Category Archives: Gene Medicine

A Phase 1 trial will evaluate the use of gene therapy in delivering brain-derived neurotrophic factor (BDNF) to the brains of people with Alzheimers disease or mild cognitive impairment (MCI), which often precedes dementia.

Researchers at the University of California San Diego (UCSD) School of Medicine are preparing to open a three-year trial in 12 people diagnosed with either with Alzheimers or MCI, according to a universitypress release. The release did not specify if eligible patients need to be at particular stages of Alzheimers.

The trial will assess the safety and efficacy of injecting the BDNF gene, carried on an engineered adeno-associated virus (AAV2), directly to certain brain regions in these 12 patients.

Another 12 people will serve as an untreated control group for comparison.

BDNF is a neurotrophin, a protein that promotes the growth and survival of both new and existing neurons. The protein also functions as a neurotransmitter, mediating communication between nerve cells.

It is active in several brain regions susceptible to degeneration over the course of Alzheimers. Past research has identified mutations in the BDNFgene that impair its signaling ability, and which associate with faster cognitive decline and a higher risk of developing Alzheimers.

The research team conducting the trial previously found that BDNF could prevent and reverse brain cell degeneration and death in rat, monkey, and mouse models of Alzheimers.

We found that delivering BDNF to the part of the brain that is affected earliest in Alzheimers disease the entorhinal cortex and hippocampus was able to reverse the loss of connections and to protect from ongoing cell degeneration, said Mark Tuszynski, MD, PhD, senior author of a 2009 study of this preclinical work.

The entorhinal cortex produces BDNF and functions as a hub for memory, navigation, and the perception of time. Although it normally produces BDNF throughout a persons life, people with Alzheimers tend to produce less of it.

The investigators plan to deliver the BDNF gene to patients via AAV2 because the BDNF protein is too large to cross the blood-brain barrier. The injections will be targeted to specific brain areas, as too much freely circulating BDNF can cause harmful side effects such as seizures.

UCSD has participated in past Alzheimers gene therapy trials, which used an AAV vector to deliver a different neurotrophin named nerve growth factor (NGF) to the brain. The university reports that data from one past trial showed increased nerve growth, the formation of new nerve connections, and activation of functional markers in participants brains.

Tuszynski believes that therapeutic BDNF represents an improvement over trials using NGF.

BDNF is a more potent growth factor than NGF for neural circuits that degenerate in [Alzheimers], he said. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.

The upcoming trial will be the first to evaluate the use of AAV2BDNF in humans.

BDNFgene therapy has the potential, unlike other [Alzheimers] therapies currently under development, to rebuildbrain circuits, slow cell loss and stimulate cell function, Tuszynski said. We are looking forward to observing the effects of this new effort in patients with [Alzheimers] and MCI.

Anyone wanting more information on this Phase 1 trial can contact Michelle Mendoza at 858-822-7438 or by sending an email to [emailprotected].

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

Originally posted here:
Next:Phase 1 Trial to Test BDNF Gene Therapy in Alzheimer's Patients - Alzheimer's News Today

After spending around $200 and sending a vial of spit in the mail, almost anyone can gain access to an analysis of their DNA, learning their risk levels for everything from breast cancer to Parkinson's disease. But oncologist and geneticist Kenan Onel, MD, PhD, explains that direct-to-consumer genetic testing doesn't provide the context needed to give you comprehensive results.

"I really don't think that these tests, from a medical or a health perspective, are useful. I don't think that they're interpretable," says Dr. Onel, who is the director of the Center for Cancer Prevention and Wellness at the Icahn School of Medicine at Mount Sinai. "Clinical tests and a 23andMe test or an Ancestry.com test just have different goals and different designs."

On the heels of Ancestry discontinuing its medical branchAncestryHealth, recent research looked at single nucleotide polymorphism (SNP) tests, the kind of tests used by direct-to-consumer DNA testing companies like AncestryHealth and 23andMe. They found that while they're great at searching for common variants, the tests become inaccurate when screening for rare genetic mutations for disease-carrying genes. For example, when testing for mutations in BRCA1 and BRCA2 genes (genes that put you at a higher risk of developing breast and/or ovarian cancer), the probability that subjects with a positive screening test truly had the gene was only 4.2 percent.

Dr. Onel, who is also the associate director of clinical cancer genetics and precision oncology at The Tisch Cancer Institute at Mount Sinai, explains that this is because SNP tests are genotypes from samples of people. So the more rare a mutation is, the smaller the pool of genotypes available to base results on. Basing results on SNP tests alone leads to incomplete results because they lack the nuance that's available from more robust testing that would be performed, and later interpreted, by a geneticist.

"That's why genetics is a medical profession," says Dr. Onel. "Each and every one of us, we have somewhere between 10 and 30 million variants. Given that large number of variations, you can be sure that the vast majority of these tests are completely meaningless, but some of it may have implications for wellness and illness."

In addition to offering an incomplete picture, the results from these tests are often given in relative, instead of absolute, terms. "The sort of information that you get is, 'Oh, you have a 20 percent greater likelihood than other people of having chronic stomach aches.' Twenty percent sounds like a really big deal, that's one in five. I would really panic if I was told that I have 20 percent increased risk for something," says Dr. Onel. "But what that actually means is 20 percent greater than the background rate. So if the background rate of stomach aches is one in 10, having a 20 percent increased risk means that you're now at a whopping 1.2 in 10. The problem with direct-to-consumer testing is that nobody understands probability theory. Nobody understands actually what they're telling you when they give you these percentages."

Dr. Onel says if you're serious about understanding how your genetics could impact your health, he says to seek out a geneticist instead of buying a direct-to-consumer genetic test.

