. Wallace et al., Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. 2015. Pain 16(7): 616-27 doi:10.1016/j.jpain.2015.03.008.

Gruen, M. E., Roe, S. C., Griffith, E., Hamilton, A., & Sherman, B. L.. Use of trazodone to facilitate postsurgical confinement in dogs. Journal of the American Veterinary Medical Association. (2014) 245(3), 296301. doi:10.2460/javma.245.3.296

Serra, G., & Fratta, W. A possible role for the endocannabinoid system in the neurobiology of depression. Clinical Practice and Epidemiology in Mental Health. 2007. 3(1), 25. doi:10.1186/1745-0179-3-25

Kim, E. J., Pellman, B., & Kim, J. J. Stress effects on the hippocampus: a critical review. Learning & Memory. 2015. 22(9), 411416. doi:10.1101/lm.037291.114

Demirakca, T., Sartorius, A., Ende, G., et al. Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol. 2010. Drug and Alcohol Dependence. doi:10.1016/j.drugalcdep.2010.09.020

Mateus M. Bergamaschi et al. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Nave Social Phobia Patients. Neuropsychopharmacology. 2011 36(6):1219-26 doi:10.1038/npp.2011.6.

Jos Alexandre S Crippa et al. Neural Basis of Anxiolytic Effects of Cannabidiol (CBD) in Generalized Social Anxiety Disorder: A Preliminary Report. Journal of Psychopharmacology. 2010. 25: 1doi:10.1177/0269881110379283.

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Pamplona, F. A., da Silva, L. R., & Coan, A. C. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. 2018. Frontiers in Neurology, 9. doi:10.3389/fneur.2018.00759

Palmieri B, Laurino C, Vadal M. A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars. Mar-Apr 2019;170(2):e93-e99. doi: 10.7417/CT.2019.2116.

Sangiovanni, E., Fumagalli, M., Pacchetti, B., Piazza, S., et al.. Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury. (2019). Phytotherapy Research. doi:10.1002/ptr.6400

B. Van Klingeren and M. Ten Ham. Antibacterial Activity of 9-tetrahydrocannabinol and Cannabidiol. 1976. 42(1-2): 9-12 doi:10.1007/bf00399444.

Giovanni Appendino et al. Antibacterial Cannabinoids From Cannabis Sativa: A StructureActivity Study. 2008. Journal of Natural Products 71(8):1427-430, doi:10.1021/np8002673

McIver, V., Tsang, A., Symonds, N., Perkins, N., et al. Effects of topical treatment of cannabidiol extract in a unique manuka factor 5 manuka honey carrier on second intention wound healing on equine distal limb wounds: a preliminary study. 2020. Australian Veterinary Journal. doi:10.1111/avj.12932

White, D. M., Mair, A. R., & Martinez-Taboada, F. Opioid-free anaesthesia in three dogs. Open Veterinary Journal. 2017 7(2), 104. doi:10.4314/ovj.v7i2.5

Hansen T, Smolders LA, Tryfonidou MA, et al: The Myth of Fibroid Degeneration in the Canine Intervertebral Disc: A Histopathological Comparison of Intervertebral Disc Degeneration in Chondrodystrophic and Nonchondrodystrophic Dogs. Vet Pathol 2017 Vol 54 (6) pp. 945-952.

40. Jeffery ND, Levine JM, Olby NJ, et al: Intervertebral disk degeneration in dogs: consequences, diagnosis, treatment, and future directions. J Vet Intern Med 2013 Vol 27 (6) pp. 1318-33.

41. Balducci F, Canal S, Contiero B, et al: Prevalence and Risk Factors for Presumptive Ascending/Descending Myelomalacia in Dogs after Thoracolumbar Intervertebral Disk Herniation. J Vet Intern Med 2017 Vol 31 (2) pp. 498-504.

