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Groundbreaking cancer research helps shed light on recently identified syndrome

Ayden Isaacs, 15, (middle) walks along the Mississippi River in St. Louis County with his mother, Jennifer Isaacs, and his father, Michael Isaacs. Ayden Isaacs was diagnosed with DNMT3A Overgrowth Syndrome in 2015 at Washington University School of Medicine in St. Louis. Children and young adults with the rare genetic disease may have physical and intellectual disabilities and an increased risk for blood cancers, including acute myeloid leukemia (AML). Aydens clinical samples have helped researchers learn more about his condition and AML.

In 2008, a team of scientists at Washington University School of Medicine in St. Louis became the first to decode the DNA of a patients cancer cells and trace the disease to its genetic roots. The patient, a woman in her 50s, suffered from acute myeloid leukemia (AML), an aggressive and often deadly cancer of the blood and bone marrow. The findings garnered the research team worldwide acclaim and paved the way for more personalized approaches for the treatment of cancer based on the clusters of mutations in patients tumors.

One of the most unusual mutations discovered in that patients AML cells was in the gene DNMT3A. The gene had never been linked to cancer, so the significance of the genes mutations was unknown. But it was a fascinating candidate gene to consider. DNMT3A was known to encode an enzyme that can methylate DNA at very specific places in the genome, a process that can change patterns of gene expression and that was known to be very important for normal development.

In the year that followed, the Washington University team sequenced the DNMT3A gene in 280 additional AML patients and found that it was indeed one of the most common initiating mutations for this disease and that mutations in one particular site, at the 882nd amino acid in the DNMT3A protein, was more common than all of the others. This hot spot for mutations suggested that something special was going on there, and further studies from the lab of Timothy J. Ley, MD, clarified what that something was. Ley, the universitys Lewis T. and Rosalind B. Apple Professor of Medicine and chief of the Section of Stem Cell Biology in the Division of Oncology, helped lead the first sequencing of the AML patients genome.

The mutations at amino acid 882 changed the way the protein normally interacted with itself to make a functional enzyme, and reduced the activity of the enzyme by about 80% essentially rendering it inactive. When Ley and his then-trainees David Russler-Germain, MD, PhD, and David Spencer, MD, PhD, looked at the DNA methylation patterns in AML samples with this mutation, they found a very distinct signature, with pinpoint areas of reduced DNA methylation at very specific regions of the genome in every patient who had the mutation.

This knowledge framed an essential chicken vs. egg question: Were these areas with reduced DNA methylation important for causing AML, or were they just a byproduct of cancer transformation? The only way to find out would be to get a sample of blood cells from a person with the same exact DNMT3A mutation but who did not have AML, to see whether the changes in DNA methylation were already there.

But there was no obvious way to find such a patient.

On a bright winter afternoon in 2015, serendipity graced the investigators and the families of a group of patients with a rare genetic syndrome that had been discovered the year before.

As Ley sat in his office mulling over the conundrum that was confounding the field, his phone rang.

The caller Shashikant Kulkarni, PhD, then-head of the Department of Pathology & Immunologys Cytogenetics and Molecular Pathology Laboratory bombarded Ley with a staccato of facts: A patient at St. Louis Childrens Hospital. A 9-year-old boy named Ayden, with a newly described genetic syndrome associated with a mutation in the DNMT3A gene but his blood counts were normal. And, Kulkarni noted, the boy and his parents had consented to donating his blood and tissue samples for research.

I couldnt believe it, Ley recalled.

Shortly after that conversation, Ley received a call from Marwan Shinawi, MD, a professor of pediatrics in the Department of Pediatrics Division of Genetics & Genomic Medicine. Shinawi had just diagnosed Ayden with DNMT3A Overgrowth Syndrome, also known as Tatton Brown Rahman Syndrome (TBRS), a syndrome first identified in 2014 by a pediatric geneticist in London, Kate Tatton-Brown. The condition can cause individuals to be taller than average, overweight and have a large head circumference and distinctive facial features. People with the disorder also may have intellectual disabilities, behavioral difficulties and decreased muscle tone.

In 2014, there were only 13 patients in the world with a known diagnosis of the syndrome.

Youre not going to believe this, Shinawi told Ley over the phone, but the patient has the R882H mutation that youve been studying, and his father works here in pathology.

It was truly incredible, Ley said. There were 13 known patients in the world who had this syndrome. None of them to date had the mutation at position 882 that was so strongly associated with AML. This created a remarkable opportunity to learn more about how DNMT3A mutations contributed to TBRS and how they initiated AML.

Leys prior research on the mutation and blood cancers also triggered concern for Ayden. I worried that Ayden and these other children might be at increased risk of leukemia, Ley said. I knew that it was essential to monitor Aydens health while determining whether there is an increased risk of leukemia for patients with this syndrome.

Thanks to Aydens contribution to scientific research as well as similar contributions from dozens of other families from around the world the Washington University Medical Campus is now a global beacon for patient care and research for TBRS. Now, the syndrome is known to affect about 250 children and young adults worldwide, according to the TBRS Community, a family-led rare-disease organization founded by Jill Kiernan. Her daughter, Aevary, was one of the first to be diagnosed with the syndrome, in 2014.

