Using CSF1R Suppression to Reprogram Microglia to a Neuroprotective State in ALS
Abstract
Ultimate applicability of the research: There is an urgent need for therapeutics that slow disease progression in amyotrophic lateral sclerosis (ALS) patients. Recent ALS clinical trials targeting well-validated disease mechanisms in nerve cells have yielded disappointing results. This underscores a longstanding notion that disease processes in the cells surrounding the nerve cells may actually determine the rate of disease progression in mid-late stage ALS patients. Studies suggest that one of the non-nerve cell types that plays a key role in disease progression is the immune cell of the nervous system, known as the microglial cell. Thus, there is a pressing need for therapeutic strategies that mitigate microglial disease processes in ALS. By studying microglia and nerve cells derived from ALS patients, we have identified a new potential therapeutic approach that targets microglia and may work for both familial and sporadic ALS. In the proposed study, we will use patient-derived microglia and nerve cells, as well as ALS mouse models, to test the efficacy of using antisense oligonucleotides (ASOs) to silence a gene called CSF1R in microglia. We predict that silencing CSF1R in microglia will reprogram them, or stop them from being toxic to ALS nerve cells and cause them to be protective of ALS nerve cells. We anticipate that our findings will facilitate the development of an intrathecally-administered CSF1R ASO for the treatment of both familial and sporadic ALS. Types of ALS patients it will help and how: Our data suggest this therapeutic strategy would slow disease progression in patients with C9ORF72 ALS and we anticipate that it could also be effective in sporadic ALS patients. It is unclear if it would be effective in patients with mutations in SOD1, TARDBP, or FUS, but it is possible. If it were feasible to begin treatment before disease onset, it is possible this approach could significantly delay disease onset. Potential clinical applications, benefits, and risks: If our study validates CSF1R suppression and reprogramming microglia as a new therapeutic strategy for ALS, we anticipate this will lead to the development of ASOs or other drugs targeting CSF1R and related proteins. These treatments could benefit ALS patients by slowing disease progression and extending survival. As with any new therapeutic approach, there is a risk of side effects or an acceleration of disease progression. Projected time to achieve a patient-related outcome: We anticipate that if our study validates CSF1R suppression as a potential therapeutic strategy for ALS, it could lead to the development of ASO or small molecule drugs that could test this in the clinic within about 3 to 5 years from the end of our study. Before then, we anticipate interim outcomes. At the completion of our study, we will publish our results to disseminate the information to the public to accelerate new mechanistic and therapeutic studies based on our results. If possible, we will also outlicense our intellectual property covering the use of CSF1R suppression to treat ALS and composition of matter on CSF1R ASOs to a commercial entity interested in developing ALS therapeutics targeting CSF1R. If no commercial entity takes this approach forward immediately, we will pursue further funding to develop a CSF1R ASO-based therapeutic. Likely contributions in advancing the development of therapeutics for ALS: Our study will likely advance the development of therapeutics for ALS in the following ways: (1) We anticipate our study will validate CSF1R suppression as a new therapeutic approach for multiple forms of ALS, including C9ORF72 and sporadic ALS. This should cause ALS drug development groups to consider developing ASO or small molecule drugs targeting CSF1R. (2) We anticipate our study will validate microglial reprogramming as a new method for rescuing ALS disease processes, which could help uncover additional therapeutic targets b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310370
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California