Analysis of Adaptive and Innate Immune Response in FUS-ALS Patients Treated With Antisense Therapy

Amyotrophic lateral sclerosis (ALS) is a disease in which patients suffer continuous loss of neurons that control muscle, leading to an inability to voluntarily move, speak, chew, or breathe Over 5,000 people in the U.S. are diagnosed with ALS each year, but because of the fatal nature of this neurodegenerative disease, only about 16,000 Americans are living with ALS at any given time. Currently there is no treatment for ALS. In recent years, a large and growing number of ALS-associated gene mutations including the FUS gene have been identified that together account for over 10% of cases. Mutations in FUS lead to its accumulation inside the cells causing toxicity for neurons. In an effort to treat this aggressive form of ALS, we have organized an expanded access, compassionate use program at the Eleanor and Lou Gehrig ALS Center at Columbia University that leverages a new therapeutic approach to reduce FUS aggregates in ALS patients with FUS mutations. We took advantage of this clinical trial to study the role of the immune system in ALS with FUS mutations. Indeed, in our preliminary analysis of paired blood and cerebral spinal fluid (fluid that bathes the brain and the spinal cord) samples from an ALS^FUS individual without symptoms, we identified a type of killing immune cell that is enriched in the CSF, suggesting that they may play a detrimental role in the disease initiation and progression.

The overall goal of our study is to understand the role of these toxic and inflammatory cells circulating in the blood and also found in the brain and the spinal cord of ALS patients. We are leveraging cutting-edge technologies that are available to us through Columbia's genetic and human immunology cores to dissect the immune system cell by cell. Our proposed study will provide the larger scientific/ALS community with a great number of potential druggable targets to explore in vitro and in animal models of ALS. This will be the first step towards eventual clinical trials either by repurposing existing FDA-approved drugs or by generating novel tool compounds and biologics for testing in ALS animal models.