The nonprofit, which emphasizes advocacy, education and research, is collecting information from families in a clinical registry to study the genetics, development and health of children with DNMT3A Overgrowth Syndrome and of their families.

Dr. Ley has been amazing about talking directly to families whose children have DNMT3A variants, Kiernan said. He says, Well do what we can. Well coordinate with their team. Well tell them what we know and what we dont know. And he does. Its not only Dr. Ley, but everyone weve worked with at Washington University has a sincere interest in helping these children and their families.

The childrens blood and tissue samples continue to be studied in laboratories across the School of Medicine, from oncology and genomics to neuroscience and pediatrics. In conjunction with the studies of clinical samples, genetically modified mouse models are proving to be an important new tool for understanding how DNMT3A mutations work. Mouse and human genomes share common genes that typically function in the same way. Such similarities make mice ideal for simulating human disorders to study how a single mutation can cause all of the features of a complex disease like TBRS. Remarkably, when the amino acid 882 mutation is created in mouse germline cells that make eggs and sperm, the animals develop virtually all of the features of the human syndrome including the reductions in DNA methylation noted in the AML patients. They also have an increased likelihood of developing blood cancers, including AML. These findings were published last year in Nature Communications.

The key to understanding genetic conditions such as TBRS is having both clinical data and samples, as well as mouse models, explained the papers first author, Amanda M. Smith, PhD, a former researcher in Leys lab who led the development of the mouse model with the amino acid 882 mutation.

Harrison Gabel, PhD, an assistant professor in the Department of Neuroscience, has created additional DMNT3A mouse models and focused on how they affect brain function. Were looking at it from a molecular level, how genes get turned on and off, and how that affects development to drive the overgrowth, obesity and neurologic dysfunction that occur in the disorder, he said. The collaborative environment and resources at Washington University position us to attack this particular disorder from all sides. Dr. Ley and I are working side by side, studying the gene in blood cells and in the brain. Combining our efforts with Dr. Shinawi, who understands the clinical aspects of this disorder, and adding in the remarkable relationship with patients and their families, it all adds up to a powerful synergistic approach.

Gabel is a member of the TBRS Communitys scientific advisory committee, and Ley and Shinawi serve on the medical advisory board. This nonprofit recently secured a three-year, $600,000 grant from the Chan Zuckerberg Initiative. It is a total game changer for our little organization thats been fueled by parent volunteers, said Kerry Grens, the groups vice president and the Department of Neurosciences new marketing administrator. Her son Adrian was diagnosed with TBRS in 2019, when he was 3 years old.

Shortly after Adrian was born, Grens and her husband noticed their son was delayed on milestones such as holding up his head and sitting. He also had strabismus (crossed eyes) and a congenital heart defect. We saw a lot of doctors before we came to Washington University, underwent genetic sequencing and received an official diagnosis from Dr. Shinawi, Grens said. It can feel hopeless to have a child with an incurable rare disease, and volunteering with the organization gives me a chance to feel like Im making progress, making a difference. A lot still needs to be answered about this genetic mutation and the associated risks for other diseases such as leukemia.

Research led by Margaret Ferris, MD, PhD, an instructor of pediatrics at Washington University and an oncologist at St. Louis Childrens Hospital, recently confirmed the scientists initial concerns: Patients with TBRS are at an increased risk about 250 times more than the general population for blood cancers, including acute myeloid leukemia. The study was published in November in Blood, the journal of the American Society of Hematology.

This can be difficult news to tell the families, obviously, but its the truth, and they need the truth, said Ley, the studys senior author. Do we need to monitor these children for early signs of the development of leukemia? The answer is, clearly, yes, we do.

Aydens dad, Michael Isaacs, said the truth, no matter what it may be, gives him hope. Not knowing is the biggest burden, said Isaacs, director of informatics and of external affairs for the Department of Pathology & Immunology. Knowing, and having a diagnosis, help set expectations for what the future may look like, but most of all, it gives me hope. The research being done, the dedication of the parents, and the collaborations at Washington University all give me hope.

Washington University School of Medicines 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, and currently is No. 4 in research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Serendipity unites physicians, researchers, families to fight rare genetic disease in kids Washington University School of Medicine in St. Louis -...

A recent study published by researchers at Baylor College of Medicine and Texas Childrens Hospital, in collaboration with the German Center for Infection Research, identified two main subtypes or endotypes of tuberculosis according to the persons immune response to the infection. They found that one subtype had a better prognosis for curing tuberculosis than the other. Their findings, published in the European Respiratory Journal, could improve personalized treatment options for the disease in the future.

We conducted this research under the assumption that tuberculosis is not a uniform disease, that there are many pathways by which a person could develop the condition and that the outcome depends on the immune response produced by the infected person, said Dr. Andrew DiNardo, assistant professor of medicine infectious diseases at Baylor and Texas Childrens.

For people who contract tuberculosis, the course of the disease can vary significantly. Most people do not become ill after infection with Mycobacterium tuberculosis, the bacterium that causes the disease. However, people can develop chronic pneumonia and some also have disease in the lymph nodes, bones or the central nervous system. Some TB patients have suppressed and exhausted immune responses, while others have an overacting response that makes the condition worse.