"I wouldn't use them for anything clinicalI would use them because they're fun, because they're cheap, because they're entertaining," he says. "And it's like, 'Oh, look, I'm supposed to have blue hairin fact, I do. Hahaha!' That's great, but I don't think that you can actually draw meaningful medical conclusions, health conclusions, from these sort of direct-to-consumer tests right now."

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Im a Geneticist, and This Is What Direct-to-Consumer Tests Can (and Cant) Tell You About Your Health - Well+Good

SALT LAKE CITY (ABC4) A new study may take the guilt out of wanting to take a nap.

Many animals who are awake during the day and sleep at night take naps. Dogs, flies, and people. But what makes some people morning people, night people, and nap people?

New research suggests it may be in your genes especially the urge to take a nap.

Call it what you will, a power nap, a siesta, or just an afternoon dropout. Researchers have learned that people who like to take naps share some genetic traits that may make them enjoy naps.

In the largest study of its kind, a team led by Harvard Investigators at Harvard-affiliated Massachusetts General Hospital (MGH) collaborated with colleagues at the University of Murcia in Spain and several other institutions then published inNature Communications.

The study says, Naps are short daytime sleep episodes that are evolutionarily conserved across diverse diurnal species ranging from fliesto polyphasic mammals. In human adults, daytime napping is highly prevalent in Mediterranean cultures and is also common in non-Mediterranean countries including the United States

The study discovered dozens of gene regions that govern the tendency to take naps during the day.

In a statement to the Harvard Gazette, Napping is somewhat controversial, says Hassan Saeed Dashti of the MGH Center for Genomic Medicine, co-lead author of the report with Iyas Daghlas, a medical student at Harvard Medical School (HMS). Dashti notes that some countries where daytime naps have long been part of the culture (such as Spain) now discourage the habit. Meanwhile, some companies in the United States now promote napping as a way to boost productivity.

It was important to try to disentangle the biological pathways that contribute to why we nap, says Dashti.

Researchers first used the UK Biobank data for the GWAS (genome-wide association study), which holds the genetic information on 452,633 people. The participants were asked whether they nap during the day never/rarely, sometimes, or usually.

Some of the participants wore accelerometers to monitor their activity during the day.

The accelerometers helped the researchers determine if the responses from the people matched with activity. That gave an extra layer of confidence that what we found is real and not an artifact, says Dashti.

The team discovered certain genes play a factor, according to the results posted in the Harvard Gazette. People who needed naps expressed the need and the reason why differently.

The study says, Genetic variation constitutes an important contributor to inter-individual differences in napping preference. A twin study estimated heritability of self-reported napping and objective daytime sleep duration to be 65% and 61%, respectively, demonstrating heritability similar or even higher than heritability found for other sleep traits such as nighttime sleep duration and timing

Once they dug into the data the team discovered different mechanisms in each of us that promotes napping.

What does it all mean? They all needed naps.

This tells us that daytime napping is biologically driven and not just an environmental or behavioral choice, says Dashti.

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Want to take a nap? Dont feel guilty, it might be in your genes - ABC 4

For the third year in a row, a discovery from the University of Virginia School of Medicine has been selected as one of the years most significant biomedical discoveries. The finding identifying the gene responsible for one of the deadliest cancers is among 64 contenders fighting it out to win the publics votes in an online bracket tournament.

Voting opens today for STAT Madness, which is like the scientific version of the NCAA basketball tournament. The annual competition is sponsored by the STAT health news site to identify the years best biomedical innovation, and you can vote by clicking here. The first round is open through Sunday.

UVA is one of 64 competitors in the first round of the tournament, which features a roster of scientific heavy hitters. Other top institutions that have made it to the first round include Duke University, Stanford University, the University of Notre Dame and the Massachusetts Institute of Technology.

The UVA discoverys first-round opponent is the discovery of a genetic risk factor for melanoma, from Rockefeller University.

UVAs entry comes from researcher Hui Li and his collaborators, who identified the oncogene (a cancer-causing gene) responsible for glioblastoma, an aggressive form of brain cancer.The discoveryoffers a promising new treatment target for a cancer that is often fatal within a year of diagnosis.

Li and his colleagues say the oncogene is essential to the survival of glioblastoma cells. Without it, they found, the cancer cells die. Scientists have already developed many targeted therapies for other cancers with a similar oncogene addiction, and Li hopes his discovery will lead to more effective treatments for glioblastoma.

We feel honored that our work has been selected as one of the top discoveries, but even more honored to be able to provide some hope to the patients with this deadly disease, said Li, of UVAs Department of Pathology and the UVA Cancer Center. We believe thisAVILgene is one of the Achilles heels of glioblastoma, and are working hard to figure out a way to target it.

The 64 finalists in this years STAT Madness were winnowed from more than 130 submissions from universities and affiliated research institutions.

This is the third year in a row UVA has made the cut. Last years contest featured an artificial pancreas developed at UVA that automatically regulates blood sugar for people with type 1 diabetes. The previous years contest featured a game-changing neuroscience discovery revealing the existence of tiny vessels connecting the brain to the immune systemvessels that textbooks had long insisted did not exist.

Its wonderful to see outstanding work from the School of Medicine consistently recognized among the years most exciting and promising biomedical discoveries, said Dr. K. Craig Kent, UVAs executive vice president for health affairs. Its a testament to the caliber of the research being conducted here, and Im proud to see our institution performing important work that will ultimately benefit the health and lives of people everywhere.

To keep up with the latest medical research news from UVA, subscribe to theMaking of Medicineblog.

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Cancer Find Up for Year's Biggest Biomedical Advance in a Different 'March Madness' - University of Virginia

GAINESVILLE, Fla.--(BUSINESS WIRE)--Cyclo Therapeutics, Inc. (Nasdaq: CYTH) (Cyclo Therapeutics or the Company), a clinical stage biotechnology company developing cyclodextrin-based products for the treatment of Niemann-Pick Disease Type C and Alzheimers Disease, today announced the appointment of Gerald F. Cox, MD, PhD as Acting Chief Medical Officer.

