Researchers have developed a gene therapy that significantly slowed motor function loss in preclinical models of amyotrophic lateral sclerosis (ALS), offering new hope for treating the devastating neurodegenerative disease.
“Silencing” a gene associated with regulating TDP-43, the protein that accumulates in the brain and causes ALS, with a technique called RNA interference (RNAi) allowed mice to survive an average of 54% longer. Subjects also experienced improvements in strength and reduced inflammation in the brain and spinal cord, according to research from the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia, published today in Nature Communications.
“There are currently no treatments to slow the progression in people with ALS that have no family history or other risk factors. While we are not yet ready to treat humans with this therapy, these preclinical results are a very encouraging step,” said first author Defne Amado, Ph.D., an assistant professor of Neurology at the University of Pennsylvania’s Perelman School of Medicine. “Our finding also shines a light on the underlying biology of ALS, which will inform future research of therapies that treat the causes of the disease, not just symptoms.”
ALS affects approximately 30,000 Americans, with 5,000–6,000 new cases diagnosed annually. Most patients survive only 2-5 years after diagnosis, and current treatments primarily address symptoms rather than slowing disease progression.
Gene therapy for ALS without a genetic cause
While a small group of people with ALS have a specific genetic cause for their disease, the vast majority do not. However, 97% of all individuals with ALS have a buildup of TDP-43 in their brains. Discovered at Penn Medicine, TDP-43 is a protein that lives in the nucleus of cells and regulates RNA splicing, part of the protein synthesis process.
In people with ALS, the TDP-43 leaves the nucleus of the cell and aggregates in the cytoplasm, both of which contribute to the death of motor neurons and the symptoms associated with ALS, including muscle weakness, difficulty speaking, and respiratory failure.
Previous research revealed that lowering levels of a protein in cells called Ataxin-2 (ATXN2) was able to reduce TDP-43 leaving the nucleus in error and accumulating to cause the death of motor neurons. These efforts involved the use of strategies that required repeated delivery via spinal tap, which is difficult for humans to tolerate, and did not achieve strong reduction in a previous clinical trial.
To lower ATXN2 levels more and with a single treatment, researchers used a technique called RNA interference (RNAi), to “silence” ATXN2. Researchers delivered the RNAi to cerebrospinal fluid of mouse models of sporadic ALS using an Adeno-Associated Virus (AAV) vector.
Viruses are effective at entering other cells and sharing genetic information. Once the genetic information is transferred, it is expressed in the cell permanently. The Penn research team engineered AAVs to target the parts of the nervous system affected by ALS and deliver instructions to the nucleus of motor neurons.
Researchers found that mice treated with RNAi showed a reduction in ATXN2 protein in their brain, brainstem, and spinal cord, all critical areas affected by ALS. The average survival of mice treated with RNAi was 54% longer than those with ALS that received no treatment. The mice that received the treatment also performed better on strength assessments and had less inflammation in their brains and spinal cords.
Insights into the underlying biology of ALS
The mouse model of ALS used in this study has over 1,300 significant genetic differences compared to mice without ALS. Of these 1,300 different expressions, over 450 gene expressions were corrected after the mice received the RNAi treatment, and many of these genes correspond to those in humans with ALS.
“Sporadic ALS is an extremely complicated condition that involves many different genes and systems malfunctioning,” said Amado. “By learning what this treatment corrects, we can also understand more about how the disease is caused and how it progresses, and develop new treatments”
To determine if this method might also be effective in humans with ALS, researchers treated spinal cord neurons from human patients with ALS with the RNAi treatment. In these models, the engineered AAV was able to deliver the RNAi to 95% of cells, and reduced ATXN2 levels by 85%. The team is now embarking on studies to determine whether this treatment corrects pathology in a large cohort of these patient-derived cells.
“To address the questions posed in this work required a delivery system that targeted the cell types relevant to ALS,” said senior author Beverly Davidson, Ph.D., Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and Chief Scientific Strategy Officer at Children’s Hospital of Philadelphia, and Professor of Pathology and Laboratory Medicine at Penn Medicine. “That is where our newly discovered capsids were fundamentally important.”
More information:
Defne A. Amado et al, AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice, Nature Communications (2025). DOI: 10.1038/s41467-025-60497-8
Citation:
Gene therapy may slow loss of motor function in ALS (2025, June 25)
retrieved 25 June 2025
from https://medicalxpress.com/news/2025-06-gene-therapy-loss-motor-function.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
Researchers have developed a gene therapy that significantly slowed motor function loss in preclinical models of amyotrophic lateral sclerosis (ALS), offering new hope for treating the devastating neurodegenerative disease.
