Daily Archives: June 2, 2021

Gene therapy seeks to modify or introduce genes into a patients body with the goal of durably treating, preventing or potentially even curing disease, including several types of cancer, viral diseases, and inherited disorders. Gene therapy approaches include replacing a mutated gene that causes disease with a functional copy; or introducing a new, correct copy of a gene into the body in order to fight disease.

Gene therapy may be performed in vivo, in which a gene is transferred to cells inside the patients body, or ex vivo, in which a gene is delivered to cells outside of the body, which are then transferred back into the body.

Typically, gene therapy developers introduce new or corrected genes into patient cells using vectors, which are often deactivated viruses. Deactivated viruses are unable to make patients sick, but rather serve as the vehicle to transfer the new genetic material into the cell. Viruses that have been used for human gene therapy include retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus (AAV). Other ways of introducing new genetic material into cells include non-viral vectors, such as nanoparticles and nanospheres.

Gene therapy techniques can also be used to genetically modify patient cells ex vivo, which are then re-introduced into the patients body in order to fight disease, an approach known as gene-modified cell therapy. This approach includes a number of cell-based immunotherapy techniques, such as chimeric antigen receptors (CAR) T cell therapies, T cell receptor (TCR) therapies, natural killer (NK) cell therapies, tumor infiltrating lymphocytes (TILs), marrow derived lymphocytes (MILs), gammadelta T cells, and dendritic vaccines.

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Gene-Based Medicine - Alliance for Regenerative Medicine

It has been several weeks since I came back from Berlin. I was visiting the international mRNA health conference, where I presented our latest development in the mRNA therapy field. Unlike the USA and Europe, mRNA research in Australia is still a young concept. As far as we know, we are probably one of the only groups in Australia who are actively working on mRNA therapy. On my way back to Australia thinking of all the great discoveries I just witnessed in the conference- I had a thought. I must write about mRNA therapy, so more people can know about it. Because when mRNA therapy reaches its age, it will touch most of us.

To understand this new class of therapies, we must first understand what makes up mRNA and gene therapies. These molecules are known as nucleic acids. In our cells, there are two major types of nucleic acid molecules: Genomic DNA and mRNA. These carry the manual for all the instructions your cells and body need. They are the code for life. The basic principle of traditional gene therapy is to insert or add a DNA molecule, with specific designed instructions and is translated by your cell as a protein. In the case of gene therapy, it treats people who lack that protein. mRNA, also known as messenger RNA, is naturally found in all our cells. mRNA is responsible for carrying out a message from the DNA that lies inside the nucleus to the cytoplasm. In there, the proteins are made from the mRNA sequence in a process known as translation. So mRNA therapy uses mRNA molecules instead of DNA molecules, thereby bypassing the need for DNA and simplifying the process (See the figure below).

Nucleic acid therapy, whether it is derived from mRNA or DNA, is a transformational concept in medicine. In contrast to conventional drugs- small molecules acting on a protein or a target inside your body- nucleic acid therapy instead instruct your body to make or break the proteins inside your cells at a more fundamental level. You could imagine your DNA and mRNA as the operating program system (OS) for life. Much like computer OS, mRNA therapy can reprogram your body to produce its own therapies. An intriguing concept, indeed.

Back to Berlins conference, many academic and biotech groups presented a wide range of medical applications using mRNA. We and others have envisaged, many times, the range of applications mRNA therapy can have.

Given the mRNA inherent programmability, its relatively easy to adjust the sequence of mRNA to make, theoretically, any therapeutic protein. This means it can cover a wide range of diseases. Examples of applications that have gone into clinical trials (i.e. trialled in a small number of humans) are cancer immunotherapy, viral vaccines and enzyme replacement therapy for the liver. But the list, as we all expect, wont stop here. In the context of the human application, many groups and biotech companies presented impressive findings, but these results are still early.

Effectiveness: Conventional DNA gene therapy needs to overcome many challenges before it becomes a therapeutically viable option. For DNA gene therapy to be active, it requires to reach not only the cell but the very nucleus inside that cell. This is an incredibly difficult task given that our nuclei have evolved to prevent any foreign DNA from entering (Think viruses!). While mRNA therapy shares some of the difficulties of traditional gene therapy, it requires to reach only the cytoplasm of the cells, not the nucleus. Arguably, this is a simpler technical challenge compared to DNA therapy.