Dr. Cox is an internationally renowned biotechnology executive with over 20 years of experience in drug development for rare diseases. Over the course of his career, he has made major contributions to more than 15 Investigational New Drug applications (INDs) and 6 orphan drug marketing authorizations for serious and life-threatening diseases that have generated over $5.0 billion in revenue. He brings with him extensive worldwide regulatory expertise, invaluable clinical acumen, and deep scientific insights.

As we continue to advance our Trappsol Cyclo clinical development programs, we are incredibly pleased to have secured the interest of Dr. Cox. The expertise and guidance he can provide as we execute on our clinical and regulatory strategies to treat systemic and neurologic manifestations of Niemann-Pick Type C and Alzheimers Disease will be invaluable. We look forward leveraging Gerrys breadth of knowledge and expertise to drive forward these programs as effectively and expeditiously as possible, commented, N. Scott Fine, CEO of Cyclo Therapeutics.

Dr. Cox is the founder of Gerald Cox Rare Care Consulting, LLC, where since 2018 he has been providing expert advice to small companies in all phases of clinical development for investigational rare disease drugs. From 2016-2018, Dr. Cox was the Chief Medical Officer of Editas Medicine, where he led the clinical development of CRISPR-based genome editing medicines to treat human diseases, including the first approved IND for a CRISPR-based medicine to be delivered in vivo that is designed to treat a genetic form of blindness called Leber congenital amaurosis type 10. Prior to Editas Medicine, Dr. Cox held increasingly senior roles at Genzyme (now Sanofi Genzyme) for over 15 years, advancing to Vice President of Rare Disease Clinical Development. While at Genzyme, he played an instrumental role in the global development and approval of treatments for several lysosomal storage disorders, including the enzyme replacement therapies Aldurazyme (laronidase) for Mucopolysaccharidosis type I in 2003, Elaprase (idursulfase) for Mucopolysaccharidosis type II in Japan and the Asia Pacific region in 2007, and Cerezyme (imiglucerase) for a label expansion in Gaucher disease type 3 in Australia and China in 2016, as well as the substrate reduction therapy Cerdelga (eliglustat) for Gaucher disease type 1 in 2014. He also led the early clinical development of the enzyme replacement therapies Myozyme (alglucosidase alfa) for infantile Pompe disease, which was approved in 2006, and olipudase alfa for Niemann-Pick disease type B, which recently completed a successful Phase 3 study. Dr. Cox has been affiliated with Boston Childrens Hospital during his entire career, where he is a Part-time Staff Physician in Genetics. He is also an Instructor in Pediatrics at Harvard Medical School.

Dr. Cox added, Niemann-Pick C is a devastating childhood disease for which there is no satisfactory treatment. With Cyclo Therapeutics pivotal Phase 3 study in NPC commencing next quarter and topline results from the NPC Phase 1/2 study expected in the near future, this is an exciting time for the Company. I am thrilled to be joining the Cyclo Therapeutics management team and believe they have great potential to provide potentially life-changing medicines for patients with rare diseases where there remains significant unmet need.

Dr. Cox received his MD and PhD from the University of California at San Diego and his B.A. from Harvard College. He completed an internship and residency in pediatrics followed by clinical and post-doctoral research fellowships in genetics at Boston Childrens Hospital and was Director of the Medical Genomics Mapping Facility. Dr. Cox is board-certified by the American College of Medical Genetics and Genomics in Clinical, Biochemical, and Molecular Genetics, and he was board-certified by the American Academy of Pediatrics in the past. He serves on the Board of Directors for the National Tay-Sachs and Allied Diseases organization.

About Cyclo Therapeutics

Cyclo Therapeutics, Inc. is a clinical-stage biotechnology company dedicated to developing life-changing medicines through science and innovation for patients and families suffering from disease. The Companys Trappsol Cyclo, an orphan drug designated product in the United States and Europe, is the subject of three ongoing formal clinical trials for Niemann-Pick Disease Type C, a rare and fatal genetic disease, (ClinicalTrials.gov NCT02939547, NCT02912793 and NCT02912793). The company is planning an early phase clinical trial using Trappsol Cyclo intravenously in Alzheimers Disease based on encouraging data from an Expanded Access program for late-onset Alzheimers Disease (NCT03624842). Additional indications for the active ingredient in Trappsol Cyclo are in development. For additional information, visit the companys website: http://www.cyclotherapeutics.com.

Safe Harbor Statement

This press release contains forward-looking statements about the companys current expectations about future results, performance, prospects and opportunities, including, without limitation, statements regarding the satisfaction of closing conditions relating to the offering and the anticipated use of proceeds from the offering. Statements that are not historical facts, such as anticipates, believes and expects or similar expressions, are forward-looking statements. These statements are subject to a number of risks, uncertainties and other factors that could cause actual results in future periods to differ materially from what is expressed in, or implied by, these statements. The factors which may influence the companys future performance include the companys ability to obtain additional capital to expand operations as planned, success in achieving regulatory approval for clinical protocols, enrollment of adequate numbers of patients in clinical trials, unforeseen difficulties in showing efficacy of the companys biopharmaceutical products, success in attracting additional customers and profitable contracts, and regulatory risks associated with producing pharmaceutical grade and food products. These and other risk factors are described from time to time in the companys filings with the Securities and Exchange Commission, including, but not limited to, the companys reports on Forms 10-K and 10-Q. Unless required by law, the company assumes no obligation to update or revise any forward-looking statements as a result of new information or future events.

