Investigating therapeutic approaches for SPTLC1 ALS variants using zebrafish models

While the majority of ALS cases manifest in adulthood, pathogenic variants (mutations) in the Serine Palmitoyltransferase Long Chain Base Subunit 1 (SPTLC1) gene have been linked to an increased risk of ALS in children. Children with these variants who develop symptoms of ALS experience a slow-progressing form of the disease but will still eventually experience loss of muscle control and paralysis. The reasons why ALS can manifest at younger ages or how the disease begins remains unknown. SPTCL1 encodes an enzyme involved in lipid production, a type of fat compound which neurons use to build cell membranes. Studies using cell models suggest that variants in the SPTCL1 gene lead to overproduction of certain lipids, which become toxic to motor neurons, the specialized cells in the brain responsible for voluntary muscle control.

To address this, Dr. Gary Armstrong and his team propose to generate zebrafish models that replicate SPTLC1-ALS in the lab. These models will help them study how motor neurons are affected in juvenile ALS and evaluate two potential treatment strategies. Their first approach involves testing a type of gene therapy, called an antisense oligonucleotide (ASO), that knocks down the expression of the pathogenic variant in their zebrafish models. Their second approach will be to test pharmacological inhibitors of the pathway responsible for the overproduction of these harmful lipids.

This research aims to improve our understanding of juvenile forms of ALS, develop a new model to study ALS in the lab, and could pave the way for future treatments.

Collaborators: Dr. Eric Shoubridge

For more than 20 years, ALS Canada funding has played an important role in ALS genetic discoveries, with over 50 research grants awarded that focus on the understanding of ALS genes. We remain committed to supporting the development of gene-based therapies.