Safety: This is the second most important factor facing the field today. While viral gene therapies have been somewhat successful recently, mRNA provides three main advantages over viral gene therapies. The first is how long mRNA lasts. Unlike viral gene therapies which may last months or years, traditional mRNA last for only a short period, no more than a week or two. In the case of overdose, a real possibility with any form of medicine, mRNA overdose problem can last only for a couple of days. This is far more tolerable than an issue that sticks for a very long time- a theoretical possibility with the viral gene therapy. Secondly, the nature of mRNA (i.e. being an RNA) prevents it from integrating into your genome (a DNA). Genetic integrations using viral gene therapies, while a rare event, can have a devastating effect if the integration was placed in the wrong spot in your genome. The third safety concern comes with our immune system. Our immune system has a low tolerance for viral gene therapies because these therapies are delivered by a virus (We call it a viral vector). Our body will attack not only the virus carrying the therapy but possibly the cells that the virus reaches. Although there have been improvements to reduce the viral vector problems, mRNA therapy uses an entirely synthetic combination of materials that are well-tolerated in humans. And the chances are far lower for developing a long-lasting problematic immune reaction.

Affordability: Today, the cost of medicine is a significant concern for patients and governments alike. As the pace of new medical innovation is accelerating, new technologies to produce those medicines safely and in sufficient quantities have not caught up yet. New gene therapies based on viral vector called AAV have a gigantic price tag ranging from $750k -$2 mil USD (1,2). The reason for the enormous price comes, in part, from the difficulty of manufacturing safe viral gene therapy and from the lack of clarity on the cost-benefit balance by marketing companies. Since viral gene therapies are likely to last for years, the price for such medicine has unfortunately skyrocketed to compensate for a one-shot approach. mRNA therapy, on the other hand, has a cheaper production price-tag and can be given, regularly, just as conventional medicins. This will aid a more straightforward pricing plan at least in the near future.

Some aspects of mRNA are still under thorough testing, but the development the field has seen in the past five years is mind-boggling. mRNA could be as effective as viral gene therapies but safer and more affordable. Yet many challenges, for example, delivering to different cells in our bodies must be improved if this new class of medicines is set to reach the masses.

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mRNA therapy: A new form of gene medicine | by Harry Al ...

It has often been estimated that it takes, on average, 17years to translate a novel research finding into routine clinical practice. This time lag is due to a combination of factors, including the need to validate research findings, the fact that clinical trials are complex and take time to conduct and then analyze, and because disseminating information and educating healthcare workers about a new advance is not an overnight process.

Once sufficient evidence has been generated to demonstrate a benefit to patients, or "clinical utility," professional societies and clinical standards groups will use that evidence to determine whether to incorporate the new test into clinical practice guidelines. This determination will also factor in any potential ethical and legal issues, as well economic factors such as cost-benefit ratios.

The NHGRIGenomic Medicine Working Group(GMWG) has been gathering expert stakeholders in a series of genomic medicine meetingsto discuss issues surrounding the adoption of genomic medicine. Particularly, the GMWG draws expertise from researchers at the cutting edge of this new medical toolset, with the aim of better informing future translational research at NHGRI. Additionally the working group provides guidance to theNational Advisory Council on Human Genome Research (NACHGR)and NHGRI in other areas of genomic medicine implementation, such as outlining infrastructural needs for adoption of genomic medicine, identifying related efforts for future collaborations, and reviewing progress overall in genomic medicine implementation.

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Genomics and Medicine - NHGRI

LEXINGTON, Mass., June 1, 2021 /PRNewswire/ --LogicBio Therapeutics, Inc.(Nasdaq:LOGC), a clinical-stage genetic medicine company pioneering gene delivery and gene editing platforms to address rare and serious diseases from infancy through adulthood, today announced that Frederic Chereau, chief executive officer of LogicBio, will participate in virtual fireside chats at the following upcoming investor conferences:

Where applicable, live webcasts of the fireside chats can be accessed through the Investors section of the Company's website at https://investor.logicbio.com.