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Cyclo Therapeutics Appoints Gerald F. Cox, MD, PhD as Acting Chief Medical Officer - Business Wire

EDMONTON, AB, Feb. 25, 2021 /CNW/ -Entos Pharmaceuticals (Entos), a biotechnology company developing genetic medicines with its Fusogenix nucleic acid delivery platform, is excited to work with Alberta Cell Therapy Manufacturing and The Ottawa Hospital's Biotherapeutics Manufacturing Centre to manufacture and ready doses of Entos' made-in-Canada Covigenix VAX-001 vaccine for upcoming clinical trials at the Canadian Centre for Vaccinology.

Covigenix VAX-001 is a single-dose COVID-19 DNA vaccine that is similar to the recently approved mRNA vaccines but with the important advantages of stability at room temperature for 30 days or in the fridge for a year, and prepared in-vials at a ready-to-use concentration. In preclinical studies, Covigenix VAX-001 induced strong neutralizing antibody and durable T cell immune responses against SARS-CoV-2. Covigenix VAX-001 can be easily transported, stored, and administered for the benefit of Canadians and potentially the world. Entos received CIHR and NRC-IRAP funding for Phase 1 trial manufacturing and is actively seeking funding to advance through Phase 2 and 3 clinical trials.

Rollout of the first generation COVID-19 mRNA vaccines are underway. However, vaccine production needs to continue so enough doses are made to end the pandemic. Investing now in Canada's biotherapeutic manufacturing capacity could still produce a made-in-Canada COVID-19 vaccine. Canada could also rapidly respond to new SARS-CoV-2 variants and future pandemics and position Canada as a leader in genetic medicine.

"Finding a facility in Canada that could ready our DNA vaccine in vials time for the Phase 1 trials was extremely challenging because the few that we have here are all in high demand right now," said John Lewis, CEO of Entos Pharmaceuticals. "We were thrilled to partner with The Ottawa Hospital's Biotherapeutics Manufacturing Centre and benefit from their world-class expertise."

BMC has manufactured and readied cell, gene, and viral therapies for clinical trials for over ten years and is now instrumental in doing this for COVID-19 therapies and vaccines, including Entos' DNA vaccine. BMC also shares its world-class manufacturing and clinical trial expertise with industrial partnersand will help ACTM increase its capacity by spring 2021.

"I'm delighted that The Ottawa Hospital's Biotherapeutics Manufacturing Centre is helping to fill Canada's critical needs in COVID-19 vaccine manufacturing," said Dr. Duncan Stewart, Executive Vice-President of Research at The Ottawa Hospital and professor of medicine at the University of Ottawa. "In addition to the Entos vaccine, we will be manufacturing two other COVID-19 vaccines for clinical trials and we are already manufacturing a cell-based therapy for a COVID-19 trial. With our sustained track record of success, we are well positioned to play a key role in strengthening Canada's biotherapeutics manufacturing capacity now and into the future."

About The Ottawa Hospital's Biotherapeutics Manufacturing Centre Over the last 10 years, The Ottawa Hospital's Biotherapeutics Manufacturing Centre has successfully manufactured more than a dozen different biotherapeutics for human clinical trials in Canada and around the world, making it the most experienced facility of its kind in Canada. The Centre also leads the only hands-on training program in Canada in biotherapeutics manufacturing, in partnership with Algonquin College, the University of Ottawa and Mitacs. The Centre has been supported by the Canada Foundation for Innovation, the Ontario Research Fund, BioCanRx (a Canadian Network of Centres of Excellence) and generous donors to The Ottawa Hospital Foundation. http://www.ohri.ca/bmc.

About Alberta Cell Therapy ManufacturingLocated at the University of Alberta, ACTM offers a range of integrated services from technology transfer, process and assay development through to GMP manufacturing of products for clinical trials. The ACTM's Scientific Director Dr. Greg Korbutt and ACTM Manager Gayle Piat are excited to support the production of Ento's vaccine.With state-of-the-art equipment, a 10,000 square foot cleanroom facility and expert GMP staff, ACTM is ideally positioned to deliver biotherapeutic manufacturing services in Canada.The addition of a fill-finish suite is currently underway and will be operational in 2021. Visitwww.ualberta.ca/actm.

About Entos Pharmaceuticals, Inc.Entos develops next generation genetic therapies using their breakthrough Fusogenix nucleic acid delivery system. Fusogenix is a proteolipid vehicle (PLV) formulation that uses a novel mechanism of action to deliver molecules, intact and unmodified, directly into the cytosol of target cells. The technology is applicable to a wide range of therapeutic types including gene therapy, mRNA, miRNA, RNAi, CRISPR and small molecule drugs. Visit http://www.entospharma.com.

SOURCE Entos Pharmaceuticals

For further information: John D. Lewis, Ph.D., CEO, Entos Pharmaceuticals, Inc., Email: [emailprotected]; Jenn Ganton, Director, Communications and Public Relations, Ottawa Hospital Research Institute, Email: [emailprotected]; Greg Korbutt, Ph.D., Scientific Director, Alberta Cell Therapy Manufacturing (ACTM), Email: [emailprotected]

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Entos Pharmaceuticals Partners with Alberta Cell Therapy Manufacturing and the Ottawa Hospital Research Institute to Manufacture and Ready its...

- Enrollment anticipated to complete in 1Q21 and topline pivotal data from the GEM-3 study of B-VEC in DEB expected in 4Q21.

- Today announced Positive Opinion from the European Medicines Agency on Orphan Drug Designation for KB407 for the treatment of cystic fibrosis.

- Strong balance sheet with December 31, 2020 ending cash, cash equivalents and short-term investments of $271.3 million. In addition, our cash position was strengthened by $151.9 million of net proceeds from 2021 subsequent offerings.