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Unraveling the use of CBD in veterinary medicine - Jill Lopez

Humanigen to Host Investor KOL Conference Call – Business Wire

BURLINGAME, Calif.--(BUSINESS WIRE)--Humanigen, Inc., (HGEN) (Humanigen), announced today that the Company will host an investor call and webcast to discuss the case-control lenzilumab data in COVID-19 patients published this week in Mayo Clinic Proceedings, including a discussion with the infectious disease expert and lead author of the study, Dr. Zelalem Temesgen, Professor of Medicine at Mayo Clinic, and provide corporate updates.

Humanigen will host the conference call and webcast Thursday, September 3, 2020 at 11:00 a.m. EDT. All stakeholders are invited to attend.

To participate on the conference call, please dial toll free (833) 714-0938 or toll number (778) 560-2680. The conference ID number is 1158096. A simultaneous webcast of the call and presentation can be accessed by visiting: https://event.on24.com/wcc/r/2626581/3E36D8F5A4B03E3030E7A0D438AF9AA1.

In addition, a replay of the webcast will be available on the company website for 30 days following the event.

More details on Humanigens programs in COVID-19 can be found on the companys website at http://www.humanigen.com under the COVID-19 tab, and details of the US Phase III potential registration study can be found at clinicaltrials.gov using Identifier NCT04351152.

About Humanigen, Inc.

Humanigen, Inc. is developing its portfolio of clinical and pre-clinical therapies for the treatment of cancers and infectious diseases via its novel, cutting-edge GM-CSF neutralization and gene-knockout platforms. We believe that our GM-CSF neutralization and gene-editing platform technologies have the potential to reduce the inflammatory cascade associated with coronavirus infection. The companys immediate focus is to prevent or minimize the cytokine release syndrome that precedes severe lung dysfunction and ARDS in serious cases of SARS-CoV-2 infection. The company is also exploring the effectiveness of its GM-CSF neutralization technologies (either through the use of lenzilumab as a neutralizing antibody or through GM-CSF gene knockout) in combination with other CAR-T, bispecific or natural killer (NK) T cell engaging immunotherapy treatments to break the efficacy/toxicity linkage, including to prevent and/or treat graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, Humanigen and Kite, a Gilead Company, are evaluating lenzilumab in combination with Yescarta (axicabtagene ciloleucel) in patients with relapsed or refractory large B-cell lymphoma in a clinical collaboration. For more information, visit http://www.humanigen.com.

Forward-Looking Statements

This release contains forward-looking statements. Forward-looking statements reflect management's current knowledge, assumptions, judgment and expectations regarding future performance or events. Although management believes that the expectations reflected in such statements are reasonable, they give no assurance that such expectations will prove to be correct and you should be aware that actual events or results may differ materially from those contained in the forward-looking statements. Words such as "will," "expect," "intend," "plan," "potential," "possible," "goals," "accelerate," "continue," and similar expressions identify forward-looking statements. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to, the various risks and uncertainties described in the "Risk Factors" sections and elsewhere in the Company's periodic and other filings with the Securities and Exchange Commission.

All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You should not place undue reliance on any forward-looking statements, which speak only as of the date of this release. We undertake no obligation to revise or update any forward-looking statements made in this press release to reflect events or circumstances after the date hereof or to reflect new information or the occurrence of unanticipated events, except as required by law.

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Humanigen to Host Investor KOL Conference Call - Business Wire

New genetic cause of an inherited neuropathy discovered | Penn Today – Penn Today

Inherited mutations in a gene that keeps nerve cells intact was shown, for the first time, to be a driver of a neuropathy known as Charcot-Marie-Tooth (CMT) disease. This finding is detailed in a study led by researchers in the Perelman School of Medicine, which published inNeurologyGenetics, an official journal of the American Academy of Neurology.

The findings, thanks to siblings treated at Penn since the late 1980s, present a clearer picture of the diseases genetic underpinnings that could inform the development of gene therapies to correct it.

The mutations in the gene known as dystonin (DST) add to a growing list of malfunctions found to cause their type of CMT, known as CMT2, which is defined by the loss of the nerve fibers, or axons, in the peripheral nerve cells. The researchers also showed that these mutations affect two key protein isoforms, BPAG1-a2 and BPAG1-b2, that are involved in nerve fiber function. Mutations in other isoforms of the same protein were previously tied to a blistering skin disease.