About LogicBio Therapeutics

LogicBio Therapeuticsis a clinical-stage genetic medicine company pioneering gene delivery and gene editing platforms to address rare and serious diseases from infancy through adulthood. The Company's proprietary GeneRide platform is a new approach to precise gene insertion that has the potential to harness a cell's natural DNA repair process leading to durable therapeutic protein expression levels. LogicBio's cutting-edge sAAVy capsid development platform is designed to support development of treatments in a broad range of indications and tissues. The Company is based inLexington, MA.For more information, visithttps://www.logicbio.com/, which does not form a part of this release.

Media Contacts:Adam DaleyBerry & Company Public RelationsW: 212-253-8881C: 614-580-2048[emailprotected]

Jenna UrbanBerry & Company Public RelationsW: 212-253-8881C: 203-218-9180[emailprotected]

Investor Contacts:Matt LaneGilmartin Group (617) 901-7698[emailprotected]

SOURCE LogicBio Therapeutics, Inc.

http://www.logicbio.com

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LogicBio Therapeutics to Participate in Upcoming Investor Conferences - PRNewswire

News Release

Tuesday, June 1, 2021

NIH- and USU- led study links ALS to a fat manufacturing gene and maps out a genetic therapy

In a study of 11 medical-mystery patients, an international team of researchers led by scientists at the National Institutes of Health and the Uniformed Services University (USU) discovered a new and unique form of amyotrophic lateral sclerosis (ALS). Unlike most cases of ALS, the disease began attacking these patients during childhood, worsened more slowly than usual, and was linked to a gene, called SPTLC1, that is part of the bodys fat production system. Preliminary results suggested that genetically silencing SPTLC1 activity would be an effective strategy for combating this type of ALS.

ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We found that a genetic form of the disease can also threaten children. Our results show for the first time that ALS can be caused by changes in the way the body metabolizes lipids, said Carsten Bnnemann, M.D., senior investigator at the NIHs National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in Nature Medicine. We hope these results will help doctors recognize this new form of ALS and lead to the development of treatments that will improve the lives of these children and young adults. We also hope that our results may provide new clues to understanding and treating other forms of the disease.

Dr. Bnnemann leads a team of researchers that uses advanced genetic techniques to solve some of the most mysterious childhood neurological disorders around the world. In this study, the team discovered that 11 of these cases had ALS that was linked to variations in the DNA sequence of SPLTC1, a gene responsible for manufacturing a diverse class of fats called sphingolipids.

In addition, the team worked with scientists in labs led by Teresa M. Dunn, Ph.D., professor and chair at USU, and Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland. Together they not only found clues as to how variations in the SPLTC1 gene lead to ALS but also developed a strategy for counteracting these problems.

The study began with Claudia Digregorio, a young woman from the Apulia region of Italy. Her case had been so vexing that Pope Francis imparted an in-person blessing on her at the Vatican before she left for the United States to be examined by Dr. Bnnemanns team at the NIHs Clinical Center.

Like many of the other patients, Claudia needed a wheelchair to move around and a surgically implanted tracheostomy tube to help with breathing. Neurological examinations by the team revealed that she and the others had many of the hallmarks of ALS, including severely weakened or paralyzed muscles. In addition, some patients muscles showed signs of atrophy when examined under a microscope or with non-invasive scanners.

Nevertheless, this form of ALS appeared to be different. Most patients are diagnosed with ALS around 50 to 60 years of age. The disease then worsens so rapidly that patients typically die within three to five years of diagnosis. In contrast, initial symptoms, like toe walking and spasticity, appeared in these patients around four years of age. Moreover, by the end of the study, the patients had lived anywhere from five to 20 years longer.

These young patients had many of the upper and lower motor neuron problems that are indicative of ALS, said Payam Mohassel, M.D., an NIH clinical research fellow and the lead author of the study. What made these cases unique was the early age of onset and the slower progression of symptoms. This made us wonder what was underlying this distinct form of ALS.

The first clues came from analyzing the DNA of the patients. The researchers used next-generation genetic tools to read the patients exomes, the sequences of DNA that hold the instructions for making proteins. They found that the patients had conspicuous changes in the same narrow portion of the SPLTC1 gene. Four of the patients inherited these changes from a parent. Meanwhile, the other six cases appeared to be the result of what scientist call de novo mutations in the gene. These types of mutations can spontaneously occur as cells rapidly multiply before or shortly after conception.

Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme, called SPT, which catalyzes the first of several reactions needed to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought the ALS-causing mutations they discovered may produce similar problems. However, blood tests from the patients showed no signs of the harmful sphingolipids.

At that point, we felt like we had hit a roadblock. We could not fully understand how the mutations seen in the ALS patients did not show the abnormalities expected from what was known about SPTLC1 mutations, said Dr. Bnnemann. Fortunately, Dr. Dunns team had some ideas.

For decades Dr. Dunns team had studied the role of sphingolipids in health and disease. With the help of the Dunn team, the researchers reexamined blood samples from the ALS patients and discovered that the levels of typical sphingolipids were abnormally high. This suggested that the ALS mutations enhanced SPT activity.

Similar results were seen when the researchers programmed neurons grown in petri dishes to carry the ALS-causing mutations in SPLTC1. The mutant carrying neurons produced higher levels of typical sphingolipids than control cells. This difference was enhanced when the neurons were fed the amino acid serine, a key ingredient in the SPT reaction.

Previous studies have suggested that serine supplementation may be an effective treatment for HSAN1. Based on their results, the authors of this study recommended avoiding serine supplementation when treating the ALS patients.

Next, Dr. Dunns team performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity.

Our results suggest that these ALS patients are essentially living without a brake on SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high then ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short circuit this feedback loop, said Dr. Dunn. We thought that restoring this brake may be a good strategy for treating this type of ALS.

To test this idea, the Bnnemann team created small interfering strands of RNA designed to turn off the mutant SPLTC1 genes found in the patients. Experiments on the patients skin cells showed that these RNA strands both reduced the levels of SPLTC1 gene activity and restored sphingosine levels to normal.

These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. In addition, we are also exploring other ways to step on the brake that slows SPT activity, said Dr. Bonnemann. Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.

This study was supported by the NIH Intramural Research Program at the NINDS; NIH grants (NS10762, NS072446); the U.S. Department of Defenses Congressionally Directed Medical Research Programs (W81XWH-20-1-0219); the Swiss National Foundation (31003A_179371); the Deater foundation, Inc. The views expressed here do not represent those of the Department of Defense.

NINDSis the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Mohassel, P. et al., Childhood Amyotrophic Lateral Sclerosis Caused by Excess Sphingolipid Synthesis. Nature Medicine, May 31, 2021 DOI: 10.1038/s41591-021-01346-1

###

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Scientists discover a new genetic form of ALS in children - National Institutes of Health

Engine Biosciences is a Singapore- and San Francisco-based company combining machine learning and genomics to decipher complex biology and uncover novel drugs and targets for areas of high unmet need. The venture-backed biotech received $10m in seed funding in 2018, and last week announced it had raised $43m in a series A round to fund the development of its NetMAPPR and CombiGEM technologies.

NetMAPPR is a searchable biology platform, which uses advanced computational tools to analyse large patient disease datasets. It can assess millions-to-billions of gene interactions to generate promising gene combinations and drug targets for specific patient populations.

The companys patented CombiGEM technology tests hundreds of thousands of gene interactions experimentally in diseased cells. The resulting data improves Engines machine learning algorithms, while high-ranking genes are prioritised for drug discovery and development.

Leveraging chemistry, artificial intelligence, combinatorial genetics and data science, Engines technologies enable researchers and drug developers to uncover the gene interactions and biological networks underlying diseases faster and more cost-effectively than conventional methods.

The companys growing pipeline of novel drugs for genetically defined patient populations has shown promise in treating liver, ovarian, colorectal and breast cancers, which represent approximately 2.5 million deaths every year in total. Engine is already progressing its novel biology findings into drug discovery programmes and proprietary small molecule inhibitors, and is exploring other disease areas through a series of collaborations.

The series A funding round was led by Polaris Partners and included several existing investors. The new funds will be used to expand Engines portfolio of precision oncology therapeutics, prepare for its first clinical programmes and scale its proprietary technology platform. Amy Schulman, managing partner at Polaris Partners, has also joined the Engine Biosciences Board of Directors.

Engine co-founder and CEO Jeffrey Lu said in a statement: Many breakthrough tools to edit, programme and modulate biology have emerged and matured in recent years. The fundamental question continues to be whether we know the disease-driving errors in the genetic code of biology to direct these tools, including therapeutics.

We are honoured that this preeminent group of life science and technology investors has recognised the progress our team has made and is supporting our mission to unleash new medicines by deciphering biology.

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Regenerative medicine: moving next-gen treatments from lab to clinic - Pharmaceutical Technology

NIH researchers discovered a new form of ALS that begins in childhood. The study linked the disease to a gene called SPLTC1. As part of the study, NIH senior scientist Carsten Bonnemann, M.D., (right) examined Claudia Digregorio (left), a patient from the Apulia region of Italy. Credit: Courtesy of the NIH/NINDS

NIH- and USU- led study links ALS to a fat manufacturing gene and maps out a genetic therapy.

In a study of 11 medical-mystery patients, an international team of researchers led by scientists at the National Institutes of Health and the Uniformed Services University (USU) discovered a new and unique form of amyotrophic lateral sclerosis (ALS). Unlike most cases of ALS, the disease began attacking these patients during childhood, worsened more slowly than usual, and was linked to a gene, called SPTLC1, that is part of the bodys fat production system. Preliminary results suggested that genetically silencing SPTLC1 activity would be an effective strategy for combating this type of ALS.

ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We found that a genetic form of the disease can also threaten children. Our results show for the first time that ALS can be caused by changes in the way the body metabolizes lipids, said Carsten Bnnemann, M.D., senior investigator at the NIHs National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published inNature Medicine.We hope these results will help doctors recognize this new form of ALS and lead to the development of treatments that will improve the lives of these children and young adults. We also hope that our results may provide new clues to understanding and treating other forms of the disease.

Dr. Bnnemann leads a team of researchers that uses advanced genetic techniques to solve some of the most mysterious childhood neurological disorders around the world. In this study, the team discovered that 11 of these cases had ALS that was linked to variations in the DNA sequence of SPLTC1, a gene responsible for manufacturing a diverse class of fats called sphingolipids.

In addition, the team worked with scientists in labs led by Teresa M. Dunn, Ph.D., professor and chair at USU, and Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland. Together they not only found clues as to how variations in the SPLTC1 gene lead to ALS but also developed a strategy for counteracting these problems.

The study began with Claudia Digregorio, a young woman from the Apulia region of Italy. Her case had been so vexing that Pope Francis imparted an in-person blessing on her at the Vatican before she left for the United States to be examined by Dr. Bnnemanns team at the NIHs Clinical Center.

Like many of the other patients, Claudia needed a wheelchair to move around and a surgically implanted tracheostomy tube to help with breathing. Neurological examinations by the team revealed that she and the others had many of the hallmarks of ALS, including severely weakened or paralyzed muscles. In addition, some patients muscles showed signs of atrophy when examined under a microscope or with non-invasive scanners.

Nevertheless, this form of ALS appeared to be different. Most patients are diagnosed with ALS around 50 to 60 years of age. The disease then worsens so rapidly that patients typically die within three to five years of diagnosis. In contrast, initial symptoms, like toe walking and spasticity, appeared in these patients around four years of age. Moreover, by the end of the study, the patients had lived anywhere from five to 20 years longer.

These young patients had many of the upper and lower motor neuron problems that are indicative of ALS, said Payam Mohassel, M.D., an NIH clinical research fellow and the lead author of the study. What made these cases unique was the early age of onset and the slower progression of symptoms. This made us wonder what was underlying this distinct form of ALS.

The first clues came from analyzing the DNA of the patients. The researchers used next-generation genetic tools to read the patients exomes, the sequences of DNA that hold the instructions for making proteins. They found that the patients had conspicuous changes in the same narrow portion of the SPLTC1 gene. Four of the patients inherited these changes from a parent. Meanwhile, the other six cases appeared to be the result of what scientist call de novo mutations in the gene. These types of mutations can spontaneously occur as cells rapidly multiply before or shortly after conception.

Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme, called SPT, which catalyzes the first of several reactions needed to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought the ALS-causing mutations they discovered may produce similar problems. However, blood tests from the patients showed no signs of the harmful sphingolipids.