PITTSBURGH, March 01, 2021 (GLOBE NEWSWIRE) -- Krystal Biotech Inc., (Krystal) (NASDAQ: KRYS), the leader in redosable gene therapies for rare diseases, today reported financial results and key operational progress updates for the fourth quarter ending December 31, 2020.

As the gene therapy landscape evolves, we grow increasingly confident in the unique positioning of our proprietary technology. The ability to episomally deliver therapeutic transgenes repeatedly over time has afforded us a great opportunity to develop transformative medicines for debilitating rare diseases, said Krish Krishnan, Chairman and CEO of Krystal Biotech, Inc. 2021 is an exciting year for our company as we will have Phase 3 data for B-VEC, continue to advance our rare skin pipeline, and begin dosing patients for the first time with our lung targeted vector in cystic fibrosis.

Program Highlights & Upcoming Events:

B-VEC for DEB

KB105 for TGM1-ARCI

KB407 for Cystic Fibrosis

KB301 for Aesthetic Indications

KB104 for Netherton Syndrome

Fourth Quarter and Full Year 2020 Financial Results:

Subsequent Events:

About Krystal BiotechKrystal Biotech, Inc. (NASDAQ:KRYS) is a pivotal-stage gene therapy company leveraging its novel, redosable gene therapy platform and in-house manufacturing capabilities to develop therapies to treat serious rare diseases. For more information please visit http://www.krystalbio.com.

Forward-Looking StatementsAny statements in this press release about future expectations, plans and prospects for Krystal Biotech, Inc., including but not limited to statements about the development of Krystals product candidates, such as plans for the design, conduct and timelines of ongoing clinical trials of beremagene geperpavec (B-VEC), KB105, KB104, KB301 and KB407; the clinical utility of B-VEC, KB105, KB104, KB301 and KB407, and Krystals plans for filing of regulatory approvals and efforts to bring B-VEC, KB105, KB104, KB301 and KB407 to market; the market opportunity for and the potential market acceptance of B-VEC, KB105, KB104, KB301 and KB407; plans to pursue research and development of other product candidates; the sufficiency of Krystals existing cash resources; the unanticipated impact of COVID-19 on Krystals business operations, pre-clinical activities and clinical trials; and other statements containing the words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, likely, will, would, could, should, continue, and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the uncertainties inherent in the initiation and conduct of clinical trials, availability and timing of data from clinical trials, whether results of early clinical trials or trials will be indicative of the results of ongoing or future trials, uncertainties associated with regulatory review of clinical trials and applications for marketing approvals, the availability or commercial potential of product candidates including B-VEC, KB105, KB104, KB301 and KB407, the sufficiency of cash resources and need for additional financing and such other important factors as are set forth under the caption Risk Factors in Krystals annual and quarterly reports on file with the U.S. Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Krystals views as of the date of this release. Krystal anticipates that subsequent events and developments will cause its views to change. However, while Krystal may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Krystals views as of any date subsequent to the date of this release.

Source: Krystal Biotech, Inc.

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Krystal Biotech Provides Update on Operational Progress and Reports Fourth Quarter and Full Year 2020 Financial Results - GlobeNewswire

Eight labs who were recipients of the University Cancer Centers funding in December for projects advancing cancer research will use the funds to delve into cancer biology, cancer therapeutics and population science.

Four of the eight projects are investigating immunotherapy for gastrointestinal cancers, the tumor environments impact on cancer cell growth, the potential application of an FDA-approved Parkinsons drug to treat glioma brain tumors and the ability of a novel drug to target cancer cells that exhibit heightened aggressiveness following immunotherapy, The Herald previously reported.

The Herald spoke with three of the four other principal investigators that received grants.

Assistant Professor of Medicine Hina Khans pilot project will study the effects of blocking the antibody for chitinase 3-like-1, or CHI3L1, in advanced non-small cell lung cancer. CHI3L1 is a protein that plays an important role in tissue repair, and elevated levels of the protein indicate poor outcomes in advanced stage cancer patients. The researchers will test whether blocking the antibody a molecule that binds CHI3L1 will prevent cell resistance to immune checkpoint inhibitors in this type of lung cancer.

Assistant Professor of Medicine Olin Liang is interested in exploring womens ability to fight off leukemia and other blood diseases later in life relative to men. While the effect of aging on blood cancer development has been well-studied, not much research has gone into studying sex differences, Liang said.

Past work from the Liang lab has shown that the bone marrow environment remains healthier longer in women, leading to better blood cell production and immune response. By transplanting bone marrow stem cells from young male mice into middle-aged male and female mice, the researchers were able to compare the expression of these cells amongst the two sexes. They found higher expression in female middle-aged mice, which is indicative of a healthier bone marrow environment. This observation was due to receptors molecules that can interact with hormones to produce a response in a cell on the surface of bone marrow stem cells that were uniquely responsive to sex hormones predominantly found in women.

We have narrowed it down to two sex hormone receptors that may play a role, Liang said, referring to the receptors for follicle-timulating hormone and androgen hormone. The lab plans to use the Cancer Center pilot project funds to further study the importance of these receptors.

Using gene editing technology, the researchers plan on removing genes that code for these hormone receptors from model organisms. This step will allow them to test the effect that the loss of one or both of the receptors has on female stem cell expression levels. If the elimination of the sex hormone receptor diminishes stem cell expression, that may indicate that the receptor plays a regulatory role.

The Liang lab believes that results from these experiments will not only offer greater insight to the development of blood cancers, but also help in the formulation of sex-specific treatments. Liang hopes this research leads to treatments that enhance the male (blood cell producing) system to reduce risk of age-related blood cancer, or even other diseases.