Endotype discovery based on gene expression profiles has revolutionized our understanding of cancerand tailored patient therapy. We hypothesized that a similar approach could identify distinct and clinically relevant TB endotypes, and the results exceeded our expectations, said senior author Dr. Cristian Coarfa, associate professor of molecular and cellular biology at Baylor and member of Baylors Dan L Duncan Comprehensive Cancer Center.

DiNardo said that researchers in the field are looking for new therapies for the disease, as current therapies require six months of antibiotics. To identify new treatments, researchers have been studying the human immune response to tuberculosis bacteria to better understand what it takes to build protective immunity against this disease. This approach can lead to the development of personalized precision medicine therapies.

Led by Coarfa, the team applied cutting-edge unbiased bioinformatic techniques to analyze large patient datasets to look at immune responses to tuberculosis and identified two main clusters or endotypes of the disease. They then looked at these specific endotypes in two different patient cohorts and found that one endotype had a higher risk of treatment failure and death than the other. Using computer models, they then predicted what types of drugs could be used to treat each tuberculosis endotype.

When we compared different drugs as potential personalized therapy, we found that one therapy could be inconsequential or detrimental to one TB subtype, but beneficial to the other, DiNardo said.

The results of this study will pave the way for personalized therapies, with great potential to improve treatment outcomes for the deadliest of all bacterial infectious diseases, adds Professor Jan Heyckendorf, a DZIF tuberculosis researcher from Borstel and Kiel and one of the studys lead authors.

Whereas gene expression or transcriptomic-based TB endotypes are already informative, future work will incorporate other informative omics, such as metabolomics (metabolites present) and epigenomics or the regulation of gene expression via DNA methylation, leading to further refinement of endotypes and personalized therapy, said Coarfa.

Researchers will now implement clinical trials to treat tuberculosis in a stratified personalized therapy approach, similar to the approach that oncologists take when treating different subsets of cancers.

The following researchers also took part in the study Tanmay Gandhi, Sandra L. Grimm Kimal Rajapakshe, Tomoki Nishiguchi, Maja Reimann, H. Lester Kirchner, Jaqueline Kahari, Qiniso Dlamini, Christoph Lange, Torsten Goldmann, Sebastian Marwitz, DZIF-TB cohort study group, Abhimanyu, Jeffrey D. Cirillo, Stefan HE Kaufmann, Mihai G. Netea, Reinout van Crevel and Anna M. Mandalakas.The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; Texas Childrens Hospital; German Center for Infection Research (DZIF); University of Lbeck; Baylor-Swaziland Childrens Foundation; Texas A&M Health Science Center, Bryan; Max Planck Institute for Infection Biology; Texas A&M University, College Station; Radboud University Medical Center; University of Bonn; Max Planck Institute for Biophysical Chemistry and University of Oxford.

The study was funded by NIAID (grant K23 AI141681-02), the Cancer Prevention Institute of Texas (CPRIT) grants (RP170005, RP200504 and RP210227), NIH/NIAID grants (1U19AI144297, R01AI14578), NIH/NCI P30 shared resource grant CA125123, and NIEHS grants (P30 ES030285 and P42 ES027725). Further support was provided by the German Center for Infection Research, the Texas A&M University System and National Institutes of Health grant AI104960, an ERC Advanced Grant (#833247), a Spinoza grant of the Netherlands Organization for Scientific Research,NIH grants (R01AI14578, R01AI137527, U01GH002278) and DoD grant W81XWH1910026.

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Two distinct tuberculosis subtypes IDed implications for personalized therapy - Baylor College of Medicine News

Yale researchers have further elucidated the mechanism of metformin, a widely used type 2 diabetes medication that, despite its long history of being safe and effective, works in a way that has remained elusive to scientists.

On March 1, Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, published his labs findings on how metformin works to suppress gluconeogenesis through inhibiting Complex IV activity. Now, a different study led by Yingqun Huang, MD, PhD, professor of obstetrics, gynecology & reproductive sciences, builds upon Shulmans findings and further illuminates how the drug works. Her team published its findings in Proceedings of the National Academy of Sciences on March 28. Our research not only discovered a new mechanism of metformin, but also identified potential therapeutic molecular targets, says Huang.

Shulmans findings over recent years supporting an oxidation-reduction (redox)-dependent mechanism of metforminin which cytosolic redox is increasedintrigued Huangs lab. But while Shulmans lab has focused on how inhibition of the mitochondrial enzyme Complex IV promotes an increased cytosolic redox state and inhibition of gluconeogenesis [glucose production from glycerol, lactate and amino acids], Huang is interested in how increased redox changes hepatocytes [liver cells] further downstreama mechanism researchers are now debating.

In 2020, Huangs lab published a paper in Nature Communications that found that the expression of a gene known as TET3 was increased in mice and humans with diabetes. In turn, the expression of a specific fetal isoform of the HNF4A gene was also increased. In healthy adult livers, the adult form of HNF4A is predominantly expressed. In patients with diabetes, however, the fetal isoform is chronically increased because TET3 is also chronically increased. This fetal isoform also increases gluconeogenesis by regulating key enzymes involved in the process.

