CHMP7 ASO Therapy: Repair of Nuclear Pore and TDP43 Dysfunction in Sporadic and Familial ALS
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. While multiple genetic mutations have been identified as causative of ALS, the vast majority of cases remain sporadic in nature. Additionally, the precise molecular events leading to neurodegeneration in ALS and related diseases remain largely unknown. Defects in an essential cellular process which maintains communication between nuclear and cytoplasmic compartments of the cell (nucleocytoplasmic transport, NCT) have recently emerged as a prominent pathomechanism underlying ALS and other neurodegenerative diseases. The nuclear pore complex (NPC) is made up of multiple copies of approximately 30 individual proteins (Nups) and tightly regulates NCT. However, the mechanisms leading to alterations in NPC composition and function remain understudied. We recently identified a reproducible subset of Nups that are altered as an early event in disease pathogenesis by using patient derived induced pluripotent stem cells and validating these results in actual patient autopsy tissue. Furthermore, we discovered the underlying mechanism for this early cellular event, the abnormal nuclear localization of the nuclear pore surveillance protein CHMP7. Using antisense oligonucleotide (ASO) treatment, we can reliably, specifically and effectivity repair this problem, setting the stage for the development of a CHMP7 ASO human therapy. The current program will advance the CHMP7 ASO through the necessary steps to eventually make it ready for human ALS trial in sporadic patients by our collaborating pharma company, Ionis Pharmaceuticals, and their expert team. The plans also include the development of drug efficacy biomarker, so that following therapy one can determine if the drug is, in fact, repairing the abnormal brain cell functions characteristic of ALS. The DOD support will ensure that the therapy can be readied for human trials in a relatively short timeline. Most importantly, this therapy will be targeted for sporadic and familial ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310136
Entities
People
- Jeffrey D Rothstein
Organizations
- Johns Hopkins University
- United States Army