Assistant Professor of Molecular Biology, Cell Biology and Biochemistry Mamiko Yajima studies the expression of germline molecules, which are normally only expressed during development, and how they contribute to plasticity, or the cells adaptability. Her pilot project will focus on the specific germline factor DEAD-Box Helicase 4 (DDX4), which has been found to be abnormally expressed in the tumors of certain cancers, such as small cell lung cancer and melanoma.

Yajimas lab has previously studied the expression of DDX4 in cells and organisms like sea urchins and mice. She plans to test if (DDX4) actually contributes to plasticity in the context of cancer. Yajima believes that as a germline factor, DDX4 may increase cancer cells adaptability, allowing them to develop drug resistance and migrate throughout the body more frequently.

The Yajima lab plans on using the Cancer Center funding to partner with Director of Thoracic Oncology at Rhode Island Hospital Christopher G. Azzoli and Associate Professor of Pathology and Laboratory Medicine Maria L. Garcia-Moliner to analyze DDX4 expression in cancer patient samples.

I applied for this funding with the specific goal to have access to clinical samples, Yajima said. This next stage of the project will facilitate collaboration between me, a basic biologist, and physician scientists that have the expertise to help me answer the question I want to study in a clinical setting.

To identify whether DDX4 expression correlates with patient survival, the lab will also use the funds to conduct clinical data mining of patient gene expression using the Universitys supercomputer.

Associate Professor of Dermatology and Epidemiology Eunyoung Cho studies the role of dietary factors in the development of chronic diseases. Previous work from Chos lab found that eating foods containing high levels of citrus, such as grapefruits, oranges and figs, is associated with an increased risk of skin cancer. The Cho lab plans to use the Cancer Center pilot project funds to determine the component of citrus fruit responsible for the increased risk of melanoma, the most fatal type of skin cancer.

Cho believes that furanocoumarins, a class of compounds present in high levels in citrus fruits, are what lead to the higher rates of skin cancer. These compounds can absorb ultraviolet radiation from sunlight and become activated, damaging DNA and causing mutations that can result in cancer.

To test this hypothesis, Cho has partnered with Associate Professor of Medical Science Elena Oancea, who specializes in melanoma research at the molecular level. They plan on measuring whether melanin-forming skin cells show increased levels of DNA damage when exposed to furanocoumarins and UV light.

If their data supports that furanocoumarins increase risk of cancer, this could open the door to population-based studies. Cho described one potential future direction as assessing whether furanocoumarin levels in human urine samples are indicative of melanoma risk.

Its very interesting to think about citrus fruit is something you eat all the time, Cho said. People dont understand that when you eat grapefruit (and) then go into the sunlight, you may actually increase your chance of (getting) skin cancer.

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U. Cancer Center pilot projects: investigating cancer connections - The Brown Daily Herald

February 11, 2021 -A team from Cleveland Clinic has developed a precision medicine platform designed to accelerate cancer gene therapies and genome-informed drug discovery.

In a study published in Nature Genetics, researchers describe the My Personal Mutanome (MPM) platform. The platform features an interactive database that offers insight into the role of somatic mutations in cancer acquired mutations that cant be passed to offspring and prioritizes mutations that may be responsive to drug therapy.

Although advances in sequencing technology have bestowed a wealth of cancer genomic data, the capabilities to bridge the translational gap between large-scale genomic studies and clinical decision making were lacking, said Feixiong Cheng, PhD, assistant staff in theGenomic Medicine Institute, and the studys lead author.

MPM is a powerful tool that will aid in the identification of novel functional mutations/genes, drug targets and biomarkers for cancer, thus accelerating the progress towards cancer precision medicine.

The team used clinical data to integrate nearly 500,000 mutations from over 10,800 tumor exomes the protein-coding part of the genome across 33 cancer types into the platform. The team then systematically mapped the mutations to over 94,500 protein-protein interactions (PPIs) and over 311,000 functional protein sites where proteins physically bind with one another. Researchers then incorporated patient survival and drug response data.

The platform analyzes the relationships between genetic mutations, proteins, PPIs, protein functional sites, and drugs to help users easily search for clinically actionable mutations. The MPM database includes three interactive visualization tools that offer two- and three-dimensional views of somatic mutations and their associated survival and drug responses.

According to the researchers, previous studies have linked disease pathogenesis and progression to mutations and variations that disturb the human interactome, the complex network of proteins and PPIs that impact cellular function. Mutations can disrupt the network by directly changing the normal function of a protein, known as nodetic effect, or by altering PPIs, known as edgetic effect.

Additionally, in a separate, previous study, a team of researchers found that somatic mutations were highly enriched where PPIs occurred. The group also demonstrated that PPI-perturbing mutations were significantly correlated with drug sensitivity or resistance as well as poor survival rate in cancer patients.

The results from another study published inNature Genetics, which was a collaboration between Cleveland Clinic and several other institutions, motivated us to develop the mutanome platform, said Cheng.

OurNature Geneticsfindings, along with previous research, provide proof-of-concept of both nodetic and edgetic effects of somatic mutations in cancer. What we learned from that study inspired us to develop a systems biology tool that, by mapping mutations to PPI interfaces and protein functional sites and integrating survival and drug response data, identifies cancer-driving and actionable mutations to guide personalized treatment and drug discovery.

Researchers expect that MPM will lead to a better understanding of mutations at the human interactome network level. This could lead to new insights in cancer genomics and treatments, ultimately achieving the goal of cancer precision medicine.

The team will continue to update MPM annually in order to provide researchers and physicians with the most comprehensive, complete data available. Researchers also plan to apply advanced analytics technologies to their insights to improve treatment development for other conditions.

OurNature Geneticsstudy also demonstrates the nodetic and edgetic effects of mutations/variations in other diseases, said Cheng.