There are more than 100 mutations found to be associated with CMT, with likely many more out there.Past studies from Penn researchers haveidentified some of these mutations by studying patients treated at Penn Medicine.

We are determined to fill in the blanks of this giant jigsaw puzzle, says senior authorSteven S. Scherer, a professor of neurology. This latest paper is but one of many examples of where breakthroughs have happened between patients and the doctors at Penn and the support of different organizations and institutions to bring it all together."

Read more at Penn Medicine News.

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New genetic cause of an inherited neuropathy discovered | Penn Today - Penn Today

Hansa Biopharma announces exclusive agreement with Sarepta Therapeutics to develop and promote imlifidase as pre-treatment ahead of gene therapy in se…

Hansa grants Sarepta exclusive license to develop and promote imlifidase as a potential pre-treatment prior to the administration of gene therapy in Duchenne muscular dystrophy and Limb-girdle muscular dystrophy, for patients with neutralizing antibodies (NAbs) to adeno-associated virus (AAV).

Under the terms of the license: Hansa will receive a USD 10 million upfront payment and is eligible for up to USD 397.5 million in development, regulatory and sales milestone payments. Hansa will book all sales of imlifidase and would be eligible for royalties in the high single-digits to mid-teens on any gene therapy sales enabled through pre-treatment with imlifidase in NAb-positive patients.

Lund, Sweden July 2, 2020. Hansa Biopharma (Hansa), the leader in immunomodulatory enzyme technology for rare IgG mediated diseases, announced today that it has entered into an agreement with Sarepta Therapeutics Inc. (Sarepta), the leader in precision genetic medicine for rare diseases, through which Sarepta is granted an exclusive, worldwide license to develop and promote imlifidase as a pre-treatment to enable Sarepta gene therapy treatment in Duchenne muscular dystrophy (DMD) and Limb-girdle muscular dystrophy (LGMD). The pre-treatment is intended for patients with pre-existing neutralizing antibodies (NAb-positive patients) to adeno-associated virus (AAV), the technology that is the basis for Sareptas gene therapy products.

Sarepta will be responsible for conducting pre-clinical and clinical studies with imlifidase and any subsequent regulatory approvals. Sarepta will also be responsible for the promotion of imlifidase as a pre-treatment to Sareptas gene therapies following potential approval.

Under the terms of the agreement, Hansa will receive a USD 10 million upfront payment, and is eligible for a total of up to USD 397.5 million in development, regulatory and sales milestone payments. Hansa will book all sales of imlifidase, and earn high single-digit to mid-teens royalties on Sareptas incremental gene therapy sales when treating NAb-positive patients enabled through pre-treatment with imlifidase.

Sren Tulstrup, President & CEO of Hansa Biopharma comments,We see significant potential for our enzyme technology in the gene therapy space overall, and we are excited to partner with Sarepta, a leading player in the field, to use the unique features of imlifidase to potentially enable gene therapy treatment in patients who today arent eligible for these breakthrough therapies due to pre-existing neutralizing antibodies in two conditionswith a very high unmet medical need.

Doug Ingram, President & CEO, Sarepta Therapeutics said,As we expand our leadership position in genetic medicine and build out our gene therapy engine, one of Sareptas central ambitions is to find scientific solutions that bring our potentially life-saving therapies to the greatest number of the rare disease patients we serve. One of the current limitations of gene therapy is the inability to treat patients who have pre-existing neutralizing antibodies to the AAV vector. While our AAVrh74 vector has been associated with a low screen out rate for neutralizing antibodies, even that low rate is inconsistent with our mission.

In pre-clinical and clinical models, Hansas technology has shown the ability to clear the IgG antibodies that prevent dosing AAV-based gene therapies. If successful, this could offer the potential of extending our gene therapy treatments to DMD and LGMD patients who would otherwise have been denied access due to pre-existing antibodies.