At that point, we felt like we had hit a roadblock. We could not fully understand how the mutations seen in the ALS patients did not show the abnormalities expected from what was known about SPTLC1 mutations, said Dr. Bnnemann. Fortunately, Dr. Dunns team had some ideas.

For decades Dr. Dunns team had studied the role of sphingolipids in health and disease. With the help of the Dunn team, the researchers reexamined blood samples from the ALS patients and discovered that the levels of typical sphingolipids were abnormally high. This suggested that the ALS mutations enhanced SPT activity.

Similar results were seen when the researchers programmed neurons grown in petri dishes to carry the ALS-causing mutations in SPLTC1. The mutant carrying neurons produced higher levels of typical sphingolipids than control cells. This difference was enhanced when the neurons were fed the amino acid serine, a key ingredient in the SPT reaction.

Previous studies have suggested that serine supplementation may be an effective treatment for HSAN1. Based on their results, the authors of this study recommended avoiding serine supplementation when treating the ALS patients.

Next, Dr. Dunns team performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity.

Our results suggest that these ALS patients are essentially living without a brake on SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high then ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short circuit this feedback loop, said Dr. Dunn. We thought that restoring this brake may be a good strategy for treating this type of ALS.

To test this idea, the Bnnemann team created small interfering strands of RNA designed to turn off the mutant SPLTC1 genes found in the patients. Experiments on the patients skin cells showed that these RNA strands both reduced the levels of SPLTC1 gene activity and restored sphingosine levels to normal.

These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. In addition, we are also exploring other ways to step on the brake that slows SPT activity, said Dr. Bonnemann. Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.

Reference: Childhood Amyotrophic Lateral Sclerosis Caused by Excess Sphingolipid Synthesis by Mohassel, P. et al., 31 May 2021, Nature Medicine.DOI: 10.1038/s41591-021-01346-1

This study was supported by the NIH Intramural Research Program at the NINDS; NIH grants (NS10762, NS072446); the U.S. Department of Defenses Congressionally Directed Medical Research Programs (W81XWH-20-1-0219); the Swiss National Foundation (31003A_179371); the Deater foundation, Inc. The views expressed here do not represent those of the Department of Defense.

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Study of 11 Medical-Mystery Patients Results in Discovery of New Genetic Form of ALS in Children - SciTechDaily

DALLASMay 28, 2021A study of gene activity in the brains hippocampus, led by UT Southwestern researchers, has identified marked differences between the regions anterior and posterior portions. The findings, published today in Neuron, could shed light on a variety of brain disorders that involve the hippocampus and may eventually help lead to new, targeted treatments.

Genevieve Konopka, Ph.D.

These new data reveal molecular-level differences that allow us to view the anterior and posterior hippocampus in a whole new way, says study leader Genevieve Konopka, Ph.D., associate professor of neuroscience at UTSW.

She and study co-leader Bradley C. Lega, M.D., associate professor of neurological surgery, neurology, and psychiatry, explain that the human hippocampus is typically considered a uniform structure with key roles in memory, spatial navigation, and regulation of emotions. However, some research has suggested that the two ends of the hippocampus the anterior, which points downward toward the face, and the posterior, which points upward toward the back of the head take on different jobs.

Bradley C. Lega, M.D.

Scientists have speculated that the anterior hippocampus might be more important for emotion and mood, while the posterior hippocampus might be more important for cognition. However, says Konopka, a Jon Heighten Scholar in Autism Research, researchers had yet to explore whether differences in gene activity exist between these two halves.

For the study, Konopka and Lega, both members of the Peter ODonnell Jr. Brain Institute, and their colleagues isolated samples of both the anterior and posterior hippocampus from five patients who had the structure removed to treat epilepsy. Seizures often originate from the hippocampus, explains Lega, who performed the surgeries. Although brain abnormalities trigger these seizures, microscopic analysis suggested that the tissues used in this study were anatomically normal.

