Silencing of ALS-Causing Mutant Genes

Research Summary

Principle Investigators: Robert Brown D.Phil., MD & Merit Cudkowicz MD

About 10% of cases of ALS run in families and are caused by mutant genes, including the first-identified ALS gene known as superoxide dismutase 1 (SOD1). In most cases, the mutant genes make a mutant, toxic gene product, which in the case of SOD1 is a protein with a propensity to misfold. Data also argue that non-mutant forms of these proteins may also play a role in non-familial ALS. Several lines of study indicate that when SOD1 is implicated in ALS, the goal is to turn off or silence the gene, so that it can no longer make the toxic SOD1 protein. One approach to silencing genes like SOD1 is to use non-infectious viral vectors (adeno-associated viruses or AAV) to deliver small DNA molecules to cells in the brain and spinal cord. In mouse models of ALS this therapy significantly prolongs survival. The goal of this project is to use AAV-mediated delivery of silencing elements to shut off the SOD1 gene, first in monkeys and then in individuals with ALS related to SOD1.

Impact of Study

We believe this study will have a high impact for three reasons. First, it will allow treatment of ALS mediated by mutant SOD1. Second, it will potentially also provide a treatment for individuals in whom SOD1 is misfolded, even without a SOD1 gene mutation. And third, if proof-of-concept can be proven for this viral vector and this gene, this method should be a general platform for treating many types of disorders caused by toxic gene products.

Common Goals

Everyone in the field shares the view that we must find ways to silence ALS genes as rapidly as possible. This project is also aligned with the general goal of the ALS Finding A Cure Foundation to develop innovative, well-grounded new strategies for treating ALS.


Massachusetts General Hospital
Merit Cudkowicz MD
James Berry MD

University of Massachusetts Medical School
Robert Brown D.Phil., MD
Chris Mueller PHD
Guangping Gao PHD