Hansa Biopharma will be hosting a conference call with President & CEO Sren Tulstrup, CSO & COO Christian Kjellman and CFO Donato Spota.

Conference Call Partnership agreement with Sarepta TherapeuticsA conference call will take place July 2nd, 2020 at 10:00am CET. The audio cast will be recorded and subsequently be available on the Hansa website https://hansa.eventcdn.net/202007

Participants dial-in numbersSE: + 46 81 241 09 52UK: + 44 203 769 6819US: + 1 646 787 0157

This is information that HansaBiopharma AB is obliged to makepublic pursuant to the EU MarketAbuse Regulation.

About imlifidaseImlifidase is a unique antibody-cleaving enzyme originating from Streptococcus pyogenes that specifically targets IgG and inhibits IgG-mediated immune response. It has a rapid onset of action, cleaving IgG-antibodies and inhibiting their activity within hours after administration. CHMP/EMA has adopted a positive opinion, recommending conditional approval of imlifidase for the desensitization treatment of highly sensitized adult kidney transplant patients with a positive crossmatch against an available deceased donor. Endorsement of the positive opinion by the European Commission is expected in the third quarter of 2020.Hansa has also reached an agreement with the FDA on a regulatory path forward for imlifidase in kidney transplantation of highly sensitized patients in the U.S. and has three ongoing phase 2 trials in autoimmune diseases and post-transplant indications.

About gene therapy and neutralizing antibodiesGene therapy is a growing and revolutionizing treatment technology in which healthy gene sequences are inserted into cells of a patient. The treatments are potentially curative in monogenic diseases like hemophilia and muscular dystrophy through a single dose. Harmless recombinant viruses are used to carry the healthy genes into the cell. Due to the partial viral origin of the gene therapy constructs, a certain subset of patients carry neutralizing anti-AAV antibodies towards gene therapy products, depending on what AAV serotype being used, forming a barrier for treatment eligibility.Antibodies prevent effective transfer of healthy gene sequence and can be a safety concern. Imlifidase as a pre-treatment may have the potential to eliminate neutralizing antibodies prior to gene therapy. Similarly, imlifidase may have the potential to enable any potentially necessary re-dosing of gene therapy for all patients.

About Duchenne Muscular Dystrophy (DMD)Duchenne muscular dystrophy is a rare genetic disease caused by mutation in the DMD gene, encoding for the protein dystrophin. Duchenne is an irreversible, progressive disease that causes the muscles in the body to become weak and damaged over time. It is eventually fatal and there is no cure. DMD affects one in 3,500 to 5,000 males born worldwide (approximately 400-500 annual cases in the US) and causes muscles in the body to become weak and most patients use wheelchair by the age of 12.

About Limb-Girdle Muscular Dystrophy (LGMD)Limb-girdle muscular dystrophy or (LGMD) is a genetically and clinically heterogeneous group of rare muscular dystrophies. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD has an autosomal pattern of inheritance and currently has no known cure or treatment. It can be caused by a single gene defect that affects specific proteins within the muscle cell, including those responsible for keeping the muscle membrane intact. LGMD has a global prevalence of approximately 1.63 per 100,000 individuals worldwide.

For further information, please contact:Klaus Sindahl, Head of Investor RelationsHansa Biopharma Mobile: +46 (0) 709-298 269E-mail: klaus.sindahl@hansabiopharma.com

About Hansa BiopharmaHansa Biopharma is leveraging its proprietary immunomodulatory enzyme technology platform to develop treatments for rare immunoglobulin G (IgG)-mediated autoimmune conditions, transplant rejection and cancer.The Companys lead product candidate, imlifidase, is a unique antibody-cleaving enzyme that potentially may enable kidney transplantation in highly sensitized patients with potential for further development in other solid organ transplantation and acute autoimmune indications. CHMP/EMA has adopted a positive opinion, recommending conditional approval of imlifidase for the desensitization treatment of highly sensitized adult kidney transplant patients with a positive crossmatch against an available deceased donor. Endorsement of the positive opinion by the European Commission is expected in the third quarter of 2020. Hansas research and development program is advancing the next generation of the Companys technology to develop novel IgG-cleaving enzymes with lower immunogenicity, suitable for repeat dosing in relapsing autoimmune diseases and oncology.Hansa Biopharma is based in Lund, Sweden and also has operations in Europe and US.

