Category Archives: Gene Medicine

Before March 2020, many people saw pandemics as a thing of the past. Then came COVID-19. Scientists still do not know exactly where the virus that caused it SARS-CoV-2 came from, but it soon reached almost every country worldwide. Over 2 years, the virus has evolved, producing several variants. In this Special Feature, we look at the evolution of SARS-CoV-2 and ask what lessons scientists have learned.

In late 2019, there was a sudden increase in pneumonia cases in central China. By January 7, scientists had identified and isolated a previously unknown coronavirus, now designated SARS-CoV-2.

On March 11, 2020, the World Health Organization (WHO) declared COVID-19 a pandemic.

Now, 2 years on, authorities have recorded more than 458 million cases of COVID-19, the disease resulting from SARS-CoV-2. The disease has also played a role in the deaths of more than 6 million people.

However, the actual death toll may well be far higher than 6 million. According to a recent paper in The Lancet, the actual death toll may be at least three times that.

On December 29, 2019, experts linked four cases of pneumonia of unknown etiology to the Huanan Seafood Wholesale Market in Wuhan, central China.

On January 7, 2020, researchers isolated the causative agent, SARS-CoV-2, and on January 10, they sequenced its genome.

By January 2, 2020, doctors had confirmed that 41 people in a Wuhan hospital with severe respiratory illness had a SARS-CoV-2 infection. Of these individuals, 27 had had exposure to the seafood market.

Many coronaviruses exist, affecting both animals and people. Most cause infections with mild to moderate symptoms in the upper respiratory tract, such as colds.

In recent years, two coronaviruses SARS-CoV and MERS-CoV have caused more severe disease. SARS-CoV, which scientists identified in November 2002, was responsible for severe acute respiratory syndrome (SARS), which emerged in Asia. The Centers for Disease Control and Prevention (CDC) note that of the 8,096 people with a known SARS infection, 774 died. There have been no reported cases since 2004.

Scientists first identified Middle East Respiratory Syndrome (MERS), the disease that MERS-CoV-2 causes, in 2012 in Saudi Arabia. The mortality rate for MERS is high of every 10 people with the infection, three or four die. There continue to be occasional, localized outbreaks of this disease.

Both of these coronaviruses caused diseases with high fatality rates, but it was possible to contain the spread before they reached pandemic levels. So, were we ready for the next coronavirus?

Experts believe that SARS came from bats and that MERS crossed over to people from camels. However, for SARS-CoV-2, researchers have not all agreed on any of the many existing theories.

At first, people thought that SARS-CoV-2 might have come directly from bats. Scientists discounted that theory, though, as the spike protein on SARS-CoV-2 is very different from that on the coronaviruses present in bats.

Now, researchers think it is likely that the virus originated in bats but had an intermediate host between bats and people. A recent study which has not yet undergone peer review suggests that live mammals for sale at the Huanan Seafood Wholesale Market in Wuhan, the epicenter of early cases, might have been the intermediate host.

Another recent study also yet to undergo peer review that analyzed the evolution of SARS-CoV-2 suggests that SARS-CoV-2 emergence likely resulted from multiple zoonotic events. The researchers do not suggest what the intermediate animal hosts might be.

Alternatively, did SARS-CoV-2 escape from a laboratory in Wuhan, as some media outlets have suggested? The WHO has dismissed this theory as extremely unlikely.

So, there is still uncertainty about the origins of SARS-CoV-2. And this may be due, in some measure, to a lack of international cooperation, as Prof. Jonathan Stoye, a virologist at the Francis Crick Institute in London, United Kingdom, told Medical News Today.

In his opinion, one mistake was to start pointing fingers at China and blaming them for the origin of this virus. I think that, naturally, led to pushback from the Chinese [authorities].

He added: I absolutely believe in natural origins [of SARS-CoV-2], but the Chinese [authorities] could have made things easier if theyd opened up their books straightaway. They werent going to do that when they were being accused of being responsible [for the virus].

For almost a year, the original Wuhan variant of SARS-CoV-2 moved across the globe. Then, in late 2020, the number of COVID-19 cases increased rapidly in South East England, in the United Kingdom.

Researchers discovered that a new variant, which was 50% more transmissible than the original and had 17 unique mutations, was responsible. In December 2020, the WHO designated it B.1.1.7, or the Alpha variant.

Scientists have since identified many other variants, but the WHO has only designated five as variants of concern (VOC). The VOCs and the location of their initial identification are:

Each variant has different features. Some variants are more transmissible than others, and some are more virulent. It is these features that have caused the multiple waves of COVID-19.

The regular and rapid emergence of new variants in the past 2 years have made the course of the pandemic very unpredictable.

Dr. Arturo Casadevall, distinguished professor and chair of molecular microbiology and immunology and infectious diseases at the Johns Hopkins Bloomberg School of Public Health in Baltimore

Viruses mutate all the time. Each time they replicate, which they do frequently, their genetic material is copied. A mutation happens when part of the genetic material is copied incorrectly.

In a coronavirus, the genetic material is ribonucleic acid (RNA). An enzyme called RNA polymerase controls the replication, and it often makes errors. Most mutations create a virus that cannot replicate and spread among people. However, some mutations lead to a virus that can replicate: a variant.

A mutation might give the virus a selective advantage, such as better transmissibility or greater virulence. If it is more transmissible, the variant may spread faster and outcompete previous variants. This is what happened with the Alpha, Delta, and Omicron variants of the coronavirus.

Some situations give viruses more opportunities to mutate, as Dr. Christopher Coleman, assistant professor of infection immunology at the University of Nottingham, U.K., explained to MNT:

Viruses naturally mutate as they replicate, so in an immunocompromised host where the virus replicates more easily, there will be a correspondingly increased number of mutations.

Omicron has more than 50 mutations, of which some 30 are in the spike protein that the virus uses to gain entry to host cells. One theory suggests that it may have evolved in people with HIV, a virus that suppresses the immune system.