In our published paper two years ago, we identified that the upregulation of TET3 and the HNF4A fetal isoform in humans and mice with diabetes contribute to unabated gluconeogenesis in the liver, says Da Li, professor at China Medical University and co-author on both studies. Now, through its latest work, Huangs lab has discovered that when metformin induces an increase in cellular redox, this in turn increases let-7, a small microRNA molecule. When let-7 increases, it binds to and downregulates TET3, suppressing the HNF4A fetal isoform and also gluconeogenesis mproving diabetes

In the livers of diabetes, let-7 is depressed, explains Di Xie, associate research scientist in Huangs lab and first author of the study. Metformin brings let-7 back to normal levels and inhibits gluconeogenesis.

Unabated glucose production from the liver is one of the key mechanisms of diabetes. Through better understanding how metformin works to suppress gluconeogenesis, Huang hopes her work will lead to more effective drugs with fewer side effects. The study also identified potential therapeutic targets including let-7. Scientists could potentially use a vector such as a mild virus known as adeno-associated virus, for example, to specifically deliver a let-7 mimic to the liver of patients with diabetes to enhance let-7 expression and treat the condition. Huang hopes to develop such a vector for delivering therapeutics like a let-7 mimic in future research.

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Yale Researchers Continue to Unravel the Mystery of Metformin - Yale School of Medicine

Background

What are immune checkpoint inhibitors (ICI)? When a foreign tumor cell presents itself, it can talk with cells and instruct the human immune system to not kill the cancer, functioning as brakes. Immune checkpoint inhibitor therapies (ICI) function by releasing these natural brakes of the human immune system (Figure 1). By blocking this communication, ICIs allow the immune cell to perform its function and kill the foreign tumor cell.

Selecting who to treat with ICIs. Currently in clinic, we look at a tumor and decide who is going to receive ICIs by measuring the amount of a specific protein called programmed cell death ligand 1 (PD-L1). However, using this criteria for selection, only 1/5 patients with non-small cell lung cancer (NSCLC) who receive ICIs have a good response, as measured by improved survival. This means that only looking at the expression of PD-L1 is not sufficient for determining who to treat.

This proposed research aims to find an alternative way to identify which persons with NSCLC will respond, and not respond, to this kind of treatment.

Tissues from patients with NSCLC treated with ICIs from 2011 to 2020 were retrospectively collected. Tissues were pre-ICI treatment to allow to look at tissues that have not been altered by ICI treatment. The tumor-specific areas of these tissues were selected and analyzed using a research use only version of a clinical test. This is an inexpensive, simple diagnostic assay that is easy to operate. It measures mRNA levels. We looked at the mRNA of 4 target immune genes, CD274 (PD-L1), PDCD1LG2 (PD-L2), CD8A, and IRF1 (depicted in Figure 1) and a control gene. Gene expression levels were analyzed for associations with response.

PD-L1 protein is associated with survival (TPS >50) and is weakly correlated with PD-L1 mRNA

Lower PD-L1 mRNA is associated with worse outcome (decreased overall survival and no benefit at 24 months; Figure 2 below) and a high negative predictive value (92% NPV, meaning a negative test has a 92% chance of being associated with no benefit).

This assay, because of its high NPV, has the potential to identify patients who are not likely to benefit from ICIs and could be spared the risk of immune-related adverse effects.

Submitted by Renee Gaudette on March 30, 2022

Originally posted here:
PD-L1 and PD-L2 mRNA are Associated with Outcome and High Negative Predictive Value in Immunotherapy-treated Non-small Cell Lung Cancer - Yale School...

Germline genetic testing where clinicians test for inherited mutations is essential for patients with colon cancer, as the results may not only help guide their treatment options but can also let them know if they or their family members are at an increased risk for other cancers.

However, current recommendations call for screening of patients and then deciding if they are appropriate candidates for germline testing, which could lead to some patients with genetic mutations or inherited cancer syndromes falling through the cracks and not being identified, according to Rachel Pearlman, a genetic counselor at The Ohio State University College of Medicine.

In a recent interview with CUREs sister publication, CancerNetwork, Pearlman discussed her research in genetic testing in patients with colon cancer, and why germline testing for all should be the way of the future.

Question: Can you explain your research regarding colon cancer genetic testing, and how it can help both patients and their family members?

Pearlman: The Ohio Colon Cancer Prevention Initiative, which we affectionately referred to it as the OCCPI study was exactly what the name implies. It was a statewide initiative in Ohio that was created to prevent colon cancer.

We know that individuals who are born with a germline pathogenic variant in a cancer predisposition gene have increased risk to develop specific types of cancer. Obviously the types of cancer depend on which gene isn't working correctly. By identifying individuals with colon cancer who have these germline pathogenic variants, we could then hopefully prevent them from getting different cancers in the future, and we could help their family members reduce their risk for cancers too.

The OCCPI study is the largest study to date that performed universal tumor screening on everyone in the study. And we also did germline genetic testing with multi-gene, pan-cancer panels for those who met our germline testing criteria. And then we also did tumor sequencing for those with unexplained mismatch repair deficiency.

We also provided genetic counseling locally for those who tested positive for a germline pathogenic variant and no cost cascade testing and genetic counseling for the relatives of those found to have Lynch syndrome.

What were some of the highlights that came out of that research?