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Hansa Biopharma announces exclusive agreement with Sarepta Therapeutics to develop and promote imlifidase as pre-treatment ahead of gene therapy in se...

The Future of Medicine Is Bespoke – Fair Observer

There was a time when modern medicine was primitive. There were no antibiotics, so every infection took its own course, leading to decline in health. Hypertension and diabetes were largely untreatable. X-ray was new, and remedies had changed but little from medieval times. No one ever embarked on the goodness of preventative treatment, not to speak of predictive medicine, beyond taking a distasteful cod liver oil capsule.

During the last hundred years, modern medicine has undergone a sea change. Just think of it an ever-expanding repertoire of medicines, high-tech procedures, therapies and reams of clinical data to employ when one gets sick. Yet modern medicine remained (in)complete, notwithstanding the therapeutic advances.

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Things are now changing thanks to the integration of all such advances, from how a persons diet interacts with ones unique genetic profile to how environmental pollutants affect our thinking, not to speak of preventative medical approaches in health and wellness. The bigperestroikahas begun, and it is poised to transform health care for a growing number of people in the near future. Welcome to a whole new world of personalized, bespoke medicine.

Personalized medicine is, in essence, tailored or customized medical treatment. It treats while keeping in mind the unique, individual characteristics of each patient, which are as distinct as ones fingerprint or signature. It also includes scientific breakthroughs in our understanding of how a persons unique molecular and genetic profile makes them susceptible to certain illnesses. Personalized medicine expands our ability to envisage medical treatments that would not only be effective but also safe for each patient while excluding treatments that may not provide useful objectives.

Personalized medicine is, in simple terms, the use of new methods of molecular scrutiny. It is keyed to help better manage a patients illness or their genetic tendency toward a particular illness or a group of diseases. In so doing, it aims to achieve optimal therapeutic outcomes by helping both clinicians and patients choose a disease management approach that is likely to work best in the context of the patients unique genetic and environmental summary. In other words, it allows to accurately diagnose diseases and their sub-types while prescribing the best form and dose of medication most suited to the given patient.

Personalized, or precision, medicine is not rocket science it is, in essence, an extension of certain traditional approaches to understanding and treating disease. What jazzed up the therapeutic fulcrum of personalized medicine are tools that are more precise. This is what also offers clinicians better insights for selecting a treatment protocol based on a patients molecular profile. Such a patient-specific methodology, as has been practiced for long in certain complementary and alternative medical (CAM) or integrative approaches, not only curtails harmful side effects but also leads to more successful outcomes, including reduced costs in comparison to the current trial-and-error approach to treatment, which has distressingly come to the fore during these extraordinary and unprecedented times of COVID-19.

It is still early days, but the fact remains that personalized medicine has changed the old ways of how we all thought about, identified and managed health issues. As personalized medicine increasingly bids fair to an exciting journey in terms of clinical research and patient care, its impact will only further expand our understanding of medical technology.

What personalized medicine has done is bring about a paradigm shift in our thinking about people in general and also specifically. We all vary from one another what we eat, what others eat, how we react to stress or experience health issues when exposed to environmental factors. It is agreed that such variations play a role in health and disease. It is also being incrementally accepted that certain natural variations found in our DNA can influence our risk of developing a certain disease and how well we could respond to a particular medicine.

All of us are unique individuals, perhaps with the exemption of identical twins, albeit the genomes are unique in them, too. While we are genetically similar, there are small differences in our DNA that are unique, which also makes us distinctive in terms of health, disease and our response to certain medicinal treatments.

