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Columbia University researchers will use a $15 million federal grant to design individualized gene therapies for nine people with ultra-rare genetic forms of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The three-year grant comes from the National Institute of Neurological Disorders and Stroke’s (NINDS) <a href="https://www.ninds.nih.gov/current-research/research-funded-ninds/translational-research/ultra-rare-gene-based-therapy-urgent-network">Ultra-rare Gene-based Therapy (URGenT) Network</a>, a program supporting the development of genetic treatments for ultra-rare neurological diseases. NINDS is part of the National Institutes of Health.
The funding directly supports <a href="https://alsnewstoday.com/news/silence-als-aims-personalized-aso-therapy-rare-mutation-als-patients/">Silence ALS</a>, an initiative aimed at developing customized treatments for ALS patients whose disease derives from ultra-rare genetic mutations, or mutations occurring in fewer than 30 patients globally.
Researchers are confident that as they gain additional knowledge about ALS biology, the project could ultimately also help those with more common disease forms.
“We don&#8217;t fully understand the links yet,&#8221; Neil Shneider, MD, PhD, associate professor of motor neuron diseases at Columbia, said in a <a href="https://www.cuimc.columbia.edu/news/columbia-awarded-15-million-create-medicines-ultra-rare-forms-als">university press release.</a> &#8220;By comparing these ultra-rare patients and their response to individualized therapy, we hope to learn something about the biology of the disease that will eventually help a larger percentage of ALS patients.&#8221;
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<h3>Focus is ASO gene therapies</h3>
“There are clinical and pathological similarities between genetic and more common forms of ALS, which gives us real reasons to think they have a common underlying biology and that these different mutations are entry points into shared pathways of disease,” Shneider said.
Silence ALS was<a href="https://alsnewstoday.com/news/silence-als-aims-personalized-aso-therapy-rare-mutation-als-patients/"> launched in 2022</a> by Shneider, who is also director of the Eleanor and Lou Gehrig ALS Center at Columbia&#8217;s Vagelos College of Physicians and Surgeons, in collaboration with the <a href="https://www.nlorem.org/">n-Lorem Foundation</a>. The idea was to develop customized therapies employing a gene-silencing technology called antisense oligonucleotides (ASOs).
ASOs are small molecules that can bind to messenger RNA, the intermediary molecules made from a specific gene and used as a template for protein production, targeting them for degradation and reducing protein production. They can be quickly developed to target the mutation of each patient, potentially enabling individualized treatments for ALS and other ultra-rare conditions.
An ASO molecule sold under the brand name <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) is already approved to reduce abnormal SOD1 protein levels in ALS patients carrying mutations in the SOD1 gene.
Th U.S. Food and Drug Administration (FDA) in 2022 cleared the first Silence ALS therapy to treat a single ALS patient with an ultra-rare mutation in the TARDBP gene, which provides the instructions for making the TDP-43 protein.
The new grant will build on that success, funding development of potential ASO treatments for ALS patients with mutations in the TARDBP gene or in the CHCHD10 gene, which also causes frontotemporal dementia. The project will also seek to target other ALS genetic mutations that are dominantly inherited — or in which a single mutated copy of the gene is enough to develop the disease.
The funds will support all treatment development activities, including animal toxicology studies that will support submissions to the FDA requesting the initiation of first-in-human trials.
As its infrastructure grows through URGenT funding, Silence ALS hopes to produce a model that can be followed by other ultra-rare disease communities. The program is in contact with international partners to see whether similar treatment programs are possible in other countries.
“Silence ALS aims to create knowledge, experience, and efficiencies that will inform our understanding and approach across diseases and treatment modalities,&#8221; said Chris Boshoff, PhD, program director of the URGenT Network. “It is poised to establish a model for therapeutic development in ultra-rare disease.”
“The FDA is the only regulatory body that allows ASO development for ultra-rare cases, and my hope is that the Silence ALS experience will help to de-risk this approach and convince other regulatory agencies to allow something similar,” said Shneider.