As a next step, we are developing new artificial intelligence algorithms to translate these genomic medicine findings into human genome-informed drug target identification and precision medicine drug discovery (i.e., protein-protein inhibitors) for other complex diseases, including heart disease and Alzheimers disease.

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Precision Medicine Platform Aims to Advance Cancer Gene Therapies - HealthITAnalytics.com

Misfolded proteins (orange) in the endoplasmic reticulum may play a role in Wolfram syndromes many symptoms.

By Mitch LeslieFeb. 11, 2021 , 2:00 PM

Maureen Marshall-Doss says the first sign that her vision was deteriorating came when she misidentified the color of a dress. At a backyard get-together about 20 years ago, the Indianapolis resident pointed out an attractive yellow dress another woman was wearing. You see that as yellow? Shes wearing a pink dress, Marshall-Doss recalls her husband responding.

Today, Marshall-Doss is virtually blind. With help from custom made eyeglasses that magnify objects 500 times, I can see shapes, she says. But she can no longer drive and had to quit the job she loved as a school librarian. Along with her dimming vision, she has type 1 diabetes and has lost her sense of taste and smell.

Marshall-Doss is one of 15,000 to 30,000 people around the world with Wolfram syndrome, a genetic disease. For decades, the condition remained enigmatic, untreatable, and fatal. But in the past few years, insights into its mechanism have begun to pay off, leading to the first clinical trials of drugs that might slow the illness and sparking hopes that gene therapy and the CRISPR DNA-editing tool might rectify the underlying genetic flaws. Here is a rare disease that the basic science is telling us how to treat, says physiologist Barbara Ehrlich of the Yale School of Medicine.

The research could also aid more than the relatively few patients with Wolfram syndrome. Driving the diseases many symptoms is a malfunction of the endoplasmic reticulum (ER), the multichambered organelle that serves as a finishing school for many cellular proteins. Known as ER stress, the same problem helps propel far more common illnesses, including type 2 diabetes, amyotrophic lateral sclerosis (ALS), Parkinsons disease, and Alzheimers disease. Wolfram syndrome is the prototype of an endoplasmic reticulum disorder, says medical geneticist Fumihiko Fumi Urano of Washington University School of Medicine in St. Louis. Because Wolfram syndrome is simpler, says Scott Oakes, a cell biologist and pathologist at the University of Chicago, researchers think it could illuminate the mechanisms of other ER-disrupting diseases, which affect hundreds of millions of people worldwide.

In the late 1930s,four children with diabetes were going blind, and doctors were stumped. Like many other people in the United States struggling through the Great Depression, the siblings ate a paltry diet, subsisting on potatoes, bread, oatmeal, and a little milk. But after examining three of the children, Donald Wolfram, a physician at the Mayo Clinic in Rochester, Minnesota, and an ophthalmologist colleague ruled out malnutrition as the cause of their puzzling condition. Lead poisoning and syphilisthough common enoughwerent to blame, either. When Wolfram and his partner wrote up the cases in 1938, they concluded that the symptoms could be manifestations of an hereditary or acquired cerebral lesion.

The physicians were right that the syndrome eventually named for Wolfram is hereditary. Recessive mutations in the gene for a protein called wolframin are responsible for most cases, with glitches in a second gene causing most of the rest. However, the pair was wrong to think the defect lies only in the brain. Instead, the symptoms stem from widespread cell death. Its definitely a disease that affects the whole body, Marshall-Doss says.

The first sign of the illness, appearing when patients are children, is usually diabetes mellitus, or faulty sugar metabolism, sparked by the demise of insulin-secreting beta cells in the pancreas. Most patients also develop the unrelated condition diabetes insipidus, in which the pituitary gland doesnt dole out enough of a hormone that helps control the bodys fluid balance, causing the kidneys to produce huge amounts of urine.

Mutations in the gene for wolframin disrupt the endoplasmic reticulum and lead to cell death throughout the body, causing a range of symptoms.

V. Altounian/Science

Ellie White, 19, of Centennial, Colorado, who was diagnosed with Wolfram syndrome 12 years ago, says she hasnt had a full night of sleep since she was 3 years old. She gets up again and again to use the bathroom and monitor her blood sugar.

Yet she and other patients say that as disruptive as those problems are, they are not the diseases most dismaying consequence. The biggest symptom of Wolfram syndrome that affects me the most is my vision, White says. Because neurons in the optic nerve perish, patients usually go blind within 10 years of their first visual symptoms.

Other neurons die as well. As the disease progresses, brain cells expire, and walking, breathing, and swallowing become difficult. Most people with Wolfram syndrome die before age 40, often because they can no longer breathe. At 57, Marshall-Doss is one of the oldest patients; one of her mutated genes may yield a partly functional version of wolframin, triggering a milder form of the disease, Urano says.

Two advanceshave made it possible to begin to tackle those symptoms. The first was Uranos discovery nearly 20 years ago that linked Wolfram syndrome to ER stress. The ER is where about one-third of a cells newly made proteins fold into the correct shapes and undergo fine-tuning. Cells can develop ER stress whenever they are under duress, such as when they dont have enough oxygen or when misfolded proteins begin to pile up inside the organelle.

In test tube experiments, Urano and his colleagues were measuring the activity of genes to pinpoint which ones help alleviate ER stress. One gene that popped up encodes wolframin, which scientists had shown in 1998 was mutated in patients with Wolfram syndrome. Following up on that finding, Urano and his team determined that wolframin takes part in whats known as the unfolded protein response, which is a mechanism for coping with ER stress in which cells take steps including dialing back protein production.

Scientists think wolframin plays a key role in the unfolded protein response, though they havent nailed down exactly how. When wolframin is impaired, cells become vulnerable to ER stress. And if they cant relieve that stress, they often self-destruct, which could explain why so many neurons and beta cells die in the disease.

