Researchers have developed a gene therapy that significantly slowed motor function loss in preclinical models of amyotrophic lateral sclerosis (ALS), bringing new hope to a population in need of breakthrough treatment. The study, led by investigators from the Perelman School of Medicine and Children’s Hospital of Philadelphia and published in Nature Communications, involved “silencing” a gene associated with regulating TDP-43—the ALS-causing protein that accumulates in the brain—with a technique called RNA interference (RNAi), allowing mice to live an average of 54 percent longer. Subjects also experienced improvements 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. 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, assistant professor of neurology at the 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.

While a small group of people with ALS have a specific genetic cause for their disease, the vast majority do not, and 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. However, these efforts involved 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. They 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.

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