Category Archives: Gene Medicine

The aim of the present study was to investigate mutation status of the cKit and PDGFRA genes in patients with a gastrointestinal stromal tumor (GIST).In total, 96 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 12, 13, 14, 17, and 18 in KIT and exons 12, 14, and 18 in PDGFRA.KIT mutations were detected in 65 cases (67.71%), of which 81.54% (53/65) were located on exon 11, 12.31% (8/65) were located on exon 9, 4.61% (3/65) were located on exon 17, which included a concomitant mutation of exon 9 and 11, and 4.08% (2/65) were located on exon 13, which included a concomitant mutation on exon 11. The most common mutation in exon 11 was deletion, which accounted for 77.36% (41/53) of the cases, followed by a point mutation observed in 22.64% (12/53) of the cases. Among the 31 GIST cases without a KIT mutation, a mutation in PDGFRA was detected in 5 cases (5.21%, 5/96; 16.13%, 5/31). With respect to gender, age, tumor max diameter, tumor position, and mitotic index, there were no significant differences between KIT/PDGFRA mutations and non-mutations.GIST mainly occurs in the stomach, and the cytological morphology is mainly spindle cells, and the mutations mainly occur in KIT genes. We need a large sample size to analyze the regularity of GIST gene mutations in Hakka population and understand the independent prognostic correlation of all KIT/PDGFRA genotypes.

Originally posted here:
Mutations of the and gene in gastrointestinal stromal tumors among hakka population of Southern China. - Physician's Weekly

SEOUL, Korea, June 14, 2021 (GLOBE NEWSWIRE) -- On June 14, GENECAST (CEO, SeungChan Baek), a specialist in liquid biopsy-based cancer diagnostics, announced that it will begin a clinical study for the early diagnosis of non-small cell lung cancer (NSCLC). The team will be led by Professor Jhingook Kim in the Lung and Esophageal Surgery Division within the Department of Thoracic Surgery at Samsung Medical Center.

This study evaluates whether the results of liquid biopsy-based EGFR testing with GENECAST's ADPS technology can represent the results of EGFR testing on tumor tissue DNA. This study is especially significant for identifying the clinical effects of liquid biopsies on early cancer detection, given that it involves early-stage cancer patients at the 1B to 3A clinical stages.

To date, the clinical effects of liquid biopsies applied to lung cancer patients have mostly been researched with a focus on lung cancer that has been systemically spread through blood. In other words, lung cancer containing a portion of multiple tumor cells in the blood. On other hand, little research has been done about the power to detect EGFR gene mutations before surgery in patients with lung cancer that is resectable due to the absence of lesions spread through blood. This is because carrying out this research is considerably difficult.

In recent years, active discussions have globally been under way over the possibility of researching the pre-surgical administration of EGFR inhibitors for resectable early-stage lung cancer. This is because the pre-surgical administration of EGFR inhibitors is expected to not only enable surgery by blocking the spread of tumors in early stages and reducing the size of tumors, but also increase the actual survival rate of patients. In addition, it is easier to administrate drugs before surgery. Using EGFR inhibitors should be preceded by the diagnosis of EGFR gene mutations, but traditional biopsies often involve high risks or are impossible due to the nature of sites of lung cancer.

If the clinical effects of liquid biopsies with ADPS technology prove that this diagnostic method can detect early-stage NSCLC, then it is expected that this will lead to more active research efforts on the administration of EGFR inhibitors in these early-stage patients.

GENECAST's chief technical officer (CTO) Byungchul Lee ph.D commented, "With the recent FDA approval of Osimertinib as an adjuvant therapy for early-stage NSCLC, the early diagnosis of this cancer using liquid biopsies is receiving attention again. If liquid biopsies can diagnose not only metastatic lung cancer, but also operatable early-stage lung cancer, then they are likely to improve the survival rates of NSCLC patients."

Professor Jhingook Kim, a specialist in lung cancer in the Department of Thoracic Surgery at Samsung Medical Center, expressed his expectations for this study: "The study is very significant in terms of identifying the effects of liquid biopsies on early-stage patients considering resective surgery for a complete recovery, not patients with systemic metastases. Depending on the study results, follow-up studies will likely be conducted on various topics such as the use of liquid biopsies in the early diagnosis of cancer.

# Overview of GENECAST

GENECAST is a specialist in liquid biopsy-based cancer diagnostics that analyze cancer genes. This company has achieved 0.01% of actual detection sensitivity and the highest sensitivity of 0.0001% through its own original technology called the Allele-Discriminating Priming System (ADPS). ADPS is a qPCR-based technology that provides simpler and faster testing than other liquid biopsy-based diagnostic methods. It enables the analysis of cancer genes in Stage 1 cancer patients by realizing the highest detection sensitivity available today. GENECAST is operating a range of businesses including precision medicine, LDT commercialization, and companion diagnostics based on ADPS technology, and is dedicated to the development of new technologies that can realize early diagnostics according to the type of cancer. More information can be found at http://www.igenecast.com.

Contact:

Soobin ShinGENECAST Press OfficeTel: +82-2-2157-3151E-mail: comm@genecast.co.kr

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/96d91465-1699-41a3-89f2-6be43bf58df5

Excerpt from:
GENECAST begins clinical research on early diagnosis of lung cancer with Samsung Medical Center - GlobeNewswire

The two entities are looking to expand the potential applications of mRNA therapeutics to tackle a range of diseases.

The delivery of mRNA effectively and safely into the cell is one of the biggest challenges for expanding the use of mRNA therapeutics to promising fields such as cancer immunotherapy, protein replacement and gene editing.

The German company said a polymer-based delivery system was developed at the US university and complements its own technology platform for mRNA delivery. Known as ChargeAlteringReleasableTransporters (CART), the system was developed by Professor Robert Waymouth, Professor Paul Wender and Professor Ronald Levy.

Starting this month, Evonik and Stanford scientists will begin a three-year sponsored research collaboration to develop CART, which Evonik will license and commercialize.

Through this project we look forward to enabling the next generation of mRNA-based medicine, said Dr Thomas Riermeier, head of Evoniks Healthcare business line.

Evonik said its team will work together with Stanford University scientists to scale up the synthesis and formulation, and further develop its innovative technology for organ selective delivery based on a non-animal-derived, synthetic degradable polymer.

Evonik said it is aiming to make this technology GMP quality and available for use in clinical-stage developments and, ultimately, on a commercial scale.

The move is intended to expand Evoniks portfolio as a system solutions partner for advanced drug delivery.

Evonik said it recognized the potential of gene-based therapeutic approaches early on, making a targeted investment in this space with the acquisition of Transferra Nanosciences in 2016, a Vancouver-based lab with a strong focus on parenteral drug formulation development using lipid nanoparticles and liposomes.

Continued here:
Evonik collaborating with Stanford University on 'next generation' of mRNA-based medicine - BioPharma-Reporter.com

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.

Original post:
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.

Continued here:
Genomics and Medicine - NHGRI

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

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

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