“Silencing” a gene associated with regulating TDP-43, the protein that accumulates in the brain and causes ALS, with a technique called RNA interference (RNAi) allowed mice to survive an average of 54% longer. Subjects also experienced improvements in strength and reduced inflammation in the brain and spinal cord, according to research from the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia, published today in Nature Communications.
“There are currently no treatments to slow the progression in people with ALS that have no family history or other risk factors. While we are not yet ready to treat humans with this therapy, these preclinical results are a very encouraging step,” said first author Defne Amado, Ph.D., an assistant professor of Neurology at the University of Pennsylvania’s Perelman School of Medicine. “Our finding also shines a light on the underlying biology of ALS, which will inform future research of therapies that treat the causes of the disease, not just symptoms.”
ALS affects approximately 30,000 Americans, with 5,000–6,000 new cases diagnosed annually. Most patients survive only 2-5 years after diagnosis, and current treatments primarily address symptoms rather than slowing disease progression.
Gene therapy for ALS without a genetic cause
While a small group of people with ALS have a specific genetic cause for their disease, the vast majority do not. However, 97% of all individuals with ALS have a buildup of TDP-43 in their brains. Discovered at Penn Medicine, TDP-43 is a protein that lives in the nucleus of cells and regulates RNA splicing, part of the protein synthesis process.
In people with ALS, the TDP-43 leaves the nucleus of the cell and aggregates in the cytoplasm, both of which contribute to the death of motor neurons and the symptoms associated with ALS, including muscle weakness, difficulty speaking, and respiratory failure.
Previous research revealed that lowering levels of a protein in cells called Ataxin-2 (ATXN2) was able to reduce TDP-43 leaving the nucleus in error and accumulating to cause the death of motor neurons. These efforts involved the use of strategies that required repeated delivery via spinal tap, which is difficult for humans to tolerate, and did not achieve strong reduction in a previous clinical trial.
To lower ATXN2 levels more and with a single treatment, researchers used a technique called RNA interference (RNAi), to “silence” ATXN2. Researchers delivered the RNAi to cerebrospinal fluid of mouse models of sporadic ALS using an Adeno-Associated Virus (AAV) vector.
Viruses are effective at entering other cells and sharing genetic information. Once the genetic information is transferred, it is expressed in the cell permanently. The Penn research team engineered AAVs to target the parts of the nervous system affected by ALS and deliver instructions to the nucleus of motor neurons.
Researchers found that mice treated with RNAi showed a reduction in ATXN2 protein in their brain, brainstem, and spinal cord, all critical areas affected by ALS. The average survival of mice treated with RNAi was 54% longer than those with ALS that received no treatment. The mice that received the treatment also performed better on strength assessments and had less inflammation in their brains and spinal cords.
Insights into the underlying biology of ALS
The mouse model of ALS used in this study has over 1,300 significant genetic differences compared to mice without ALS. Of these 1,300 different expressions, over 450 gene expressions were corrected after the mice received the RNAi treatment, and many of these genes correspond to those in humans with ALS.
“Sporadic ALS is an extremely complicated condition that involves many different genes and systems malfunctioning,” said Amado. “By learning what this treatment corrects, we can also understand more about how the disease is caused and how it progresses, and develop new treatments”
To determine if this method might also be effective in humans with ALS, researchers treated spinal cord neurons from human patients with ALS with the RNAi treatment. In these models, the engineered AAV was able to deliver the RNAi to 95% of cells, and reduced ATXN2 levels by 85%. The team is now embarking on studies to determine whether this treatment corrects pathology in a large cohort of these patient-derived cells.
“To address the questions posed in this work required a delivery system that targeted the cell types relevant to ALS,” said senior author Beverly Davidson, Ph.D., Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and Chief Scientific Strategy Officer at Children’s Hospital of Philadelphia, and Professor of Pathology and Laboratory Medicine at Penn Medicine. “That is where our newly discovered capsids were fundamentally important.”
More information:
Defne A. Amado et al, AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice, Nature Communications (2025). DOI: 10.1038/s41467-025-60497-8
Citation:
Gene therapy may slow loss of motor function in ALS (2025, June 25)
retrieved 25 June 2025
from https://medicalxpress.com/news/2025-06-gene-therapy-loss-motor-function.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