Importantly, we found that one in 14 (or 7%) of individuals with colon cancer will have at least one gene mutation increasing cancer risk. And we know that this is actually an underestimate of the true prevalence, because only our high-risk patients receive germline testing. In our study, the true prevalence is probably closer to 10 to 15%, as shown by some other studies.

We also found that one in 25, (or a little bit over 4%) of patients with colon cancer actually have Lynch syndrome, which is a higher frequency than what we had previously reported, which is likely due to improved technology with both the universal tumor screening and germline testing and it truly being universal being done on all-comers rather than targeted (and) based on your diagnosis or family history.

Also importantly, we found that 3% had a pathogenic variant and a non-Lynch syndrome gene, the most commonly being in ATM, which is thought it was a breast and pancreas gene (mutation). (We also saw mutations in the CHEK2 gene) which is thought of as a breast and colon (cancer) gene. APC, which is known to cause polyposis. Interestingly, (there were) BRCA 1 and 2 (mutations), which increases risk for breast and ovarian cancer.

So we were finding gene mutations that we weren't necessarily expecting based on their colon cancer diagnosis. And for some of them, we weren't expecting them based on the family history either.

We also have some really interesting data in our young-onset cohort. We found that 16% of individuals diagnosed with colon cancer under the age of 50 had at least one gene mutation. We had published that a few years earlier. About 8% of those individuals have Lynch syndrome and 8% had no different hereditary syndrome.

The most import (finding), to come out of this research was that if universal tumor screening, which is recommended for every person who's diagnosed with colon cancer, had been the only method used to screen for hereditary cancer syndrome, then almost 40%, so 38.6%, of our patients identified to have a mutation would have been missed. (Thats) including 6.3% of those who are identified to have Lynch syndrome. We found that we're missing Lynch syndrome and mismatch repair proficient patients, and we found unexpected mutations in both the proficient and efficient mismatch repair patients.

What is on the horizon for genetic testing in colon cancer?

Hopefully genetic testing or germline genetic testing will be recommended for all individuals with colon cancer, which is a pretty big shift from our current guidelines, which are really based mostly on mismatch repair deficiency status, or age at diagnosis or family history criterion. There's a lot of burden on the practitioner trying to figure out who is the appropriate person to offer genetic testing to.

Once germline genetic testing is recommended for all colon cancer patients, or if that were to happen, that would certainly eliminate a lot of the burden on trying to figure out who is the right person to test. We know that everybody who has colon cancer is appropriate for testing.

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Universal Genetic Testing Should be Recommended for All Patients With Colon Cancer, Says Expert - Curetoday.com

Published in Molecular Psychiatry, a team of scientists from the University of Minnesota Medical School, University of Texas Health San Antonio, and the Biomedical Research Institute (BRI) of the Foundation for Research and Technology Hellas (FORTH) in Greece found that the disruption of a circadian clock gene may be involved in the development of autism spectrum disorder.

Autism spectrum disorder, or ASD, refers to a neurodevelopmental disorder characterized by a wide range of behavioral conditions including challenges with social skills, repetitive behaviors, speech and nonverbal communication. According to the Centers for Disease Control and Prevention, ASD affects one in 44 children in the U.S.

About 50-80% of children with ASD have sleep problems, compared to less than 30% in the general population. The causes of sleep problems in ASD are not entirely clear, but a malfunctioning body clock could be the culprit.

It has long been recognized that the function of the body clock is frequently disrupted in autism patients and these patients often exhibit various sleep problems, said Ruifeng Cao, MD, PhD, an assistant professor of neuroscience at the U of M Medical School, Duluth Campus and co-author of the study. But, it is not known whether clock gene disruption can directly cause autism.

The study found that the disruption of an essential clock gene in preclinical models can lead to autistic-like phenotypes. Specifically, the global or cerebellar deletion of the Bmal1 gene can cause severe impairments in sociability, social communication and excessive repetitive behaviors.

The models also illustrated damages to their cerebellum or cerebellar ataxia. The research team further studied the pathological changes in the cerebellum and found a number of cellular and molecular changes that indicate neurodevelopmental deficits.

Clock gene disruption could be a mechanism underlying several forms of autism and potentially other neurodevelopmental conditions, and this finding paves the way for further exciting research, said Christos Gkogkas, PhD, a lab principal investigator in neurobiology at BRI of FORTH.

The research team plans to continue to study other clock genes that are found mutated in ASD. More importantly, they recommend development of novel therapeutic strategies based on their findings.

The study is supported by grants from the National Institute of Health and the Winston and Maxine Wallin Neuroscience Discovery Fund.

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The research team consists of Drs. Harry Orr, Alfonso Araque, Paulo Kofuji, and Jonathan Gewirtz (now at Arizona State University) from the U of M Medical School; Dr. Victor Jin from UT Health San Antonio; and Dr. Christos Gkogkas from BRI-FORTH in Greece.

About the University of Minnesota Medical SchoolThe University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School, both the Twin Cities campus and Duluth campus, is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. For more information about the U of M Medical School, please visit med.umn.edu.

The Biomedical Research Institute of FORTHThe Biomedical Research Institute (BRI) of FORTH at Ioannina consists of 18 research teams that comprise 140 members. The groups of BRI work in basic molecular and cellular biology areas of biomedical research with high interest in public health and biomedicine, such as vascular biology, stem cell biology and regenerative medicine, cancer biology, neurobiology, and biomedical technology.