Personalized medicine is poised to tap natural variations found in our genes that may play a role in our risk of getting or not getting certain illnesses, along with numerous external factors, such as our environment, nutrition and exercise. Variations in DNA can, likewise, lead to differences in how medications are absorbed, metabolized and used by the body. The understanding of such genetic variations and their interactions with environmental factors are elements that will help personalized medicine clinicians to produce better diagnostics and drugs, and select much better treatments and dosages based on individual needs not as just fixing a pill or two, as is the present-day conventional medical practice.

It is established that a majority of genes function precisely as intended. This gives rise to proteins that play a significant role in biological processes while allowing or helping an individual to grow, adapt and live in their environment. It is only in certain unusual situations, such as a single mutated or malfunctioning gene, that our apple cart is disturbed. This leads to distinct genetic diseases or syndromes such as sickle cell anemia and cystic fibrosis. In like manner, multiple genes acting together can impact the development of a host of common and complex diseases, including our response to medications used to treat them.

New advances will revolutionize bespoke medical treatment with the inclusion of drug therapy as well as recommendations for lifestyle changes to manage, delay the onset of disease or reduce its impact. Not surprisingly, the emergence of new diagnostic and prognostic tools has already raised our ability to predict likely outcomes of drug therapy. In like manner, the expanded use of biomarkers biological molecules that are associated with a particular disease state has resulted in more focused and targeted drug development.

Molecular testing is being expansively used today to identify breast cancer and colon cancer patients who are likely to benefit from new treatments and to preempt recurrences. A genetic test for an inherited heart condition is helping clinicians to determine which course of treatment would maximize benefit and minimize serious side effects while bringing about curative outcomes.

Such complexities exist for asthma and other disorders too. This is precisely where molecular analysis of biomarkers can help us to identify sub-types within a disease while enabling the clinician to monitor their progression, select appropriate medication, measure treatment outcomes and patients response. Future advances may make biomarkers and other tools affordable and allow clinicians to screen patients for relevant molecular variations prior to prescribing a particular medication.

It is already clear that personalized medicine promises three strategic benefits. In terms of preventative medicine, personalized medicine will improve the ability to identify which individuals are predisposed to develop a particular condition. A better understanding of genetic variations could also help scientists identify new disease subgroups or their associated molecular pathways and design drugs to target them. This could also help select patients for inclusion, or exclusion, in late-stage clinical trials. Finally, it will allow to work out the best dosage schedule or combination of drugs for each individual patient.

Yet not everything is hunky-dory for personalized medicine. Critics of precision medicine believe that the whole idea is too much of overhyped razzmatazz, among other things. Proponents, however, argue that when it comes to managing our own health, most of us are used to the idea of taking a one-size-fits-all approach be it medicines, supplements, diets and diagnoses. This may be wrong.

What works, as they put it, for one may be a gaffe for another. As the award-winning oncologist and medical technology innovator, Dr. David B. Agus, author of the groundbreaking bookThe End of Illness, puts it, each patients individual risk factors are based on ones DNA, the environment and a preventative lifestyle plan in response. He begins with simple, profound pointers: How is your sense of smell? and Is your ring finger longer than your middle finger? He explains with statistics-backed guidelines that moving and walking regularly is mandatory because exercising and then sitting is equivalent to smoking cigarettes, while eating and sleeping at consistent hours is imperative because irregularity causes inflammation.

The inference is obvious: We should all understand our physiology and quiz doctors with the thorough, exploratory frame of mind of a gadget buyer. This holds the key to making medicine truly personal, more humane, effective and safe while keeping in mind the individual in us all as unique and distinctive, the sum of the whole not just the parts.

The views expressed in this article are the authors own and do not necessarily reflect Fair Observers editorial policy.

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The Future of Medicine Is Bespoke - Fair Observer

The Alliance for Regenerative Medicine Announces Its 2020 Cell & Gene Meeting on the Mesa Goes Virtual – GlobeNewswire

Washington, DC, June 24, 2020 (GLOBE NEWSWIRE) -- via NEWMEDIAWIRE -- The Alliance for Regenerative Medicine (ARM), an international multi-stakeholder advocacy organization representing the regenerative medicine and advanced therapy sector, today announced a new virtual format for its annual Cell & Gene Meeting on the Mesa, which will take place October 12-16, 2020.