Defective wolframin may harm cells in other ways. The ER tends the cells supply of calcium, continually releasing and absorbing the ion to control the amount in the cytoplasm. Changes in calcium levels promote certain cellular activities, including the contraction of heart muscle cells and the release of neurotransmitters by neurons. And wolframin affects calcium regulation.

Beta cells genetically engineered to lack functional wolframin brim with calcium, Ehrlich and colleagues reported in July 2020 in theProceedings of the National Academy of Sciences. When exposed to lots of sugar, the altered cells release less insulin and are more likely to die than healthy beta cells, the team found. The cells share that vulnerability with beta cells from patients with Wolfram syndrome. We think that excess calcium is leading to excess cell death, Ehrlich says.

ER malfunctions could hamstring other organelles as well. The ER donates calcium to the mitochondria, the cells power plants, helping them generate energy. In 2018, a team led by molecular biologist Ccile Delettre and molecular and cellular biologist Benjamin Delprat, both of the French biomedical research agency INSERM, discovered that in cells from patients with Wolfram syndrome, mitochondria receive less calcium from the ER and produce less energy. Those underpowered mitochondria could spur the death of optic nerve cells, the researchers speculate.

Fumihiko Urano holds dantrolene, a muscle relaxant drug he helped test as a treatment for Wolfram syndrome.

The link between ER stress and Wolfram syndrome has been crucial for identifying potential treatments because otherwise we would have nothing to target, Urano says. But a second development was also key, he says: the advocacy and support of patient organizations, such as the Snow Foundation and the Ellie White Foundation, headed by its namesakes mother. The foundations have stepped up with money for lab research and clinical trials when other sources, including government agencies, didnt come through.

Scientists, patients, and their advocates say Urano also deserves much of the credit. Besides treating patients, he heads the international registry of cases and has taken the lead in organizing clinical trials, screening compounds for possible use as treatments, and devising potential therapies. Fumi is clearly the driving force, says Stephanie Snow Gebel, co-founder of the Snow Foundation, who about 10 years ago helped persuade him to forgo a plum job as department chair at a Japanese university and take over the Wolfram program at Washington University.

Patients could soonstart to reap the benefits. In 2016, Urano and colleagues started the worlds first clinical trial for the disease: a phase 1/2 study of dantrolene, an approved muscle relaxant. The molecule was a top performer when they screened 73 potential treatments for their ability to save cells with terminal ER stress. Dantrolene didnt improve vision in the 22 participants, including White, the scientists reported in an October 2020 preprint. But in some patients, beta cells appeared to be working better and releasing more insulin. The drug is safe, but Urano says it will need to be chemically tweaked to target its effects before future trials are warranted.

Researchers are pursuing other possible treatments targeting ER stress or calcium levels. In 2018, U.K. scientists launched a trial that will include 70 patients to evaluate sodium valproate, a therapy for bipolar disorder and epilepsy that, in the lab, prevents cells with faulty wolframin from dying. Last year, another compound that emerged from Uranos screens, the diabetes drug liraglutide, entered a clinical trial. Also last year, an experimental drug developed by Amylyx Pharmaceuticals for Alzheimers disease and ALS received orphan drug designation from the U.S. Food and Drug Administration for Wolfram syndrome because it curbs ER stress. That designation offers tax breaks and other incentives, and it will get trials started sooner, Urano says.

Ehrlich and her team have a candidate of their own that they have begun to test in rodents: the drug ibudilast, which is approved in Japan to treat asthma. The researchers found it reduces calcium levels in beta cells lacking wolframin and boosts their survival and insulin output. New screening projects may reveal still more candidates.

But Urano knows that even if a treatment receives approval, it would be only a Band-Aid for Wolfram syndrome. Hoping to develop a genetic cure, he and colleagues are introducing replacement genes into cells from patients and from mice engineered to replicate the disease. The researchers are endowing the cells with healthy copies of the gene for wolframin or the gene for a protein that reduces ER stress to determine whether they restore cellular function and reduce cell death. At INSERM, Delettre and colleagues are also evaluating whether directing a working gene into optic nerve cells can curtail vision loss in mice with faulty wolframin. The scientists are still gathering data, but early results suggest the treatment can halt the deterioration.

Urano and his collaborators have also turned to the genome editor CRISPR, deploying it to correct the gene defect in patients stem cells and then growing them into beta cells. When the researchers transplanted the revamped cells into mice with diabetes, the animals blood sugar returned to healthy levels, the team reported in April 2020 inScience Translational Medicine.

Stem cell biologist Catherine Verfaillie of KU Leuven is collaborating on the CRISPR research. But she notes that because the faulty wolframin gene affects so many tissues, researchers will have to figure out how to deliver the CRISPR components to most cells in large organs such as the brain and livera prospect she calls pretty daunting. Urano agrees, predicting that CRISPR-based Wolfram therapies might take 10 to 20 years to develop. The alternative approach, gene therapy, could reach clinical trials more quickly, in 3 to 10 years, he says, because researchers have more experience with gene therapy and have created several treatments that have already been approved for other illnesses.

Because it stems from a single genetic glitch, Wolfram syndrome could also help scientists tease out the role of the ER in more complex diseases, including neurological conditions, type 2 diabetes, and cancer. The ER also falters in those diseases, causing cells to die, but the mechanism is harder to discern because they stem from myriad genetic and environmental factors. In Alzheimers disease, for instance, neurons develop ER stress as misfolded proteins accumulate inside and outside the cells.

Besides deepening researchers understanding of other conditions, the research on Wolfram syndrome might even deliver candidate treatments. Everyone would be very excited if we can make advances in targeting ER stress in Wolfram syndrome, Oakes says. It would open up the whole field to doing this in other degenerative diseases.

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The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine