Researchers from the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia have developed a gene therapy that significantly slowed motor function loss in preclinical models of amyotrophic lateral sclerosis (ALS). The study, published in Nature Communications, shows promise for treating this neurodegenerative disease.
The technique involves “silencing” a gene associated with TDP-43, a protein that accumulates in the brain and is linked to ALS. Using RNA interference (RNAi), researchers extended mice’s survival by an average of 54 percent. Improvements were also noted in strength and reduced inflammation in the brain and spinal cord.
“There are currently no treatments to slow the progression in people with ALS that have no family history or other risk factors,” said Defne Amado, PhD, an assistant professor at Penn Medicine. “While we are not yet ready to treat humans with this therapy, these preclinical results are a very encouraging step.”
ALS affects approximately 30,000 Americans annually. Most patients survive only 2-5 years after diagnosis, with current treatments focusing on symptoms rather than slowing disease progression.
A small percentage of ALS cases have a genetic cause; however, 97 percent show TDP-43 buildup. This protein leaves cell nuclei and aggregates in cytoplasm in ALS patients, contributing to neuron death and symptoms like muscle weakness and respiratory failure.
Previous research indicated lowering Ataxin-2 (ATXN2) could reduce TDP-43 errors but required repeated spinal taps. The new approach uses RNAi delivered via Adeno-Associated Virus (AAV) vectors directly into cerebrospinal fluid. This method targets affected nervous system areas and provides lasting effects by transferring genetic information permanently into cells.
Mice treated with RNAi showed significant reductions in ATXN2 protein levels across critical areas like the brainstem and spinal cord. These mice lived longer and demonstrated better strength assessments compared to untreated ones.
“Sporadic ALS is an extremely complicated condition that involves many different genes and systems malfunctioning,” Amado noted. “By learning what this treatment corrects, we can also understand more about how the disease is caused.”
In human models using patient-derived neurons, RNAi treatment successfully reached 95 percent of cells and reduced ATXN2 levels by 85 percent. Further studies aim to assess pathology correction across larger cohorts.
Senior author Beverly Davidson emphasized the importance of targeting relevant cell types: “To address the questions posed in this work required a delivery system that targeted the cell types relevant to ALS.”
This research received funding from National Institutes of Health grants NS114106 and UH3NS094355 as well as support from Children’s Hospital of Philadelphia Research Institute.
Penn Medicine comprises several facilities including hospitals throughout Pennsylvania and New Jersey while CHOP operates numerous pediatric care centers regionally.
