Enhancing Exon-Skipping Antisense Oligonucleotides for Duchenne Muscular Dystrophy
Abstract
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by alterations (mutations) in the gene encoding for a protein called dystrophin that make the code unreadable. In skeletal muscle, dystrophin acts as a shock absorber, preventing muscle damage during contraction. Duchenne patients cannot produce functional dystrophin, and therefore suffer from chronic muscle damage and eventually loss of muscle tissue and function. A possible treatment for DMD is to use short pieces of synthetic DNA or RNA (antisense oligonucleotides, AON), that bind to dystrophin gene transcripts. These transcripts contain the code that is translated by the cell into protein. The goal of the AON binding is to alter the processing of the dystrophin transcripts in such a way that the code becomes readable again. This will allow translation into a dystrophin that is shorter, but partially functional. The hope is that the expression of these shorter dystrophins can slow down disease progression. There are four Food and Drug Administration-approved therapeutics, based on this concept: eteplirsen (exon 51 skipping), golodirsen and viltolarsen (exon 53 skipping), and casimersen (exon 45 skipping). However, their approval is controversial, as they only increase dystrophin levels by a small amount and it has not been shown if this will be therapeutically relevant. AONs need chemical modifications to enhance their stability and give them drug-like properties. The four therapeutics approved for DMD are based on the peptide morpholino (PMO) chemistry, but there are many more chemistries that have been developed and not had clinical utility for DMD. We have developed novel synthetic DNA chemistries which enhance AON exon skipping levels in cells. We take this one step further by showing that we can achieve high levels of skipping (70%-86 %) in a humanized DMD mouse, in multiple muscle tissues. The aim of our study is to finalize a candidate, with high levels of skipping, in multiple muscle tissues, and of clinical quality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210744
Entities
People
- Anastasia Khvorova
Organizations
- United States Army
- University of Massachusetts Medical School