Columbia gets $15M to design gene therapies for rare ALS forms

<a href="https://coavetx.com/">Coave Therapeutics</a> has received a grant from the <a href="https://www.als.org/">ALS Association</a> to support the development of its gene therapy candidate CTx-TFEB for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The grant, made through the <a href="https://www.als.org/research/research-we-fund/our-awards-and-programs/barnett-drug-development-program">Lawrence and Isabel Barnett Drug Development Program</a>, is part of the $2.9 million the ALS Association has granted to six organizations committed to advancing novel therapies for ALS.
It will help the company conduct proof-of-concept preclinical studies of CTx-TFEB that may support moving the treatment into ALS clinical trials in the future.
“Our goal is to establish a robust preclinical proof-of-concept, laying a strong foundation for advancing to the clinic in the near future,” Lolita Petit, PhD, Coave’s chief scientific officer, said in a <a href="https://www.globenewswire.com/news-release/2024/02/29/2837821/0/en/Coave-Therapeutics-Receives-Grant-from-the-ALS-Association-to-Advance-its-CTx-TFEB-Program-as-a-Potential-Treatment-for-All-Forms-of-ALS.html">company press release</a>. “Together, we are now on the brink of a breakthrough that promises hope and progress for patients impacted by ALS.”
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<h3>Importance of moving promising treatments from laboratory to clinical testing</h3>
“Getting promising treatments out of the laboratory and into clinical testing as quickly as possible is key to making ALS a livable disease until we can cure it,” said Kuldip Dave, PhD, senior vice president of research at the ALS Association.
The molecular mechanisms that cause ALS aren&#8217;t fully known, but virtually all cases are marked by the accumulation of protein clumps. This is in part due to a dysregulation in autophagy — the process by which cells recycle abnormal or defective molecules, which usually happens inside specialized compartments called lysosomes.
It&#8217;s anticipated that boosting autophagy could promote the clearance of these toxic protein clumps in ALS nerve cells, thereby slowing or halting neuronal degeneration and disease progression.
The transcription factor TFEB has emerged as a key regulator of the autophagy lysosomal pathway. This protein is found at lower levels in the brains of ALS patients, and activating it is believed to be a promising approach to increase autophagy and remove the harmful protein clumps.
CTx-TFEB is a novel genetic therapy product designed to deliver the TFEB gene specifically to nerve cells in the brain and spinal cord. The gene sequence is transported inside an adeno-associated virus that does not cause disease in humans. The virus was modified with Coave’s proprietary <a href="https://coavetx.com/#meetaligater">ALIGATER platform</a> to carry certain molecules that make the vector more specific to nerve cells.
“Modulating autophagy using TFEB gene therapy is an exciting approach to promote the clearance of accumulated toxic material in affected neurons, halt motor neuron degeneration, and preserve muscular function in people with ALS,” Petit said.
The therapy is expected to activate autophagy in ALS patients regardless of their genetic subtype, potentially serving as a therapy for all <a href="https://alsnewstoday.com/forms-of-als/">types of ALS</a>.
“We are proud to help drive the crucial transition from preclinical to clinical development for potential new ALS therapies through our Lawrence and Isabel Barnett Drug Development Program,” Dave said.