The Foundation for Research and Technology - Hellas (FORTH) is one of the largest research centers in Greece, comprising nine Research Institutes. FORTH conducts specialized scientific research in strategic high-added value sectors, focusing on interdisciplinary research and development (R&D) activities in areas of major scientific, societal and economic interest.

Molecular Psychiatry

Observational study

Animals

Autistic-like behavior and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition

17-Mar-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Research Brief: Clock gene mutation found to contribute to the development of autism - EurekAlert

Scientists have successfully restored dim-light vision to dogs with an inherited disorder that causes night blindness, a major step toward using the same gene therapy to help people with similar vision problems.

In 2015, researchers from the University of Pennsylvanias School of Veterinary Medicine learned that dogs could develop a form of inherited night blindness with strong similarities to a condition in people called congenital stationary night blindness (CSNB). People with CSNB are unable to distinguish objects in dim-light conditions, which presents challenges when artificial lighting is unavailable or when driving at night.

The term stationary refers to the fact that this very impaired vision in dim light occurs at birth and doesnt get better or worse with time, which makes it quite debilitating for patients, said neuroscientistJohn Flannery, UC Berkeley professor of molecular and cell biology. There is currently no treatment for these people.

In 2019, when the Penn Vet team identified the defective gene responsible for CSNB in dogs, the researchers reached out to Flannery to find a way to deliver a replacement gene a normal copy of the defective gene into dogs retinas.

Flannery and former postdoctoral fellow Leah Byrne, now an assistant professor at the University of Pittsburgh, designed and made a viral vector that could target the defective cells and deliver the gene. When injected into the retina, the virus an attenuated adeno-associated virus (AAV) would carry the replacement gene and a cell-specific promoter into ON-bipolar cells in the retina, which receive visual input exclusively from rods, which are the cells sensitive to dim light and the site of the mutated gene in these dogs.

This week, the journalProceedings of the National Academy of Sciencespublishedthe teams paperreporting its successful restoration of night vision to dogs born with CSNB.

In videos of the dogs after the treatment, the restoration of vision in low lighting is quite impressive and easy to appreciate in the canine behavior, said Flannery, a member of Berkeleys Helen Wills Neuroscience Institute and a faculty member in the Herbert Wertheim School of Optometry and Vision Science. The defect is in the synapse between the rod photoreceptor and the rod-specific bipolar, and this has only been attempted before in mice.

A single injection of gene therapy containing a normal version of the LRIT3 gene resulted in lasting restoration of night vision in dogs affected by a form of congenital stationary night blindness similar to one affecting humans. This image shows a cross-section of the retina and the ON-bipolar cells (red) targeted by the gene therapy. (Image credit: Keiko Miyadera, Penn Vet)

Dogs with CSNB that received a single injection of the gene therapy began to express the healthy gene in their retinas and could ably navigate a maze in dim light. The treatment also appears lasting, with a sustained therapeutic effect lasting a year or longer.

The results of this pilot study are very promising, said Keiko Miyadera, lead author of the study and an assistant professor at Penn Vet. In people and dogs with congenital stationary night blindness, the severity of disease is consistent and unchanged throughout their lives. And we were able to treat these dogs as adults, between 1 and 3 years of age. That makes these findings promising and relevant to the human patient population, as we could theoretically intervene, even in adulthood, and see an improvement in night vision.

The gene that the Penn Vet team corrected to fix the dogs night vision impairment has also been implicated in certain cases of human CSNB, which opens the door to treating people with a similar gene therapy.

While the therapy enabled functional recovery in the animals the dogs were able to navigate a maze when their treated eye was uncovered, but not when it was covered the healthy copy of the gene was expressed in only 30% or fewer of ON bipolar cells. In follow-up work, the researchers hope to augment this uptake for future dog and human trials.

Weve stepped into the no mans land of the retina with this gene therapy, said William A. Beltran, a co-author and professor at Penn Vet. This opens the door to treating other diseases that impact the ON bipolar cells.

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Success treating night blindness in dogs could lead to human gene therapy - University of California

TORONTO, March 25, 2022 /CNW/ - Vertex Pharmaceuticals (Canada) Incorporated (NASDAQ: VRTX) today announced that Health Canada has granted Marketing Authorization for the expanded use of PrKALYDECO (ivacaftor) in patients from 4 months to 18 years of age and weighing at least 5 kg with the R117H mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Vertex Pharmaceuticals (Canada) Inc. Logo (CNW Group/Vertex Pharmaceuticals (Canada) Inc.)

"KALYDECO was first approved in Canada in 2012 as the first medicine to treat the underlying cause of cystic fibrosis in patients with specific mutations," said Michael Siauw, General Manager, Vertex Pharmaceuticals (Canada). "Since then, it's been our goal to ensure that as many people with CF as possible are eligible for our treatments, and today's announcement means that approximately 25 young people with CF in Canada are now newly eligible for KALYDECO."

Vertex will work closely with all provinces, territories and private payers to secure access for eligible patients as swiftly as possible.

In Canada, PrKALYDECO is already approved for the treatment of people with CF ages 18 and older with the R117H mutation, and in people with CF ages 4 months and older weighing at least 5 kg who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

About Cystic Fibrosis

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 83,000 people globally. CF is a progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF, and these mutations can be identified by a genetic test. While there are many different types of CFTR mutations that can cause the disease, the vast majority of people with CF have at least one F508del mutation. CFTR mutations lead to CF by causing CFTR protein to be defective or by leading to a shortage or absence of CFTR protein at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus, chronic lung infections and progressive lung damage that eventually leads to death for many patients. The median age of death is in the early 30s.

Story continues

About PrKALYDECO (ivacaftor)

In people with certain types of mutations in the CFTR gene, the CFTR protein at the cell surface does not function properly. Known as a CFTR potentiator, ivacaftor is an oral medicine designed to facilitate the ability of CFTR proteins to transport salt and water across the cell membrane, which helps hydrate and clear mucus from the airways. PrKALYDECO (ivacaftor) was the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule, cell and genetic therapies in other serious diseases where it has deep insight into causal human biology, including sickle cell disease, beta thalassemia, APOL1-mediated kidney disease, pain, type 1 diabetes, alpha-1 antitrypsin deficiency and Duchenne muscular dystrophy.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 12 consecutive years on Science magazine's Top Employers list and one of the 2021 Seramount (formerly Working Mother Media) 100 Best Companies.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Michael Siauw in this press release, and statements regarding our expectations for the eligible patient population for and access to KALYDECO, and our beliefs regarding the benefits of our medicine. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons and other risks listed under the heading "Risk Factors" in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

SOURCE Vertex Pharmaceuticals (Canada) Inc.

Cision

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Health Canada Grants Marketing Authorization for KALYDECO (ivacaftor) for Patients With Cystic Fibrosis Between the Ages of 4 Months and 18 Years With...

Albany NY, United States: Protein expression, purification and large scale production is achieved by manipulation in the gene expression process of an organism such that it is able to express large amounts of a recombinant gene. It is not a trivial task and faces a huge competition in the market because of the fragmented scenario over the globe. Fermenters and bioreactors with different expression system capabilities, purity options, quality control and the production timeline differentiate various services available in the market. Various organizations have developed their own in-house methods of production and purification. Bacterial and yeast systems are mostly used in case of microbial protein production process because of simple physiology, short generation times and high yield of product, both having their own advantages and disadvantages. Among bacterial, E. coli has been most widely used for recombinant protein expression and production. Clients can use the service for the manufacture of either the regular proteins whose gene sequence is available in the public domain or can manufacture its customized gene expression

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Producing recombinant proteins is often the limiting and most expensive step in life science research. Expression yield of recombinant proteins vary by orders of magnitudes from protein to protein reflecting the difference in the cost of production process. These services are more preferred due to the increasing customization in the genetic sequences. Microbial protein production services also involves the use of various types of tags for purification purposes such as FLAG-tag, His-tag, Fc-fusion tag, GST-tag, Myc-tag, HA-tag, MBP-tag and others.

Microbial Protein Production Services Market: Drivers & Restraints

Increase in the number of applications of microbial proteins such as the increasing enzymatic applications and their requirement in various industries, increase in the production of bio-pharmaceuticals like monoclonal antibodies, hepatitis B vaccine and HPV vaccine are increasing the need of microbial protein production services to meet the demand. Recent advances in proteomics and rapid growth in protein drug market also constantly increasing the market of pure and active proteins. Increasing number of CROs also fuels the services market. One of the limiting factor for the growth is not possessing the same capability as eukaryotic cells for protein glycosylation and other post-translational modifications and thus limits its applications. Increasing regulatory pressure on CROs, high cost involved, lack of skilled manpopwer, infrastructure and skilled expertise may also restricts the growth.

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Microbial Protein Production Services Market: Segmentation

By Production Type:

By Service Type:

By End User:

By Geography

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Microbial protein production services constitutes of companies and research organizations engaged in protein production and purification services. Bio therapeutic protein and vaccine manufacturers faces various challenges related to time and cost in the drug discovery and development process. The service units take only the protein sequence and adjust the amount and purity required for protein production. These type of services help in saving time and cost to accomplish the research needs. Competitive prices of different products and the quality differentiates the market players. Continuous innovations and improvements in the protein expression systems are the need of the market. Various mergers and partnership deals in this sector also fuels the market such as Ewos recently offered a US $30 million funding package to Calysta which is planning to manufacture novel high quality microbial proteins for the fish feed industry in the UK.

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A geographic condition regarding the Microbial Protein Production Services Market, it has been segmented into five key regions: North America, Latin America, Europe, Asia-Pacific and the Middle East & Africa. With large number of research organizations and usage in number of applications in various industries, North America depicts an established market for these services. Extensive competition is faced by the European countries because of the excellent number of contract research organizations and established network of universities and research institutions in the region. Asia Pacific is the growing market because of establishment of more biotechnological and pharmaceutical industries and opening of more contract research organizations. Moreover, low cost manufacturing also attracts the market in this region.

Some of the market players in the microbial protein production service market includes Wacker, Chemie AG, Icosagen, Sino Biological, GenScript, LP3 Labs, Lonza, Biomatik, GenWay Biotech, Inc., Olympic Protein Technologies, Amid Biosciences and many others.

