Identification of a Novel Therapeutic Target and Strategy for C9-ALS
Abstract
Amyotrophic lateral sclerosis, also known as Lou Gehrig s disease, is a devastating neurodegenerative disease leading to muscle weakness and paralysis leading to a fatal conclusion, typically in 3 to 5 years after the age of onset. The most common cause of ALS is a genetic mutation in a gene known by its acronym: C9ORF72. This mutation is present in 50% of ALS families in North America and Europe and is highly atypical as it consists of hundreds to thousands of repetitions of a small DNA sequence (GGGGCC). Equally unusual is that this mutation is toxic through the non-canonical translation of these DNA repeats into novel proteins composed of repeated motifs and known by another acronym: DPR proteins. These DPR proteins are highly toxic for neurons. We and others recently refined the mechanism of production and the toxic characteristics of these DPR proteins. Importantly, these data unveiled novel pathogenic sequences that can be used as therapeutic targets. In that proposal, we plan to take advantage of these findings to test new molecules (antisense DNA oligonucleotides) aimed at blocking the expression of these toxic DPR proteins in human neuronal cells and pre-clinical animal models. In short, we uncovered novel sequences that could be of medicinal interest in ALS. Thus, in this funding request, we propose to generate pre-clinical data in cell and animal models to test therapeutic approaches for this devastating neurodegenerative disease .
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310679
Entities
People
- Nicolas Charlet-berguerand
Organizations
- United States Army