Moving between host species also increases the mutation rate. Dr. Coleman added that the [i]nfection of animals by humans will mean the virus then adapts to a new host, which involves mutations.

Domestic animals, such as cats, dogs, and ferrets, have had SARS-CoV-2 infections. The CDC notes that on one mink farm in Michigan, several animals contracted the virus, which then passed back to workers. On testing, the viral samples from the workers contained several mink-related mutations.

You are getting evolution occurring from different starting points. Whether they are occurring through immunosuppressed or immunocompromised patients, or whether they are happening through animals, or how, I dont know that we know, and I dont know that we will ever really know.

Prof. Jonathan Stoye

Decades of research into coronaviruses led to the rapid development of vaccines, many of them using new technologies. These have been incredibly effective in reducing the impact of COVID-19 and allowing society to regain some measure of normality.

But, as Prof. Stoye explained, [i]n retrospect, we have been lucky that it has been possible to make a vaccine against this particular virus, whereas for things like HIV [], we still dont have vaccines.

However, vaccines designed against one variant might be ineffective against another.

The evolution of SARS-CoV-2 variants upended many optimistic predictions made when the vaccines were rolled out in 2020.

Dr. Arturo Casadevall

Despite the evolution of variants, vaccines still guard against severe COVID-19, particularly in those who have received multiple vaccinations.

Despite suggestions that vaccines might even drive the evolution of new vaccine-resistant variants, this does not seem to be the case, as a recent report states: Given the emergence of immunity-evading variants even before vaccines were broadly deployed, it is hard to implicate vaccines or vaccine deployment strategies as the major drivers of immune evasion.

Prof. Stoye feels that vaccines will continue to be important. I suspect we will have to have yearly boosters of the vaccine, at least for the foreseeable future, he said.

And he expressed a hope that research might create more powerful vaccines:

It would be very nice if scientists could establish a pan-coronavirus vaccine that worked against multiple viruses. That has to be one of the hopes of the future that you will have a method of vaccination that will protect you against various viruses.

After 2 years, people are becoming tired of restrictions, feeling that the pandemic should surely be over. However, Prof. Stoye is one of many experts expressing concern that governments are removing COVID-19 testing and control measures too early.

One of the things Im frightened about is that we will, in fact, lose our ability to follow these processes as we stop testing and sequencing so much. [] As we test less, as we sequence less, we will lose that ability to recognize new variants in real time, he told us.

These things will come again. We need to realize that, and we need to have a response ready quickly. I think we need to be able to recognize very rapidly the appearance of new diseases this comes back to geopolitics.

Prof. Jonathan Stoye

This is not the first pandemic, and it is unlikely to be the last. Some aspects have been well-handled, while others have not, and the geopolitical debates will continue for years. At least vaccines are continuing to protect against severe illness and death from all variants.

Possibly the most important lesson is that it is crucial to address future disease outbreaks globally. Although people in high income countries have had ready access to vaccines and boosters, many African countries have yet to vaccinate even 10% of their population due to inequitable vaccine distribution.

The lack of widespread vaccination can also contribute to the development of new variants.

Prof. Stoye stressed the importance of global cooperation in countering pandemics:

The global aspects of this are the interesting and important ones. Whether those lessons will be learned, I dont know. [] I would hate to think that, suppose in 2 or 3 years down the track, we are living comfortably with this virus, and SARS-3 comes along or HIV5, and we have forgotten all the lessons we have learned. Its trying to retain that memory that is the important lesson.

For live updates on the latest developments regarding COVID-19, click here.

More:
2 years of COVID-19: Origins, variants, and the future - Medical News Today

At first glance, two 50-something women with breast cancer appear to have similar cases. But an article by Wilmot Cancer Institute experts points out that technically, only one woman is eligible for a newer, potentially lifesaving treatment due to slight differences in tumor markers.

The article raises questions about rules around using the latest therapies and illustrates how nuances in tumor biology can have a major influence on treatment choices. It also speaks to the critical need for consistent, high standards for pathology testing across the U.S.

Ruth O'Regan, MD

Co-author Ruth ORegan, M.D., a national thought-leader in breast cancer and executive at Wilmot, would like to see the U.S. follow Europe and loosen the limitations for the breast cancer treatment in question, known as CDK inhibitors.

We believe that restricting the use of these drugs is controversial and deserves more discussion, she said.

ORegan and David Hicks, M.D., a professor of Pathology and Laboratory Medicine who has devoted his career to innovations in breast tumor analysis, described two cases of breast cancer in postmenopausal women in a Grand Rounds article in the Journal of Clinical Oncology.

Both women were diagnosed with stage 2 breast cancer, which had begun to spread to the lymph nodes. Each woman faced a high risk of the cancer recurring after initial treatment was completed. Testing also showed that the hormones estrogen and progesterone were largely fueling each persons disease.

A key fact separated these Wilmot patients, however: Only one waseligible for CDK therapy, which has a proven survival advantage.

The reason? Her tumor had a higher level of a cancer-related gene known as Ki-67, indicating rapid reproduction of cancer cells.

A mixed bag of clinical trial data has shown that certain levels of Ki-67 in breast tumors support better outcomes for patients who are treated with CDK inhibitors. The FDA approved the use of CDK inhibitors for individuals whose tumors have Ki-67 levels of 20 percent or higher.

But, ORegan said, this leaves out women whose tumors have Ki-67 markers at 15-to-19 percent, for example, even though other factors in their cases may indicate that treatment with the drug would help.

One clinical trial in the U.S. does, in fact, support the use of the newer drug for tumors with lower levels of Ki-67, and Europes equivalent of the FDA approved the CDK treatment without limitations, ORegan noted.

David Hicks, MD

The lynchpin in the U.S. is that measurement of Ki-67 is notoriously inconsistent across hospital systems and clinical laboratories. Many institutions do not routinely check for this tumor marker although all breast cancer patients at Wilmot receive Ki-67 testing in optimal, standardized laboratory conditions, ORegan said.

It will take time to overcome the testing hurdle nationwide, Hicks and ORegan wrote, due to variability among practices and materials available.

Meanwhile, ORegan continues to assess cases on an individual basis, often in collaboration with Wilmots tumor board, and has achieved insurance approval for CDK therapy for a few patients that fell outside of current FDA eligibility requirements, she said.

CDK inhibitors are also available to women with stage 4 breast cancer; limitations only exist for earlier-stage disease. Breast cancer patients should ask their doctors about this newer form of treatment, O'Regan said.

ORegan is the Charles A. Dewey Professor and Chair of Medicine at the University of Rochester Medical Center, as well as the Associate Director of Wilmots education and mentoring program. Hicks has studied tumor markers in breast cancer for several years at URMC and helped to develop national guidelines on estrogen-receptor and HER2 gene testing.

More:
What is Ki-67 in Breast Cancer? It Can Spell the Difference in Treatment Options - URMC

The clinical trial of an old antibiotic for a new purpose is offering hope to thousands of patients with drug-resistant breast cancer whose early remissions have given way to resurgent tumors.

Novobiocin was once used in humans but today is largely limited to animal applications, such as treating mastitis in dairy cows. Its trial as a cancer drug is expected to begin this spring at the Dana-Farber Cancer Institute. If it proves effective, the fact that its still manufactured and already approved in people should allow it to become rapidly available to patients, trial organizers say.

While the discovery of a potentially powerful anti-cancer agent in a veterinary niche may seem serendipitous, it sits at the end of a long chain of discovery. That chain has already deepened our understanding of a group of well-known cancers breast, ovarian, pancreatic, and prostate that together afflict more than 600,000 people and kill about 140,000 each year. Research in recent decades has revealed that half of ovarian cancers, 15 percent of breast and prostate, and 10 percent of pancreatic cancers share a flaw in their DNA repair mechanism that make them susceptible to drugs like novobiocin. The work has also shown that they are related to a rare, often fatal childhood disease called Fanconi anemia.

In fact, the discoveries trace back to the suffering of Fanconi anemia families, hinging on a key moment two decades ago at a Maine summer camp where children suffering Fanconi anemia offered their blood for science. The distressing irony is that the resulting treatments, which now offer hope to thousands of cancer sufferers, are not only ineffective for Fanconi children, theyre potentially fatal.

This is a terrible disease, said Alan DAndrea, who heads Dana-Farbers Susan F. Smith Center for Womens Cancers and who has worked on Fanconi anemia since the early 1990s. The children have birth defects. They have a strong disposition to developing anemia and then leukemia. And their cells are super-sensitive to DNA damaging agents.

The condition is rare and genetic. As a recessive disease, a child must inherit two copies of a Fanconi gene one from each parent for the condition to develop. It affects just one in 130,000 U.S. births each year, which translates to about 28 children, many of whom are afflicted with short stature, microcephaly, abnormal facial features, or other birth defects. Anemia tends to emerge around age 7, often followed by acute myeloid leukemia and eventually bone marrow failure. Many patients dont live to adulthood, and the average age of death in 2000 was 30.

Sometimes the most important discoveries in science are obvious when you hit them.

DAndrea, who also directs Dana-Farbers Center for DNA Damage and Repair, became interested in Fanconi anemia in a roundabout fashion. While he was an undergraduate in Quincy House at Harvard College in the late 1970s, his mother developed breast cancer. She recovered, but the episode sparked an interest that led DAndrea to the lab of William Haseltine at Dana-Farber, then called the Sidney Farber Cancer Institute. Haseltine was studying DNA repair, a subject that grabbed DAndreas interest. The pair pioneered using new tools of gene sequencing to investigate DNA damage and repair. Later, while studying at Harvard Medical School, DAndrea became interested in leukemia and then, as an assistant professor at the Medical School and Dana-Farber in the early 1990s, in Fanconi anemia. DAndrea thought that a better understanding of the condition might not only help those afflicted with it, but also produce insights broadly applicable to leukemias, which affect 61,000 Americans and kill 24,000 per year.

DAndreas efforts were met with enthusiasm. Families of Fanconi sufferers often struggle alone, trying to manage a condition frequently unrecognized by physicians and ignored by researchers. The Fanconi Anemia Research Fund was just a year old when DAndrea got involved in 1990, but it was already beginning to support research on the condition.

I first met Alan in the year 1990; our daughter Katie died in 1991, said Lynn Frohnmayer, one of the funds founders. We were advised to consult with a DNA expert at Harvard about her condition, so we talked to him for a long time. Its hard to remember a time when he hasnt been part of what we were doing.

Community was no less important than research to Fanconi families, who gathered annually at a summer camp on Maines Sebago Lake.

Id go to this camp every summer and teach the families what we knew about the disease, said DAndrea, the Alvan T. and Viola D. Fuller American Cancer Society Professor of Radiation Oncology. At the same time, we would collect blood samples from the children or the parents, and sometimes skin biopsies. We assumed at this point that if we could clone the genes that were involved for Fanconi anemia, we might discover something very fundamental about why these children get leukemia, and also discover some kind of DNA repair pathway.

DAndreas method identifying defective Fanconi genes and using them to understand the function of the normal gene took time, but slowly revealed the diseases genetic underpinnings. As Fanconi genes were discovered scientists have so far identified 23 DAndreas lab demonstrated how the proteins they encode work together in a biochemical pathway required for DNA repair.

We figured out that these genes probably work together in some kind of a genetic DNA repair pathway and that was exciting, DAndrea said. But it was a backwater field of cancer research. I would give talks on Fanconi anemia at big meetings and thered be 12 people in the audience, and theyd be reading the newspaper, not paying attention.

In the early 2000s, DAndrea was at the camp drawing blood from an 11-year-old girl who had recently developed leukemia. He was talking with her mother, who was in her 30s, and noticed that her arm was in a sling. When she said shed had a mastectomy after a breast cancer diagnosis, his interest was piqued.

In the mid-1990s, researchers had identified mutations in two genes, BRCA1 and BRCA2, that increase the risk of early breast cancer. The BRCA genes are tumor suppressors that play a role in DNA repair. In most women, healthy BRCA genes prevent tumors by keeping DNA functioning properly. In women who inherit mutated genes, faulty DNA repair opens the door to tumor growth.

Suddenly, this rare disease, Fanconi anemia, and this rare pathway that we have been studying crashed into breast cancer and ovarian cancer research.

DAndreas work over the prior decade had pointed to faulty DNA repair as a cause of Fanconi anemia, so when he heard the young mothers story, something clicked. He tracked down the girls father and asked about his family history. The man said he had been healthy, but that his mother had died of ovarian cancer.

After DAndrea raced back to the lab, he and colleagues examined DNA from the girls samples. They found that she had two copies of a faulty breast cancer gene BRCA2 one inherited from each parent.

Suddenly, this rare disease, Fanconi anemia, and this rare pathway that we have been studying crashed into breast cancer and ovarian cancer research, DAndrea said. And not only those cancers in the general population, but BRCA2 and, subsequently, BRCA1, extremely important cancer-susceptibility genes. We call it today the Fanconi anemia/BRCA pathway.

In hindsight, the connection seems obvious, DAndrea said.

We had been studying all these other Fanconi anemia genes and we knew that process had something to do with DNA repair. It made sense. Sometimes the most important discoveries in science are obvious when you hit them. You realize this child with Fanconi anemia had mutations in the BRCA gene thats why this child got cancer. When you get cancer as a child, you get leukemia, you dont get breast cancer, you dont get ovarian cancer. Leukemia that was a very severe form of BRCA deficiency.

Subsequent research found that the Fanconi anemia/BRCA pathway was disrupted not only in some breast and ovarian cancers, but also in a significant number of prostate and pancreatic cancers.

Not only did these children have Fanconi anemia, but their parents and grandparents have other cancers: breast, ovarian, and we now know prostate cancer and pancreatic cancer, DAndrea said. These poor families, they have children with Fanconi anemia, a fatal childhood disease, and their older siblings, parents, older family members who have a mutation in one of the genes, they get breast, ovarian, prostate, pancreatic cancer.

The discovery of a common DNA repair pathway linking Fanconi anemia to deadly cancers brought immediate attention to the condition and to DNA repair as a common feature of some cancers. It also provided a new way to treat them. Subsequent research showed that cancers caused by BRCA mutations become more dependent on other DNA repair pathways. Drugs called PARP inhibitors were developed to attack a key protein in a backup DNA repair pathway used by BRCA-deficient tumors. PARP inhibitors rapidly disrupt tumor growth, leading to dramatic remissions, but only for a time.

A year to 18 months after PARP treatment begins, tumors often recur as the cancer mutates to use a third DNA repair pathway, which relies on a protein called polymerase theta. To counter that move, DAndrea turned to modern drug-screening techniques, examining thousands of compounds effectiveness against polymerase theta. Novobiocin rose to the top. Subsequent trials in mouse models confirmed its effectiveness, which led to plans for the spring trial.

Should novobiocin prove an effective tool, researchers will shift to examining how tumors respond over time and whether they can eventually evade the drugs effects by using one of the bodys other DNA repair pathways, according to Geoffrey Shapiro, Dana-Farbers senior vice president for developmental therapeutics and a professor of medicine who is collaborating with DAndrea on the novobiocin trial. Having an additional drug will also let researchers explore combination therapies that might be harder for tumors to overcome. Such therapies are already extending the lives of many patients and, in some cases, reducing cancer to a chronic disease.

Ultimately, we will be combining all these DNA repair inhibitors to try to maximize response up front if its safe enough to do that, Shapiro said. This is our next decade of work.

Fanconi anemia remains a target for DAndrea and other researchers. Thanks to recent advances, including improved survival rates for bone-marrow transplants, more patients are living into their 30s or later. This is good news for families, but the threat of cancer is ever-present, and comes with a cruel twist. While treatments such as PARP and novobiocin grew out of Fanconi-related science, the key difference between Fanconi patients and others with cancer makes those treatments not only useless but potentially deadly for people with the condition.

For most cancer patients, the DNA repair defect that is vulnerable to PARP inhibitors and, potentially, novobiocin is in their tumor cells, which creates targets for treatment. In Fanconi patients, the defect is present throughout their bodies, meaning that the inhibitors would attack all their cells, not just cancerous ones. Frohnmayer said chemotherapy and radiation therapy are also dangerous for Fanconi patients, whichlimits cancer-fighting optionstoa heavy emphasis on early detection and surgery while the search for other treatments continues.

The first gene was discovered in 1992, so we were in the dark. All we had were these horrible statistics, Frohnmayer said. Today its much more hopeful. People know that getting through the bone-marrow-failure part of the problem is at least a possibility, maybe even a likelihood. Were working really hard on the cancer problem. And you can at least have the hope that, by the time your child is in danger, theres going to be a better answer than we have today.

Sign up for daily emails to get the latest Harvardnews.

See original here:
Hope for breast cancer patients, but with a cruel caveat - Harvard Gazette

FRIDAY, March 11, 2022 (HealthDay News) -- A one-time infusion of betibeglogene autotemcel (beti-cel) gene therapy yields high levels of transfusion independence in children and adults with transfusion-dependent -thalassemia and a non-0/0 genotype, according to a study published in the Feb. 3 issue of the New England Journal of Medicine.

Franco Locatelli, M.D., Ph.D., from the University of Rome, and colleagues conducted an open-label phase 3 study to examine the efficacy and safety of beti-cel in adult and pediatric populations with transfusion-dependent -thalassemia and a non-0/0 genotype. Twenty-three patients were enrolled, underwent myeloablation with busulfan, and then received intravenous beti-cel. Patients were followed for a median of 29.5 months.

The researchers found that 20 of the 22 patients (91 percent) who could be evaluated had transfusion independence, including six of seven (86 percent) who were younger than 12 years. During transfusion independence, the average hemoglobin level was 11.7 g/dL. In patients with transfusion independence, the median level of gene therapy-derived adult hemoglobin with a T87Q amino acid substitution was 8.7 g/dL at 12 months after beti-cel infusion. Four patients had at least one adverse event considered to be related or possibly related to beti-cel; all except one were nonserious. There were no cases of cancer.

"These data suggest that in most patients with transfusion-dependent -thalassemia and a non-0/0 genotype, one-time infusion of beti-cel is potentially curative through transfusion independence and the attainment of near normal hemoglobin levels," the authors write.

Several authors disclosed financial ties to biopharmaceutical companies, including Bluebird Bio, which funded the study.

Abstract/Full Text (subscription or payment may be required)

Read more:
Gene Therapy Potentially Curative for -Thalassemia - Consumer Health News | HealthDay - HealthDay News

Specific comorbidities and conditions have been associated with severe COVID-19, including diabetes, obesity, and, of course, older age. But researchers have now identified 16 new genetic variants associated with severe COVID-19. For that and more research stories, continue reading.

16 Genetic Variants Associated with Severe COVID-19

Investigators with theUniversity of Edinburghanalyzedthe genomes of 57,000 people, part of the GenOMICC consortium, a global collaboration to study genetics in critical diseases. They identified 16 new genetic variants associated with severe COVID-19 and sequenced the genomes of 7,491 patients from 224 intensive care units in the U.K. That DNA was compared with 48,400 other people who did not have COVID-19. They were participants inGenomics Englands 100,000 Genomes Project and another 1,630 people who had mild COVID-19. The findings are published inNature.

Our latest findings point to specific molecular targets in critical COVID-19, said Professor Kenneth Baillie, the projects chief investigator and a Consultant in Critical Care Medicine at the University of Edinburgh. These results explain why some people develop life-threatening COVID-19, while others get no symptoms at all. But more importantly, this gives us a deep understanding of the process of disease and is a big step forward in finding more effective treatments.

In addition to the 16 new gene variations, they confirmed seven other genetic variations that were already linked with severe COVID-19. Part of their findings was a single gene variant that can disrupt interferon alpha-10, a key messenger molecule in immune system signaling. This variant alone was enough to increase a patients severe disease risk. Another variation is Factor 8, which is important to blood clotting, and was connected to critical COVID-19.

Nanoparticle decreases Scleroderma Skin and Lung Scarring

Researchers withMichigan Medicine University of Michiganidentifieda unique macrophage, a type of immune cell, that plays a significant role in the chronic inflammation and scarring seen in the lungs and skin of scleroderma patients. The macrophage, dubbed MARCO+, was isolated in people with the disease, which is rare and affects about 70,000 people in the U.S. They then, working with laboratory mice, injected the animals with biodegradable PLG (lactic-co-glycolic acid) nanoparticles that targeted MARCO+ inflammatory cells. This appeared to prevent the skin and lung fibrosis in the mice associated with the disease. The team theorizes that the MARCO+ cells are activated in scleroderma, circulate in the bloodstream, move to tissues, and cause scar formation.

A Predictive Model for Rheumatoid Arthritis

Scientists fromTokyo Medical and Dental Universitydevelopeda genomic model to predict the progression of rheumatoid arthritis. They utilized data from a genome-wide association study (GWAS) of R.A. susceptibility. They then developed a polygenic risk score (PRS) and tested it to predict radiographic progression in people with rheumatoid arthritis. Earlier studies identified specific genetic factors for R.A. progression, including anti-citrullinated protein antibodies (ACPAs) and variants in the human leukocyte antigen (HLA) region of the chromosome that regulates the immune system. Those are useful but not considered robust. Their new analysis found that patients with a higher PRS had a higher risk of severe progression, particularly in people who were younger at the onset.

microRNAs Unique to Human Beings

Student researchers atJohn Jay College of Criminal Justiceidentifiedhuman microRNA genes that are not found in any other primate species. They believe they may have had a significant role in the evolution of human beings. They found at least three families of microRNA genes on chromosome 21. They leveraged genome alignment tools and compared the most recent versions of human and chimpanzee genomes, working to find genetic elements unique to humans.

On chromosome 21, they found a large region of unique DNA called 21p11, which harbors several orphan microRNA genes. The long arm of human chromosome 21 matches up well with other ape species, but the short arm aligns poorly. The microRNAs in that region, specifically miR3648 and miR6724, probably evolved since the chimpanzee and human lineages split probably in the last seven million years.

Organs Age at Different Rates

Youre only as old as you feel, right? Well, maybe. Butnew researchout of theBeijing Genomics InstituteandChina National GeneBankin Shenzhen, China, found that different organs and systems have different ages from a biological perspective.

Using biomarkers, statistical modeling, and other tools, they analyzed the aging in 4,066 volunteers who supplied blood and stool samples, facial skin images, and to undergo physical fitness examinations. They were between the ages of 20 and 45 years. They measured 403 features: 74 metabolomic features, 34 clinical biomarkers, 10 electroencephalography features, 16 facial skin features, and 210 gut microbiome features. They then classified them into nine categories, including cardiovascular-related, renal-related, liver-related, sex hormone, facial skin, nutrition and metabolism, immune system, physical fitness-related and gut microbiome features. They found that the biological ages of different organs and bodily systems had diverse correlations. They also examined single nucleotide polymorphisms (SNPs) and identified certain genetic changes associated with aging-related pathways.

FDA-Approved Drug Halts RAS-Based Tumor Growth

Researchers with theUniversity of California, San Franciscousedan FDA-approved drug to stop tumor growth in cancers driven by mutations in the RAS gene. RAS mutations are typically difficult to treat and make up about one in four cancer deaths. They found that cancer cells require a reactive form of iron called ferrous iron. They then modified an anticancer drug to work only on these iron-rich cells, allowing other cells to function normally. They focused their research on RAS-mutated pancreatic and gastrointestinal cancers. Cobimetinib and similar drugs are effective at blocking the excessive growth stimulated by RAS mutations and do the same thing in non-cancer tissue, which causes serious side effects that lead many patients to discontinue treatment. They modified cobimetinib to have a small molecule that senses ferrous iron, which essentially shuts cobimetinib off until it meets up with ferrous iron in the cancer cells.

By removing toxicity from the equation, youre talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic, said Adam Renslo, a pharmaceutical chemist at UCSF and co-author of the study. That would be the home run for this approach.

See original here:
Research Roundup: Genetic Variants Associated with Severe COVID-19 and More - BioSpace

NEW YORK

U.S. regulators on Monday cleared the way for the sale of beef from gene-edited cattle in coming years after the Food and Drug Administration concluded the animals do not raise any safety concerns.

The cattle by Recombinetics are the third genetically altered animals given the green light for human consumption in the U.S., after salmon and pigs. Many other foods already are made with genetically modified ingredients from crops like soybeans and corn.

The cattle reviewed by the FDA had genes altered with a technology called CRISPR to have short, slick coats that let them more easily withstand hot weather. Cattle that arent stressed by heat might pack on weight more easily, making for more efficient meat production.

The company did not say when home cooks or restaurants might be able to buy the beef, but the FDA said it could reach the market in as early as two years.

Unlike the salmon and pigs, the cattle did not have to go through a years-long approval process. The FDA said the cattle were exempt from that because their genetic makeup is similar to that of other existing cattle and the trait can be found naturally in some breeds.

Dr. Steven Solomon, director of the FDAs Center for Veterinary Medicine, said the agencys review of Recombinetics cattle took several months. He said theres no reason that meat from the animals or their offspring would need to be labeled differently.

Solomon said a genetically altered animal marketed as having a special advantage such a higher than normal ability to withstand heat might need to go through the full approval process.

This opens up a completely different pathway, he said, noting the decision could be encouraging for other biotech companies, many of which are small startups.

The gene-edited trait in the Recombinetics cattle can be passed down so semen and embryos from them could be used to produce offspring with the same shorter coats.

The trait will make beef production more sustainable and could improve animal welfare in warmer climates, Recombinetics said in a statement without providing further details.

Greg Jaffe, who specializes in biotechnology at the Center for Science in the Public Interest, said the FDAs announcement made clear it wasnt exempting all gene-edited animals from the longer approval process.

They reinforce the idea that this is a case-by-case review, Jaffe said.

He said the agency should be more transparent about the review process so people know whats in the works. That could lead to better public acceptance and minimize any potential economic disruptions from global trade, since other countries might consider the animals genetically modified foods that need to be labeled, he said.

Jaydee Hanson, of the Center for Food Safety, said the agency should keep track of the animals for several generations to ensure there arent any unintended issues.

The genetically modified pig is intended mainly for medical purposes, not meat, according to the company that developed it. The firm recently provided a pig heart that was transplanted into a dying man in an experimental surgery.

The company behind the modified salmon said the fish are being sold to distributors in the Midwest and Northeast.

Alison Van Eenennaam, an animal geneticist at UC Davis who has worked with Recombinetics, said requiring all companies to go through the lengthy approval process could end the possibility of commercializing gene-edited animals in the U.S.

For the gene-edited cattle cleared by the FDA, she said it could take about two years for beef from the offspring to reach the market.

Once the semen is used to create embryos, she said gestation would take about nine months and the resulting calves might be slaughtered after about 10 months. She noted the market isnt limited to the U.S., given the way cattle are bred.

Lets face it, bull semen goes all over the world, she said.

Continued here:
Gene-edited beef cattle receive regulatory clearance in U.S. - Los Angeles Times

Image of the female mouse that gave birth via asexual reproduction.PNAS

Chinese scientists have managed to get a female mouse to produce live viable offspring from an unfertilized egg thanks to gene editing. This is in theory the first case of a mammal that has achieved asexual reproduction, technically known as parthenogenesis or virgin creation, which is common in many insects and reptiles, and even in some bird species. But until very recently, it was believed that mammals could not reproduce without male genetic material.

In 2004, the world learned about Kaguya, a mouse born without the need for sperm or sexual reproduction. Mammals have two copies of each gene in their genome one from their mother and one from their father. When a sperm cell penetrates an egg, something called genomic imprinting happens, meaning that some genes behave differently depending on whether they were inherited from the father or the mother.

Many of the genes involved in the process have to do with growth, which may mean, for evolutionary reasons, that the fathers imprint favors growth in order to have larger offspring, while the mothers may do the opposite to ensure that the pregnancy can be brought to term. Some of these genes are also associated with a greater risk of suffering cancer, among other diseases. The Japanese scientists who created Kaguya used two eggs: one worked as the real egg while the other one imitated the sperms contribution. The result was a baby that was born to two females.

The new study, led by Yanchang Wei, a reproductive medicine researcher at Ren Ji Hospital in Shanghai, took the concept a step further, creating a pregnancy from a single, unfertilized egg. Chinese scientists used a gene-editing technique very similar to CRISPR, which is used in medicine and biotechnology. The authors of the study used the tool to imitate the genomic imprint in seven different points of the genome of an egg that already had two copies of each gene. This triggered a biochemical process that was the equivalent of fertilization: the egg grew from one single cell to a 140-cell blastocyst.

Theyve managed something fascinating but terribly inefficient

The scientists implanted 192 embryos made with this technique in as many female mice, but only one of them gave birth to a healthy pup that survived, although it weighed less than average. Two others died shortly after birth. The survivor reached adulthood and was able to reproduce normally.

In their study, published in the scientific journal PNAS, researchers noted that parthenogenesis can be achieved by targeted epigenetic rewriting of multiple critical imprinting control regions. The team believes that the technique could be perfected to achieve a higher live birth success rate. The success of parthenogenesis in mammals opens many opportunities in agriculture, research, and medicine, says the study.

