BELINDA S. COWLING¹*, SHULING GUO²
*Corresponding author
1. Dynacure, ESBS bio-incubator, Pôle API, Illkirch, France
2. Ionis Pharmaceuticals Inc., Carlsbad, California 92010, USA

Abstract

Centronuclear and myotubular myopathies (CNM) are congenital myopathies with usually poor prognosis. Hallmarks are severe muscle and facial weakness, fibre atrophy and abnormally located nuclei in skeletal muscle. No effective treatments exist for CNM. Reduction of Dnm2 by several means (genetic deletion, antisense oligonucleotides, or adeno-associated virus-shRNA) was recently shown to rescue myopathic features observed in mouse models of X-linked and autosomal dominant forms of CNM. These results highlight targeting DNM2 as a therapeutic potential for several forms of the disease. An antisense oligonucleotide against human DNM2 is now being developed for the treatment of CNM (constrained ethyl technology, cEt).

BACKGROUND

Antisense oligonucleotides (ASO) represent a promising technology for therapeutic approaches targeting a variety of diseases including neuromuscular diseases (1, 2). This group of monogenic disorders are clinically and genetically heterogeneous. They commonly lead to muscle weakness, and place a heavy burden on patients and their families, as well as the health care system. Whilst over 400 causative genes have been identified, effective therapies are lacking for most neuromuscular disorders. Recently two ASO based approaches were approved for use in Spinal Muscular Atrophy (SMA) and Duchenne’s Muscular Dystrophy (DMD) (3, 4),
further validating the clinical utility of ASOs and helping promote ASO use in treatment of neuromuscular disorders to the next level. Targeting gain-of-function mutations may be achieved by reducing expression of the mutant gene, or splicing modulation may be applied for loss-of-function genetic diseases to allow expression of a partially functional protein (4-6). To date, this approach has been primarily applied to dystrophic muscles where muscle fiber leakiness may potentially facilitate uptake.