Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1
Abstract
Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3′ UTR of the myotonic dystrophy protein kinase (DMPK) gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2022
- Source ID
- 10.3390/ijms232113359
Entities
People
- Dominic Jauvin
- Jack Puymirat
- Mohamed Boutjdir
- Mohamed Chahine
- Siham Ait Benichou
- Thiéry De Serres‐Bérard
Organizations
- Canadian Institutes of Health Research
- Muscular Dystrophy Canada
- National Heart, Lung, and Blood Institute
- United States Department of Defense