Identifying Drugs That Restore Neurofilament Level In ALS
Abstract
ALS is a devastating motor neuron (MN) disease with no effective treatment currently. Its pathological feature is the presence of abnormal protein inclusions, especially neurofilament (NF) aggregates, in MNs and nerve (axonal) degeneration. These pathological hallmarks are replicated in model animals that express ALS-causing genes. We have recently discovered that MNs derived from ALS patients exhibit a reduced level of neurofilament light polypeptide (NF-L), followed by NF aggregation and axonal degeneration before cell death. When the NF-L is restored by genetic means, it prevents NF aggregation and mitigates axonal degeneration of MNs. Therefore, NF-L level reduction is an important target for therapeutic intervention, which is consistent with previous studies with both familial and sporadic ALS patient specimens, as well as analyses with transgenic animals that overexpression of NF-L extends the lifespan of ALS model mice. BrainXell, Inc. therefore proposes to apply a drug-screening platform using ALS patient MNs to identify drugs that restore NF-L level and/or prevent NF aggregation. The initially identified compounds will be validated in cells derived from different ALS patients, including those from sporadic ALS patients (without family history), as well as in ALS transgenic mice. If a compound exerts similar effects on MNs from various forms of ALS, it suggests that the compound regulates a common mechanism in ALS pathogenesis. More importantly, it indicates a broader application value. If a compound affects one form of ALS (e.g., SOD1) but not the other (sporadic), it may still be interesting as it suggests a therapeutic effect on a subclass of ALS. If successful, one drug candidate for increasing NF-L level in ALS MNs will get into preclinical stage in 3-5 years. Identification of drugs that delay or prevent ALS MN degeneration using ALS patient MNs will likely speed the translation to clinical application and open new options for treating ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810556
Entities
People
- Zhong-wei Du
Organizations
- Brainxell (United States)
- United States Army