Coave wins grant to advance gene therapy CTx-TFEB for ALS

<a href="https://www.vectorytx.com/" rel="nofollow">VectorY Therapeutics</a> has raised about $138 million in funding aiming to bring into clinical testing VTx-002, its lead treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS). The therapy equips nerve cells to produce antibodies against the damaging <a href="https://alsnewstoday.com/news/scientists-find-how-tdp-43-affects-important-nerve-protein-als/">TDP-43 protein clumps that are an ALS hallmark</a>.
“The investment will enable us to advance our lead program VTx-002, a potentially disease-modifying therapy for ALS, into clinical development. Our program is uniquely positioned to address TDP-43 pathology, which underlies the disease in the vast majority of ALS patients,” Sander van Deventer, CEO of VectorY, said in a <a href="https://www.vectorytx.com/news/vectory-raises-129-million-138-million-series-a-financing-to-advance-vectorized-antibody-programs-in-neurodegenerative-diseases">company press release</a>.
The accumulation of TDP-43 protein clumps in nerve cells is seen in about 97% of all ALS cases, and clearing these toxic molecules is regarded as a potential approach to delaying or preventing disease progression in nearly all patients.
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<h3>A faulty TDP-43 protein clumps in nerve cells of ALS patients</h3>
Antibodies are natural proteins made by the immune system that are able to bind a specific target. A few <a href="https://alsnewstoday.com/news/italian-researcher-granted-20k-tdp-43-antibody-research-als-treatment/">antibodies aimed at clearing misfolded TDP-43</a> proteins from nerve cells are in development.
However, traditional antibody-based therapies are usually too large and limited in their ability to reach the brain and spinal cord. They also require regular administrations, as infused antibodies eventually degrade and lose their effectiveness.
VectorY is developing <a href="https://www.vectorytx.com/vectorized-antibody-platform" rel="nofollow">vectorized antibodies</a>, a class of antibodies that essentially deliver the genetic sequence of an antibody to target cells, enabling them to produce their own therapeutic antibodies.
The platform uses harmless adeno-associated viruses (AAV) that were modified to be highly specific to cells in the brain and spinal cord. In VTx-002, that AAV carries a gene designed to enter cells, where it can be used to produce an antibody against the faulty TDP-43 protein, while leaving functional TDP-43 proteins unharmed.
Notably, because the virus stays inside cells until they die, a single administration of the therapy is expected to result in long-term antibody production and durable responses.
Proceeds from the Series A financing also will be used to boost the development of existing and new vectorized antibodies for other conditions marked by the buildup of toxic protein aggregates, diseases called proteinopathies that include <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington’s</a> and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s</a>.
“The series A will also support advancement of additional pipeline programs targeting proteinopathies in neurodegenerative diseases demonstrating the broad potential of our platform,” van Deventer said.
The financing round was co-led by EQT Life Sciences and the Forbion Growth Opportunities Fund, with the support of multiple new and past investors.
“We are very impressed with VectorY’s unique capabilities to combine gene and antibody therapy drug development with deep neuroscience expertise. The company’s technology allows for targeted protein degradation while restoring or preserving normal protein function, with applications across multiple neurodegenerative diseases,” said Arno de Wilde, director at EQT Life Sciences.
Previous and new finance round investors included MRL Ventures Fund, a corporate venture arm of Merck in the U.S., Insight Partners, ALS Investment Fund, Forbion Ventures, and BioGeneration Ventures.
“The Series A financing, supported by such a strong syndicate of European and US investors, is an endorsement of our pioneering approach &#8230; to bring much-needed therapies to patients with neurodegenerative diseases,” van Deventer said.
As part of the financing, de Wilde, Wouter Joustra, a partner at Forbion Growth Opportunities Fund, and Karin Kleinhans, a partner at MRL Ventures Fund, will join VectorY’s board of directors.

