Gene Therapy May Slow Loss of Motor Function in ALS, Penn and CHOP Research Finds | Newswise

Newswise — PHILADELPHIA – 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 percent 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, PhD, 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 percent 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 percent 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 percent of cells, and reduced ATXN2 levels by 85 percent. 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, PhD, 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.”

This research was funded by the National Institutes of Health (NS114106, UH3NS094355) and the Children’s Hospital of Philadelphia Research Institute.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school. 

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System (UPHS) and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school. 

The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $580 million awarded in the 2023 fiscal year. Home to a proud history of “firsts,” Penn Medicine teams have pioneered discoveries that have shaped modern medicine, including CAR T cell therapy for cancer and the Nobel Prize-winning mRNA technology used in COVID-19 vaccines. 

The University of Pennsylvania Health System cares for patients in facilities and their homes stretching from the Susquehanna River in Pennsylvania to the New Jersey shore. UPHS facilities include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, chartered in 1751. Additional facilities and enterprises include Penn Medicine at Home, GSPP Rehabilitation, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others. 

Penn Medicine is an $11.9 billion enterprise powered by nearly 49,000 talented faculty and staff. 

About Children’s Hospital of Philadelphia
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit