Columbia Awarded $15 Million to Create Medicines for Ultra-Rare Forms of ALS

Columbia University scientists have been awarded a $15 million grant from the NIH’s Ultra-rare Gene-based Therapy Network to design tailor-made gene-based therapies for nine people with rare forms of amyotrophic lateral sclerosis (ALS). 

Gene-based therapies for ALS have potential for the approximately one in eight patients whose disease is caused by a single genetic mutation. Pharmaceutical companies are developing gene-based therapies for patients with relatively common mutations, but these will not help the hundreds of ALS patients in the United States whose disease is caused by ultra-rare mutations—those that occur in fewer than 30 patients worldwide. 

The new grant from the Ultra-rare Gene-based Therapy Network (URGenT) of the National Institute for Neurological Disorders and Stroke will fund the Silence ALS peogram to develop new tailor-made treatments for such patients. 

Columbia neurologist Neil Shneider, MD, PhD, launched the Silence ALS program in 2022 in collaboration with the n-Lorem Foundation to design individualized treatments using a gene-silencing technology called antisense oligonucleotides (ASOs). The first Silence ALS antisense oligonucleotide drug was approved by the FDA in October 2022 to treat an ALS patient with an ultra-rare mutation in the TARDBP gene. 

Silencing ALS genes

Therapies that can silence genes have enormous potential to treat patients with genetic forms of ALS because the therapies can prevent mutated ALS genes from producing proteins that are toxic to motor neurons. 

Gene-silencing ASOs can be developed rapidly to target a patient’s unique mutation, so the technology enables individualized therapies for ALS and other ultra-rare genetic disorders.

Tackling more common forms of ALS

Though ASO therapies can only treat patients with certain ultra-rare, genetic forms of ALS, Silence ALS is expected to inform our understanding of, and therapeutic approach to, more common forms of ALS that have no known genetic cause. 

“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 says. 

“We don't fully understand the links yet. 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.” 

Columbia’s URGenT goals 

Over the next three years, the URGenT award will provide funding to develop ASO therapies for ALS patients with pathogenic mutations in the TARDBP gene, building on Silence ALS’s first successful program, as well as ALS patients with a mutation in the CHCHD10 gene, which also causes frontotemporal dementia. In addition, the project will target other dominantly inherited ALS gene mutations that are amenable to ASO therapy. 

The funding will support all drug development activities, including animal toxicology studies, to prepare each ASO for submission to the FDA for approval as an investigational new drug (IND) and to begin first-in-human trials.  

“Silence ALS aims to create knowledge, experience, and efficiencies that will inform our understanding and approach across diseases and treatment modalities,” says Chris Boshoff, PhD, program director, URGenT Network, National Institute of Neurological Disorders and Stroke. “It is poised to establish a model for therapeutic development in ultra-rare disease.” 

Silence ALS is the first non-profit initiative to design and create ASO therapies for individual ALS patients, and as its infrastructure grows with URGenT funding, “we hope to create a paradigm for other ultra-rare disease communities to follow,” Shneider says.  

“We’re also beginning to speak with international partners to see if individualized treatment programs of this type are possible in other countries. 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.”