Marked differences in gene activity were identified in the anterior portion of the hippocampus, which points downward toward the face, and the posterior, which points upward toward the back of the head. Credit: Melissa Logies

After removal, the samples underwent single nuclei RNA sequencing (snRNA-seq), which assesses gene activity in individual cells. Although snRNA-seq showed mostly the same types of neurons and support cells reside in both sections of the hippocampus, activity of specific genes in excitatory neurons those that stimulate other neurons to fire varied significantly between the anterior and the posterior portions of the hippocampus. When the researchers compared this set of genes to a list of genes associated with psychiatric and neurological disorders, they found significant matches. Genes associated with mood disorders, such as major depressive disorder or bipolar disorder, tended to be more active in the anterior hippocampus; conversely, genes associated with cognitive disorders, such as autism spectrum disorder, tended to be more active in the posterior hippocampus.

Lega notes that the more researchers are able to appreciate these differences, the better theyll be able to understand disorders in which the hippocampus is involved.

The idea that the anterior and posterior hippocampus represent two distinct functional structures is not completely new, but its been underappreciated in clinical medicine, he says. When trying to understand disease processes, we have to keep that in mind.

Other UTSW researchers who contributed to this study include Fatma Ayhan, Ashwinikumar Kulkarni, Stefano Berto, Karthigayini Sivaprakasam, and Connor Douglas.

This work was funded by grants from the National Institutes of Health (NIH grants NS106447, T32DA007290, T32HL139438, NS107357), a University of Texas BRAIN Initiative seed grant (366582), the Chilton Foundation, the National Center for Advancing Translational Sciences of the NIH (under Center for Translational Medicine award UL1TR001105), the Chan Zuckerberg Initiative (an advised fund of the Silicon Valley Community Foundation, HCA-A-1704-01747), and the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition (scholar award 220020467).

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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Same Difference: Two halves of the hippocampus have different gene activity - UT Southwestern

A massive genome-wide association study (GWAS) of genetic and health records of 1.2 million people from four separate data banks has identified 178 gene variants linked to major depression, a disorder that will affect one of every five people during their lifetimes.

The results of the study, led by the U.S. Department of Veterans Affairs (V.A.) researchers at Yale University School of Medicine and University of California-San Diego (UCSD), may one day help identify people most at risk of depression and related psychiatric disorders and help doctors prescribe drugs best suited to treat the disorder.

The study was published May 27 in the journal Nature Neuroscience.

For the study, the research team analyzed medical records and genomes collected from more than 300,000 participants in the V.A.s Million Veteran Program (MVP), one of the largest and most diverse databanks of genetic and medical information in the world.

These new data were combined in a meta-analysis with genetic and health records from the UK Biobank, FinnGen (a Finland-based biobank), and results from the consumer genetics company 23andMe. This part of the study included 1.2 million participants. The researchers crosschecked their findings from that analysis with an entirely separate sample of 1.3 million volunteers from 23andMe customers.

When the two sets of data from the different sources were compared, genetic variants linked to depression replicated with statistical significance for most of the markers tested.

Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.

Daniel Levey

What is most heartening is we could replicate our findings in independent data sets, said Daniel Levey, an associate research scientist in the Yale Department of Psychiatry and co-lead author. Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.

Like many mental health disorders, depression is genetically complex and is characterized by combinations of many different genetic variants, the researchers say.

Thats why we werent surprised by how many variants we found, said Joel Gelernter, the Foundations Fund Professor of Psychiatry at Yale, professor of genetics and of neuroscience, and co-senior author of the study. And we dont know how many more there are left to discover hundreds? Maybe even thousands?

The size of the new GWAS study will help clinicians to develop polygenic risk scores to pinpoint those most at risk of developing major depression and other related psychiatric disorders such as anxiety or post-traumatic stress disorder, the authors say.

The study also provides deep insights into the underlying biology of genetic disorders. For instance, one gene variant implicated in depression, NEGR1, is a neural growth regulator active in the hypothalamus, an area of the brain previously linked to depression. That confirms research done by the late Yale neuroscientist Ronald Duman on the role of neurotrophic factors in depression, Levey said.

Its really striking when completely different kinds of research converge on similar biology, and thats whats happening here, he said.

Insights into the functions of the variants can also help identify many drugs that hold promise in the treatment of depression, the researchers say. For instance, the drug riluzole, which is approved for the treatment of amyotrophic lateral sclerosis (ALS), modulates glutamate transmission in brain. Several gene variants linked by the new study to depression affect the glutamate system, which is actively being studied for depression treatments.