ARM's leadership and Board of Directors arrived at the decision to host the 2020 Cell & Gene Meeting on the Mesa virtually after consulting with numerous ARM members and gathering information from various health authorities. Ultimately, hosting the meeting virtually will be the safest and most inclusive solution, allowing attendees to connect with potential partners globally while avoiding any risk to safety.

This year's Cell & Gene Meeting on the Mesa will bring together senior executives from leading cell therapy, gene therapy, and tissue engineering companies worldwide, large pharma and biotech, institutional investors, academic research institutions, patient foundations and disease philanthropies, life science media, and more.

During this unprecedented period of social distancing, ARM continues to provide members with avenues to engage and connect, said ARM CEO Janet Lambert. Our virtual Meeting on the Mesa is an invaluable opportunity for stakeholders from across the sector to convene, to network, and to continue to work to ensure innovative cell and gene therapies reach patients in need.

The conference, which will now take place over five days, includes a virtual form of the meetings signature partnering system, expected to facilitate more than 3,000 one-to-one meetings between industry leaders. The program will include 15+ digital panels and workshops featuring key industry leaders discussing issues and trends in the regenerative medicine and advanced therapy sector, from market access to the latest discoveries in gene editing. Representatives from more than 80 prominent public and private companies will deliver on-demand presentations highlighting their clinical and commercial progress to interested partners and investors.

Additional event details will be updated regularly on the event website http://www.meetingonthemesa.com.

Registration is currently open, with discounted early-bird rates available through July 24. Registration is complimentary for investors and credentialed members of the media. To learn more and to register, please visitwww.meetingonthemesa.com. For members of the media interested in attending, please contact Kaitlyn (Donaldson) Dupont atkdonaldson@alliancerm.org.

For interested organizations looking to increase exposure to this fields top decision-makers via sponsorship, please contact Laura Stringham at lparsons@alliancerm.org for additional information.

About the Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is an international multi-stakeholder advocacy organization that promotes legislative, regulatory, and reimbursement initiatives necessary to facilitate access to life-giving advances in regenerative medicine worldwide. ARM also works to increase public understanding of the field and its potential to transform human healthcare, providing business development and investor outreach services to support the growth of its member companies and research organizations. Prior to the formation of ARM in 2009, there was no advocacy organization operating in Washington, D.C. to specifically represent the interests of the companies, research institutions, investors, and patient groups that comprise the entire regenerative medicine community. Today, ARM has more than 350 members and is the leading global advocacy organization in this field. To learn more about ARM or to become a member, visithttp://www.alliancerm.org.

Kaitlyn (Donaldson) Dupont

803-727-8346

kdonaldson@alliancerm.org

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The Alliance for Regenerative Medicine Announces Its 2020 Cell & Gene Meeting on the Mesa Goes Virtual - GlobeNewswire

Vision research contributes to a rethinking of what leads to a rare disorder causing blindness – UB News Center

BUFFALO, N.Y. A series of papers published recently by two teams of vision researchers at the University at Buffalo and the University of Alabama at Birmingham (UAB) is revealing important new information about the possible cause of a condition that underlies a rare form of irreversible blindness in young children.

Retinitis pigmentosa (RP) is the label given to a family of disorders characterized by the degeneration and eventual death of the eyes photoreceptor cells, which absorb and convert light into electrical signals in the retina. Symptoms begin in childhood with night blindness and loss of peripheral vision, and the disease typically results in progressive vision loss and, ultimately, blindness.

The UB team is led by Steven J. Fliesler, PhD, SUNY Distinguished Professor and the Meyer H. Riwchun Endowed Chair Professor of Ophthalmology in the Jacobs School of Medicine and Biomedical Sciences at UB. The UAB team is led by Steven J. Pittler, PhD, professor and director of the Vision Science Research Center at the School of Optometry and Vision Science at UAB.

