Amyotrophic lateral sclerosis (ALS), a progressive disease that affects nerve cells in the brain and spinal cord, is characterized by generation of upper and lower motor neurons, leading to paralysis, respiratory failure, and death—typically in 2 to 5 years from onset. For approximately 90% of all cases, there is no known family history of the disease or presence of a genetic mutation linked to ALS. Although, for the remaining 5% to 10%, there is a known family history of the disease, which has opened the door for gene therapy, a targeted approach that can potentially fix or block the negative effects of coding errors.¹

Gene therapy involves the delivery of genetic material to cells and introduction of functional copies of dysfunctional genes, trophic factors, and other disease-modifying genes, or the silencing of harmful gene expression. Some of the most promising gene-therapy–based approaches for ALS to date include antisense oligonucleotides (ASOs), RNA interference (RNAi), or gene editing technology such as CRISPR. Although a gene-targeted therapy for ALS could potentially fix the genetic mutations causing the disease, most of those in development do not target DNA directly.

The State of Therapeutics

With only 4 FDA-approved medications to treat the disease, industry leaders have been willing to explore all options. To date, researchers have discovered close to 40 different genes linked to the disease; however, a large majority are not fully validated.² “Not all of them are validated to the same extent. Some are validated, some need more validation, and some are linked to other diseases. The pipeline is robust because we have a huge number to pick from,” Kuldip Dave, PhD, senior vice president of Research, The ALS Association, told NeurologyLive^®.

For years, Dave and The ALS Association have been supporting gene therapy projects, genetic testing, and genetic counseling in ALS. In 2014, the organization announced the US arm of Project MinE, an international, large-scale research initiative devoted to discovering genetic causes of ALS. That project was supported by the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center.³ To gain insights into the relationship between mutations, gene expression, and disease mechanisms, the CGND utilizes whole-genome sequencing data with other genomic-scale data such as RNA sequencing, RNA-protein interactions, and DNA methylation proteins.

“That’s where big science is ALS has…