It is a groundbreaking study, agrees Lluis Montoliu, a researcher at Spains National Research Council (CSIC), who underscored that the eggs had a copy of their genes and another copy taken from another egg that came from a different species of mouse, allowing scientists to check the effects of the editing. In theory at least, further perfecting this technique might allow a woman to have children on her own, admits Montoliu. But the researcher adds that its use on humans is a very long way off. The main thing now is to follow the lives of these mice born through these techniques, and see whether they have problems with their lives and reproduction. There are still a lot of unanswered questions.

Theyve managed something fascinating but terribly inefficient, adds David Haig, a researcher at Harvard University who developed a theory about genomic imprinting several years ago.

English version by Susana Urra.

See original here:
Female mouse gives birth without sex or sperm - EL PAS in English

The first person to have his failing heart replaced with that of a genetically altered pig in a groundbreaking operation died Tuesday afternoon at the University of Maryland Medical Center, two months after the transplant surgery.

David Bennett Sr., who lived in Maryland, was 57. He had severe heart disease, and had agreed to receive the experimental pigs heart after he was rejected from several waiting lists to receive a human heart.

It was unclear whether his body had rejected the foreign organ. There was no obvious cause identified at the time of his death, a hospital spokeswoman said.

Hospital officials said they could not comment further on the cause of death, because his physicians had yet to conduct a thorough examination. They plan to publish the results in a peer-reviewed medical journal.

Dr. Bartley Griffith, the surgeon who performed the transplant, said the hospitals staff was devastated by the loss of Mr. Bennett.

He proved to be a brave and noble patient who fought all the way to the end, Dr. Griffith said. Mr. Bennett became known by millions of people around the world for his courage and steadfast will to live.

The heart transplant was one of a number of pioneering procedures in recent months in which organs from genetically altered pigs were used to replace organs in humans. The process, called xenotransplantation, offers new hope for tens of thousands of patients with ailing kidneys, hearts and other organs, as there is an acute shortage of donated organs.

Mr. Bennetts transplant was initially deemed successful. It is still considered a significant step forward, because the pigs heart was not immediately rejected and continued to function for well over a month, passing a critical milestone for transplant patients.

Some 41,354 Americans received a transplanted organ last year, more than half of them kidneys, according to the United Network for Organ Sharing, a nonprofit that coordinates the nations organ procurement efforts.

But there is a dire shortage of organs, and a dozen or more people on waiting lists die each day. About 3,800 Americans received human donor hearts last year as replacements, more than ever before, but demand remains high.

Scientists have been trying to produce pigs whose organs would not be rejected by the human body, a research effort that has picked up steam over the past decade because of new gene editing and cloning technologies.

New York surgeons announced in October that they had successfully attached a kidney grown in a genetically altered pig to a brain-dead human patient, finding that the organ worked normally and produced urine for 54 hours.

In January, surgeons at the University of Alabama at Birmingham reported that they had for the first time successfully transplanted kidneys from a genetically modified pig into the abdomen of a 57-year-old brain-dead man. The kidneys functioned and produced urine for three days.

U.A.B. surgeons said they hoped to launch a small clinical trial with live human patients by the end of the year.

Shortly after Mr. Bennetts heart surgery in January, The Washington Post reported that he had a criminal record stemming from an assault 34 years ago, in which he repeatedly stabbed a young man in a fit of jealousy, leaving him paralyzed.

The victim, Edward Shumaker, spent two decades in a wheelchair, paralyzed from the waist down, and suffered numerous medical complications including a stroke that left him cognitively impaired before he died in 2007 at age 40, according to his sister, Leslie Shumaker Downey, of Frederick, Md.

Mr. Bennetts son, David Bennett Jr., who was a child at the time of the stabbing, has said that he does not want to discuss his fathers past, and emphasized that his father was contributing to medical science by undergoing the experimental transplant and hoped to potentially save patient lives in the future.

The heart given to Mr. Bennett came from a genetically altered pig provided by Revivicor, a regenerative medicine company based in Blacksburg, Va.

The pig carried 10 genetic modifications. Four genes were knocked out, or inactivated, including one that encodes a molecule that causes an aggressive human rejection response.

Another gene was also inactivated to prevent the pigs heart from continuing to grow after it was implanted. In addition, six human genes were inserted into the genome of the donor pig modifications designed to make the pigs organs more tolerable to the human immune system.

On New Years Eve, the Food and Drug Administration granted an emergency authorization for the experimental surgery, which was done a week later.

The transplanted heart performed well initially, and there were no signs of rejection for several weeks. Mr. Bennett spent time with his family, did physical therapy and watched the Super Bowl, hospital officials said.

But he was not discharged, and several days ago his condition started to deteriorate, hospital officials said.

His son issued a statement thanking the hospital and staff for their exhaustive efforts on behalf of his father.

We hope this story can be the beginning of hope and not the end, Mr. Bennett said. We also hope that what was learned from his surgery will benefit future patients and hopefully one day, end the organ shortage that costs so many lives each year.

Read the original post:
Patient Who Recieved Groundbreaking Pig Heart Transplant Dies - The New York Times

LONDON--(BUSINESS WIRE)--Ixaka Ltd, an integrated cell and gene therapy company, announces that Advanced Therapy Medicinal Product (ATMP) classification has been granted by the European Medicines Agency (EMA) for its Chemically Encapsulated Lentiviral vector for Targeted In Vivo CAR T-cell therapy (CELTIC-19) targeted nanoparticle (TNP) product.

ATMP status was granted to CELTIC-19 due to its potential as a gene therapy medicinal product that targets specific cells and expression of the gene of interest directly within the patients body. Such an approach makes it possible to eliminate all the ex vivo stages of genetic modification, that are required for the production of currently marketed cell therapy products.