RP is caused by a multitude of disparate genetic mutations, explained Fliesler. However, one form known as RP59 has been classified as a congenital disorder of glycosylation (CDG). The process of glycosylation involves the addition of sugars to protein molecules to make glycoproteins, which are required for cellular development, structural integrity, and viability.

But the researchers findings published this month in a paper in iScience, and two related papers published recently in the journal Cells, demonstrate that this may not be the case.

Genetic mutation

Although the more common forms of RP have been known for many decades, RP59 was only first described in 2011, in patients of Ashkenazi Jewish heritage. Those patients have a genetic defect involving mutations in the gene that encodes DHDDS, a key enzyme required for synthesizing an essential lipid-like molecule called dolichol. These patients manifest RP-like symptoms.

Up until then, Fliesler explained, it was neither known nor imagined that defects in the biochemical pathway that synthesizes dolichol could cause the disorder.

In 2018, the National Eye Institute of the National Institutes of Health awarded Fliesler and Pittler a $2.2 million grant to study RP59 with the hope of eventually developing a gene therapy to treat or cure the condition.

The aim of the grant, which supports the current work, was to study the molecular mechanism underlying RP59 pathology by deleting the DHDDS gene selectively in specific cell types in the retina and examining the consequences to retinal structure and function, Fliesler explained.

The study described in the iScience paper involved targeted deletion in mouse retinal rod photoreceptor cells of the gene that encodes a critical enzyme (DHDDS) responsible for making dolichol and its derivatives, said Fliesler. Those mice exhibited a profound retinal degeneration with complete loss of rod photoreceptors by 6 postnatal weeks of age, which is among the most rapid photoreceptor degenerations ever observed.

Although we predicted the retinal degeneration, we expected that protein glycosylation in the photoreceptor cells would be severely compromised, since that process requires dolichol; yet, it was not, said Fliesler. That was a tremendous surprise.

We have not yet discovered why this happens, or what is the actual underlying mechanism of the very rapid photoreceptor degeneration observed in our novel mouse model, said Fliesler. Without knowing the underlying mechanism of RP59, it would be more difficult to develop targeted therapies to prevent, retard, or cure the disease. Our results, in combination with results obtained from two other recently published studies from our group, in collaboration with Dr. Pittlers lab at UAB, challenge the notion that RP59 is a congenital disorder of glycosylation.

The work is related to two previous papers, in which Fliesler and members of his UB lab are co-authors with the lead investigators at UAB. Published in Cells, the first study suggests that retinal pigment epithelium pathology may be a significant contributor to the retinal degeneration observed in humans with RP59 mutations.

More recently, the UAB and UB teams collaborated on a companion study, also reported in Cells, that showed that a knock-in mouse model (where an endogenous gene or parts of a gene have been replaced with exogenous genetic material) harboring the same mutation as found in human RP59 patients not only showed no defect in glycosylation, but failed to undergo retinal degeneration, and exhibited only very subtle physiological defects. These findings again point to a more complex mechanism for RP59 than originally thought, Fliesler noted.

Sriganesh Ramachandra Rao, PhD, formerly a graduate student in Flieslers lab at UB and now a postdoctoral researcher there, is first author on the iScience paper, as well as on the second Cells paper. Other UB authors on the paper are Lara A. Skelton, Fuguo Wu, Mark C. Butler, and Xiuqian Mu. Pittler and colleagues at UAB are co-authors, along with researchers from the Polish Academy of Sciences.

The research was supported primarily by the NIH grant with additional support from a Knights Templar Eye Foundation Career-Starter Award and a Fight for Sight Summer Student Award, as well as support from a Clinical and Translational Science Award granted to UB by the National Center for Advancing Translational Sciences of the NIH.

Fliesler conducted the research at the VA Western New York Healthcare System, where he holds a Research VA MERIT Review Award as well as a Research Career Scientist Award, both from the U.S. Department of Veterans Affairs.

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Vision research contributes to a rethinking of what leads to a rare disorder causing blindness - UB News Center