VectorY raises millions to support antibody gene therapy for ALS

SOL-257, an experimental one-time gene therapy, was well tolerated and significantly improved disease outcomes in two distinct mouse models of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Developed by <a href="https://www.sola-bio.com/">Sola Biosciences</a>, SOL-257 is designed to clear the toxic TDP-43 protein that accumulates and forms clumps in ALS nerve cells, contributing to disease progression. The therapy significantly extended survival in one model, and improved muscle strength and motor function in the other.
Data from the preclinical studies were presented this week at Neuroscience 2023 in Washington, D.C.
“Our findings underscore SOL-257 as a highly promising translational therapy for ALS,” Akinori Hishiya, PhD, chief scientific officer at Sola, said in a <a href="https://www.businesswire.com/news/home/20231109597814/en/SOLA-Biosciences-Presents-Preclinical-Proof-of-Concept-Data-for-SOL-257-a-Gene-Therapy-Targeting-Misfolded-TDP-43-in-ALS-at-Neuroscience-2023-and-ALS-One-Symposium">company press release</a>. “Demonstrating efficacy in two distinct genetic mouse models of ALS supports our confidence that by targeting misfolded TDP-43, SOL-257 holds the potential to treat a vast majority of ALS patients.&#8221;
Abnormally folded TDP-43 is a common feature in both <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic</a> and <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial</a> types of ALS. It&#8217;s observed in about 97% of all ALS cases.
TDP-43 is normally found in the nucleus, where it regulates the first step of protein production from a gene. In ALS, the protein can take an abnormal shape, one more prone to accumulate in the cytoplasm and form toxic clumps, leading to cell damage and death.
[recommended-reading id=86261]
<h3>What does SOL-257 do?</h3>
SOL-257 is designed to target the misfolded TDP-43 and either promote its proper folding or facilitate its degradation, which ishould reduce nerve cell damage and slow disease progression.
It was developed with Sola&#8217;s JUMP70 technology platform, which promotes the production of JUMP70, a protein that connects the misfolded proteins to the patient’s own HSP70 chaperones. Chaperones are proteins that help other proteins fold correctly or direct misfolded ones to be degraded.
The company is developing JUMP70-based therapies for <a href="https://www.sola-bio.com/pipeline-2/">a number of conditions</a> marked by abnormal protein folding and aggregation, including <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington&#8217;s</a>, <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s diseases</a>, as well as <a href="https://cysticfibrosisnewstoday.com/cystic-fibrosis-overview/">cystic fibrosis</a>.
The therapies use a modified and harmless adeno-associated virus (AAV) to deliver the JUMP70 gene to cells. The resulting two-part protein is specific to both HSP70 and to each disease-causing misfolded protein.
With SOL-257, the protein is designed to bring together HSP70 and the misfolded TDP-43 proteins, while leaving functional TDP-43 alone to do its job.
In an earlier study, researchers showed <a href="https://alsnewstoday.com/news/als-gene-therapy-sol-257-targeting-tdp-43-shows-promise-mouse-model/">SOL-257 significantly extended the survival</a> of mice genetically modified to allow the controlled production of misfolded TDP-43.
<h3>SOL-257 effects on two mouse models of ALS</h3>
Sola showed additional data from that model along with another mouse model in which animals carried mutations in the C9ORF72 gene, whose defects are the most common <a href="https://alsnewstoday.com/als-and-genetics/">genetic cause of ALS</a>. These mutations are thought to trigger <a href="https://www.nature.com/articles/s41598-022-08724-w#:~:text=TDP%2D43%20pathology%20correlates%20well,this%20causes%20neuronal%20death17.">TDP-43&#8217;s movement out of the nucleus</a>, where it misfolds.
&#8220;I&#8217;m thrilled to announce SOL-257, a breakthrough gene therapy poised to tackle ALS by targeting TDP-43 pathology. Our compelling preclinical data highlights a significant step toward harnessing the body&#8217;s cellular defenses,&#8221; said Keizo Koya, PhD, Sola&#8217;s CEO. &#8220;Committed to excellence, we are advancing this promising therapy, striving to bring hope to the ALS community.&#8221;
In the first model, researchers showed that pretreatment with SOL-257 before abnormal TDP-43 production was induced suppressed the toxic clumps and significantly prolonged survival. All untreated animals died in the first eight weeks, but some treated ones lived for up to 17 weeks.
The intracerebroventricular injection, that is, one directly into the brain, that was used to deliver the viral vector carrying JUMP70 was well tolerated in mice, the researchers said.
To develop the C9ORF72 mouse model, mice were injected into the brain with a C9ORF72 gene carrying 149 repetitions of six specific DNA building blocks (GGGGCC) in its genetic sequence. In these animals, toxic TDP-43 clumps were found to build up over time and cause death.
The animals were treated with SOL-257 after letting the disease progress for three months. At this more advanced stage, the gene therapy also significantly reduced toxic TDP-43 clumps in the brain.
Mice were subjected to an open-field test, which uses the distance walked over a given time as a proxy to assess hyperactivity, a sign of neurodegeneration. Hyperactivity steadily declined between six and nine months after the SOL-257 injection, but increased in untreated mice.
Mice also underwent a wire hang test, which measures how long it takes to fall off a wire, to assess motor function and muscle strength. At nine months, untreated mice fell off significantly faster than SOL-257-treated mice.
The data supports the continued development of SOL-257 to treat ALS.
&#8220;The robust &#8230; proof-of-concept data makes me excited to complete the preclinical studies necessary to take SOL-257 into ALS clinical trials,&#8221; Gerry Cox, chief medical officer at Sola, said in an email to ALS News Today. &#8220;The unmet medical need in ALS remains high, despite the current therapeutic landscape, and the prospect of a broadly applicable, one-time therapy brings new hope to the ALS community.&#8221;

