Validation of SYF2 Suppression as a Therapeutic Strategy for Diverse Forms of ALS
Abstract
Ultimate Applicability of the Research: Amyotrophic lateral sclerosis (ALS) is a complex disease that results from many diverse genetic etiologies. Although therapeutic strategies that specifically target causal gene mutations may protect against individual forms of ALS, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS, and the fact that each genetic form is rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS, particularly those with unknown genetic etiologies. By testing a large number of drugs on motor neurons derived from several different ALS patients, we have identified a new potential therapeutic approach for both familial and sporadic ALS. In the proposed study, we will use patient-derived motor neurons and an ALS mouse model to evaluate the efficacy of using antisense oligonucleotides (ASOs) to silence a gene called SYF2 to prevent neurodegeneration in diverse forms of ALS. We anticipate that our findings will facilitate the development of an intrathecally administered SYF2 ASO for the treatment of ALS. Types of ALS Patients It Will Help and How: We anticipate that this therapeutic strategy would slow disease progression in most ALS patients, including sporadic ALS patients and those with mutations in C9ORF72, TARDBP, or several other genes. It is unclear if it would be effective in patients with mutations in SOD1 or FUS. If it were possible 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 SYF2 and RNA export proteins as a new therapeutic strategy for ALS, we anticipate this will lead to the development of ASOs or other drugs targeting SYF2 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 SYF2 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 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 out-license our intellectual property covering the use of SYF2 suppression to treat ALS, and composition of matter on SYF2 ASOs, and SYF2 target engagement biomarkers to a commercial entity interested in developing ALS therapeutics targeting SYF2. If no commercial entity takes this approach forward immediately, we will pursue further funding to develop an SYF2 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 SYF2 suppression as a new therapeutic approach for diverse forms of ALS, including sporadic ALS. This should cause ALS drug development groups to consider generating ASO or small molecule drugs targeting SYF2. (2) We anticipate our study will validate modulation of RNA export proteins as a new method for rescuing ALS disease processes, which could help uncover additional therapeutic targets beyond SYF2. (3) Our patient-derived ALS motor neuron panel and phenotypic assays optimized in our study could be used by other groups to test other therapeutic approaches or new drugs for ALS in the future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110131
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California