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Microbial Identification Market: The stellar pace of developments in the field of microbiology have aided the growth of the global microbial identification market. There have been several developments in the domain of microbial studies, and this has hugely contributed towards developing effective treatment mechanisms within medicine.

Rapid Microbial Detection Systems Market: Increasing efficiency in medical research and development, coupled with the advent of extra safety measures for diagnostic purposes are the two notable features aiding in expansion of the global rapid microbial detection systems market growth. The forecast period for the growth of this market is set between 2020 and 2030 and the market is likely to gain acceleration during the current COVID-19 pandemic.

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Microbial Protein Production Services Market Opportunities and Forecasts 2025 - BioSpace

TUESDAY, March 29, 2022 (HealthDay News) -- Babies born to fathers who were taking the common diabetes drug metformin may have a slightly increased risk of certain birth defects, a large new study suggests.

Among over 1 million babies born in Denmark, just over 3% had a birth defect of some kind. But that rate was roughly 5% among babies whose fathers had used metformin in the three months before they were conceived, the findings showed.

In particular, the medication was tied to a higher risk of genital birth defects, all in baby boys, according to the report published March 28 in the Annals of Internal Medicine.

Experts stressed that the study does not prove metformin is to blame, and there is no known mechanism to explain the connection. And men should not stop using their medication based on a single study, they added.

"We know metformin works well for controlling diabetes," said senior researcher Dr. Michael Eisenberg, a professor of urology at Stanford University School of Medicine in California.

But the results do bring up a "signal" that should be studied further, Eisenberg said. On a broader level, he added, the study highlights the importance of understanding fathers' influence on birth defect risks.

Metformin is an oral medication widely used for controlling high blood sugar in people with type 2 diabetes a common disease that is often related to obesity.

In the United States alone, more than 37 million people have diabetes, most of whom have type 2, according to the U.S. Centers for Disease Control and Prevention. While it is most common in people older than 45, the agency says, type 2 diabetes is increasingly being diagnosed in younger adults and even children and teenagers.

Studies have found that when pregnant women have poorly controlled diabetes, their babies' risk of birth defects rises.

Meanwhile, some research has tied diabetes in men to poorer sperm quality. But it has not been clear whether fathers' diabetes is related to the odds of birth defects in their children.

Even then, Eisenberg said, a key question would be whether it is because of the diabetes or the medications used to treat it?

For the new study, the researchers turned to Denmark's national birth registry, analyzing data on over 1 million babies born between 1997 and 2016.

The investigators found that when fathers had used metformin within the three months before conception, their babies' risk of birth defects was about 40% higher, on average, versus the study group as a whole.

There was a particular link to genital birth defects, all among boys: Of all babies whose fathers used metformin in the three months before conception, 0.9% had a genital birth defect, versus just over 0.2% of the overall group.

That three-month window is critical, Eisenberg said, because sperm take roughly that long to develop.

The researchers dug into other factors that might explain the link, including parents' age, education level and smoking habits. But fathers' metformin use remained tied to birth defect risk.

That still left the question of whether it was the medication, or the diabetes.

There were some strikes against that notion, Eisenberg said. For one, there was no clear link between birth defects and fathers' metformin use in the year before or after the three-month window before conception.

The researchers also looked at two other types of diabetes medication used by fathers in the study: insulin and drugs called sulfonylureas. Insulin use was not tied to birth defects.

On the other hand, there was an elevated rate of birth defects when fathers used sulfonylureas. But the finding was not "statistically significant" once the researchers weighed other factors meaning it could have been due to chance.

However, an expert not involved in the study said the metformin finding could also easily be due to chance, or "confounding" due to other factors.

Dr. Anthony Scialli is a member of the Organization of Teratology Information Specialists. The group runs MotherToBaby, a free service that provides research-based information on the effects of medications during pregnancy.

Scialli explained that the study made many different comparisons, which increases the odds of chance findings. Beyond that, he said, genetic factors could be at play.

Scialli noted that the genital birth defects in boys would mostly be hypospadias, where the opening of the urethra is on the underside of the penis rather than the tip. And hypospadias, he said, often runs in families.

The researchers did do a comparison to try to account for genetics: They found that babies "exposed" to fathers' metformin use had a higher rate of birth defects than their siblings who were not exposed.

But, Scialli pointed out, that difference was not statistically significant once the researchers adjusted for other variables.

"So both chance and confounding could explain these results," Scialli said. "Causation seems unlikely given the lack of a plausible mechanism."

Eisenberg agreed that the mechanism is unknown, and more research is needed. He also said the findings need to be replicated in other countries, including ones more diverse than the relatively homogenous Denmark.

The bigger point is that fathers' health and exposures, and their potential impact on their children, should not be ignored, Eisenberg said.

"The health of fathers matters, too," he said.

More information

MotherToBaby has more on fathers' exposures and pregnancy.

SOURCES: Michael Eisenberg, MD, professor, urology, Stanford University School of Medicine, Stanford, Calif.; Anthony Scialli, MD, reproductive and developmental toxicology specialist, member, Organization of Teratology Information Specialists, Brentwood, Tenn.; Annals of Internal Medicine, March 28, 2022, online

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Rise in Birth Defects for Babies Whose Fathers Took Common Diabetes Drug - HealthDay News