One of the real goals of the research is bringing forward new ways to treat people suffering from depression, added co-senior author Dr. Murray Stein, staff psychiatrist at the V.A. San Diego Healthcare System and Distinguished Professor of Psychiatry and Public Health at UCSD.

Research was primarily funded by the U.S. Department of Veterans Affairs, including the Million Veteran Program and the Cooperative Studies Program. Levey also received support from a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation.

See more here:
Roots of major depression revealed in all its genetic complexity - Yale News

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD patients are at higher risk of developing Non-alcoholic steatohepatitis (NASH), which causes severe and chronic liver inflammation, fibrosis and liver damage. A patient with NASH is believed to be at high risk for developing a form of liver cancer called hepatocellular carcinoma (HCC).

Apart from lifestyle interventions, there are currently no approved treatments for NASH. A liver transplant is sometimes the only remedy.

While risk factors for NASH (obesity, type-2 diabetes and gene mutations like PNPLA3) and HCC (Hepatitis B and C infections, alcohol overconsumption and cirrhosis) are well known, the precise mechanism of how simple fatty liver progresses to chronic inflammation, liver fibrosis, NASH and HCC is not known.

Debanjan Dhar, PhD, is co-senior author of the study and assistant professor in the Department of Medicine, Division of Gastroenterology at UC San Diego School of Medicine.

A recent study led by researchers at University of California San Diego School of Medicine found in a mouse model that when fed a Western diet rich in calories, fat and cholesterol, the mice progressively became obese, diabetic and developed NASH, which progressed to HCC, chronic kidney and cardiovascular disease.

The findings, published in the May 31, 2021 online edition of Cellular and Molecular Gastroenterology and Hepatology, showed that by simply changing the Western diet in a mouse model to a normal chow diet, where calories are derived from proteins and carbohydrates rather than fats, with no cholesterol, NASH and liver fibrosis were improved; and cancer progression and mortality prevented.

While the mice that continued on a Western diet developed HCC and had an increased risk of death, 100 percent of the mice that stopped the diet survived the length of the study without developing HCC, said Debanjan Dhar, PhD, co-senior author of the study and assistant professor in the Department of Medicine, Division of Gastroenterology at UC San Diego School of Medicine.

David Brenner, MD, is co-senior author and vice chancellor of UC San Diego Health Sciences.

This indicates that NASH and HCC may be a preventable disease and that diet plays a crucial role in the disease outcome.

In mice no longer fed the Western diet, researchers also found a decrease in liver fat and improvement in glucose tolerance an indicator of diabetes and several genes and cytokines that were affected in NASH returned to normal levels and function. In addition, Dhar and his team found key changes in the gut microbiome that modulate liver disease progression.

Although NASH is a liver disease, our results show its development and progression is orchestrated by multiple organs.

A surprising finding, said the researchers, was that when they switched the Western diet of the mice with NASH to normal chow, the effect was more pronounced on the liver rather than on whole body weight.

This could mean that slight changes in the liver might have profound effects on the disease outcome, said David Brenner, MD, co-senior author and vice chancellor of UC San Diego Health Sciences.

Researchers also compared mouse model findings to human patient datasets, indicating that gene expression changes in mouse livers were similar to human counterparts.

Our animal model provides an important pre-clinical testing platform to study the safety and efficacy of drugs that are currently being developed, as well as to test the repurposing of other drugs that are already FDA approved for other diseases, said Dhar.

Co-authors include: Souradipta Ganguly, Linshan Shang, Ruoyu Wang, Yanhan Wang, Bernd Schnabl, Rob Knight, Sara Brin Rosenthal, Gibraan Rahman, Anthony Diomino, Tatiana Kisseleva, Mojgan Hosseini and Mojgan Hosseini, all with UC San Diego; German Aleman Muench and Pejman Soorosh with Janssen Research and Development; and Hyeok Choon Kwon with National Medical Center, South Korea.

The research was funded, in part, by the National Institutes of Health (Grants DK120515, KL2TR001444 and 5P50AA011999), an ALF Liver Scholar award, the Southern California Research Center for ALPD and Cirrhosis.

See original here:
Diet Plays Critical Role in NASH Progressing to Liver Cancer in Mouse Model - UC San Diego Health