CELTIC-19 is Ixakas lead TNP program for CD19 haematological malignancies. It consists of a polymer nanoparticle encapsulating a bald lentiviral vector encoding for a T-cell specific promoter and the chimeric antigen receptor (CAR). The nanoparticle is coated with a CD3 binding molecule allowing in vivo targeting and transduction of the T-cells. The construct can then be infused systemically into the bloodstream to target and genetically modify T-cells within the body. This approach allows the generation of CAR T-cells which are potentially more efficacious, safer, and considerably less expensive to produce than established CAR T-cell therapies, which have been shown to be effective and have been approved for use in CD19-malignancies.

CELTIC-19s numerous advantages over established ex vivo CAR T-cells therapies, include but are not limited to its high specificity and transduction efficiency, retreatment possibility, no cytokine requirement and persistent expression.

Gilbert Wagener, Senior Vice President, Chief Medical Officer at Ixaka commented:

TNP-based in vivo CAR T-cell therapies such as Ixakas represent a significant advance over recently approved ex vivo CAR T-cell therapies, and hold the promise of delivering more effective, universal, and safer treatment option for patients. It is great to see this potential recognized by the Europeans Medicine Agency.

Joe Dupere, CEO at Ixaka commented:

Our nanoparticle-based in vivo gene delivery technology is ideally positioned to deliver on the promise of in vivo CAR-T therapies to transform cancer treatment without the need for costly dedicated manufacturing sites for T-cell modification. The designation of CELTIC-19 as an Advanced Therapy Medicinal Product further signifies its potential as a ground-breaking new treatment option and is an important step on our continued journey.

About Ixaka

Ixaka is a cell and gene therapy company focused on using the natural powers of the body to cure disease.

Ixakas proprietary technologies enhance the naturally therapeutic power of cells by increasing the presence of curative cells at the site of disease, or by directly modifying cells within the body to improve disease targeting and boost their restorative effect.

Ixakas technologies concentrated multi-cell therapies and nanoparticle therapeutics demonstrate potential for the treatment of a broad range of serious diseases across oncology, cardiovascular, neurological and ocular diseases, and genetic disorders.

Ixaka has offices in London, UK with R&D and manufacturing operations in Seville, Spain and Paris, France and additional manufacturing capability in Frankfurt, Germany.

For more information, please visit http://www.ixaka.com

Connect with us: Twitter: https://twitter.com/ixaka_Ltd; LinkedIn: https://www.linkedin.com/company/ixaka-limited/

Here is the original post:
CELTIC-19 Granted Advanced Therapy Medicinal Product Classification by European Medicines Agency - Business Wire

In the United States, 1 in 10 people has type 2 diabetes. Someone dies every 36 seconds from cardiovascular disease (CVD) in the U.S., and CVD causes one-third of all deaths worldwide.

Both conditions may develop slowly, and the symptoms are not always evident. Doctors assess a persons risk of developing them by taking a patient history and observing current lifestyle factors.

Now, a study led by Prof. Dr. Chris Lauber, of Twincore in Germany, has shown that lipids in blood plasma can predict future risk of type 2 diabetes and CVD.

The method known as lipidomic profiling can provide a quantitative measurement of risk long before symptoms develop.

The authors of this study have added to the growing evidence that lipidomics profiling could very well usher in the next generation of detection of cardiovascular diseases as well as diabetes.

Dr. Suneet Singh, Medical Director of CareHive.

The longitudinal study included just over 4,000 healthy, middle-aged Swedish people from the Malm Diet and Cancer-Cardiovascular Cohort.

Participants ranged from 4668 years at the start of the study. Around 10% had a body mass index (BMI) of more than 30.

The researchers took one baseline blood sample from each participant. They then centrifuged these blood samples to separate out the plasma for analysis.

Researchers measured concentrations of 184 different lipids in the blood plasma using mass spectrometry. They used these lipidomic profiles to calculate risk scores and assign participants into one of six risk groups.

Dr. Singh told Medical News Today the study could add to previous methods of assessing risk:

This new approach allows for a novel framework of risk stratification which also allows for enhancement when used in conjunction with the measurement of standard clinical variables.

He did, however, note that there was little diversity in the study population: It is advisable to continue to expand upon this research by increasing the patient population to include several more variables. This includes different patient ages, racial groups, ethnicities, and physical activity levels.

The researchers followed up participants for more than 20 years from baseline assessments made between 1991 and 1994. In that time, 13.8% of the cohort developed type 2 diabetes, and 22% developed CVD.

For those in the highest risk groups, these values rise to 37% for developing type 2 diabetes and 40.5% for developing CVD as compared to the group averages above.

People in the lowest risk groups had a decreased risk of developing both conditions.

The researchers also found that people with high lipid risk scores had a much greater likelihood of developing obesity during the follow-up period. Obesity is a risk factor for both type 2 diabetes and CVD.

The authors suggest that this risk-score-based approach could indicate the risk of both type 2 diabetes and CVD many years before disease onset.

[T]his earlier disease detection occurs at a time where the disease has not become clinically evident. As a result, researchers and clinicians can now take on diseases from a more proactive preventive lens and not simply one that starts at the treatment stage, Dr. Singh commented.

Using mass spectrometry to measure blood plasma lipids is quick, relatively inexpensive, and gives quantitative results.

The authors of this study suggest that it could identify lipids that contribute most to the risk of developing subsequent health conditions and, potentially, lead to new drug treatments.

Dr. Singh told MNT: Research [] demonstrated in this paper helps to advance the field of clinical mass spectrometry as a whole by continuing to demonstrate the potential for earlier disease detection in advance of conventional means.

The authors stress that further research is needed to verify their hypothesis and demonstrate how informative the plasma lipidome is for health and disease.

The lipidome may provide insights much beyond diabetes and cardiovascular disease risk.

Prof. Chris Lauber, lead author of the study.

So, this simple test could tell people their risk of developing both type 2 diabetes and CVD. By making diet and lifestyle changes, they may then be able to decrease that risk.

More here:
Blood test may predict long-term risk of diabetes and heart disease - Medical News Today