SOL-257 gene therapy improves outcomes in 2 ALS mouse models

<a href="https://www.anewmeds.com/">Anew Medical</a>&#8216;s targeted gene therapy candidate, ANEW-202, eased multiple mechanisms associated with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), leading to improved muscle function and survival in a mouse model of the disease.
The gene therapy, licensed on an exclusive worldwide basis from the Autonomous University of Barcelona, in Spain, is designed to provide muscle and nerve cells with long-term supplementation of the protein secreted-Klotho (s-KL).
Referred to as the &#8220;anti-aging&#8221; protein, mice lacking s-KL age rapidly and soon develop diseases related to aging, whereas mice that over-produce the protein live longer.
According to Anew, studies suggest that s-KL <a href="https://www.anewmeds.com/products/genes/">may treat many age-related disorders</a>, including dementia, heart disease, bone degeneration, kidney disease, and neuromuscular conditions such as ALS.
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&#8220;Our s-KL gene therapy construct exhibits robust and prolonged bioactivity in this model of ALS and these results support ALS as the first indication in clinical trials of this new approach to treat ALS,&#8221; Joseph Sinkule, Anew&#8217;s CEO, said in a <a href="https://www.prnewswire.com/news-releases/gene-therapy-candidate-for-amyotrophic-lateral-sclerosis-als-demonstrates-bioactivities-in-a-murine-model-of-the-disease-301769759.html">press release</a>.
ALS is a progressive disorder marked by the loss of motor neurons, which are nerve cells that control voluntary movements. As a result, the brain&#8217;s ability to control muscle movement declines over time, and muscles become smaller and weaker.
ANEW-202 uses a modified and harmless virus to deliver the gene that encodes s-KL directly to muscle cells and those of the nervous system. Its goal is to have these cells produce s-KL protein in large quantities, potentially preventing motor neuron death and slowing disease progression.
Researchers evaluated the gene therapy in SOD1-G93A mice, an animal model of the disease that carries a mutation in the SOD1 gene. Such mutations cause up to 20% of <a href="https://alsnewstoday.com/forms-of-als-2/familial-als/">familial ALS</a> cases, and these mice recapitulate most ALS neuromuscular deficits, including low levels of s-KL protein in their muscles and spinal cord.
According to Anew, ANEW-202 treatment resulted in over-production of the s-KL protein in muscle and nerve cells in the brains and spinal cords of mice.
Compared with untreated control mice, treated animals showed a reduction in neuroinflammation and oxidative stress, two hallmark signs of ALS. Oxidative stress is a type of cell damage caused by an excess of highly reactive oxygen-containing molecules that cannot be cleared properly by the body&#8217;s anti-oxidant defenses.
<h3>Neuromuscular communication</h3>
This resulted in ALS treated mice having more connections between nerves and muscles, improved neuromuscular communication, and increased muscle strength and mass. Disease onset also was delayed, and treated mice lived longer than controls.
These preclinical data were presented at a European Society of Cell and Gene Therapy meeting.
The company now is planing to test ANEW-202 in the Profilin1 mouse model, which mimics the <a href="https://alsnewstoday.com/forms-of-als-2/sporadic-als/">sporadic form of ALS</a> that occurs in about 90% of patients.
&#8220;We look forward to expanding the testing of our lead candidate, ANEW-202, in the Profilin1 animal model of ALS that represents 90-95% of all human ALS cases called Sporadic ALS,&#8221; Sinkule said.
Because of its mechanism of action, s-KL gene therapy may treat other conditions related to neuromuscular degeneration, including <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> (MS), <a href="https://musculardystrophynews.com/what-is-muscular-dystrophy/">muscular dystrophy</a>, <a href="https://smanewstoday.com/what-is-spinal-muscular-atrophy/">spinal muscular atrophy</a> (SMA), and spinal cord injuries.
&#8220;The delivery and expression of the s-KL protein by the s-KL gene may be an effective therapy in this degenerative neuromuscular disease,&#8221; Sinkule said. &#8220;The data open up additional avenues for the use of ANEW-202 in an expanding array of other neuromuscular and motor neuron diseases such as multiple sclerosis, muscular dystrophy, myasthenia gravis, and rare diseases like Lambert-Eaton disease, <a href="https://friedreichsataxianews.com">Friedreich&#8217;s ataxia</a>, and <a href="https://smanewstoday.com">spinal muscular atrophy</a>.&#8221;
&#8220;There may even be potential use in spinal cord injuries and peripheral nerve injuries, but clearly, ALS is our lead indication,&#8221; Sinkule added.

Tag: ALS gene therapy

Columbia gets $15M to design gene therapies for rare ALS forms

Coave wins grant to advance gene therapy CTx-TFEB for ALS

VectorY raises millions to support antibody gene therapy for ALS

SOL-257 gene therapy improves outcomes in 2 ALS mouse models

Anew’s ALS gene therapy shows promise in mice