New preclinical project on improving targeted delivery for CMD therapeutics
NATA is excited to be at the heart of a pioneering preclinical project aimed at improving targeted delivery of antisense oligonucleotides (ASOs) for the treatment of collagen VI-related congenital muscular dystrophy (COL6-CMD).
Muscular dystrophies are a group of inherited neuromuscular disorders that cause severe muscle weakness, joint contractures, and respiratory complications from early life. Among them, Duchenne muscular dystrophy (DMD) is the most widely known and studied. However, collagen VI-related congenital muscular dystrophy (COL6-CMD) represents one of the most common non-DMD forms, and one of the most difficult to treat.
Unlike DMD, which is caused by defects in dystrophin that destabilise the muscle cell membrane, COL6-CMD is caused by mutations in the COL6A1, COL6A2, or COL6A3 genes, disrupting production of the collagen VI protein (COL6). The ECM is a network of proteins and molecules that surrounds and supports cells in tissues. COL6 is a key component of this matrix in muscle, acting as a bridge that connects muscle cells to their surroundings. When COL6 is deficient or faulty, muscle cell function breaks down, leading to progressive muscle weakness in CMD patients; unfortunately, there is currently no effective treatment available.
Over the last few years, researchers at UCL have identified antisense oligonucleotides (ASOs) that can correct COL6 gene defects using exon-skipping strategies. This approach holds significant promise, but a critical barrier remains: delivering these molecules to the specific cells responsible for producing collagen VI embedded within muscle tissue.
As part of a new preclinical project led by Professor Haiyan Zhou at UCL and funded by LifeArc and Muscular Dystrophy UK, NATA is developing peptide-conjugated ASOs designed to target those elusive cells. These novel compounds are engineered to recognise and bind to specific surface receptors on skeletal muscle interstitial fibroblasts (MIFs), enhancing the uptake of therapeutic oligonucleotides.
Why this matters: getting the treatment to where it’s needed
Current nucleic acid therapies work well for tissues like liver or blood, but struggle to reach cells deep within the muscle’s ECM. COL6-CMD is particularly challenging because its root cause lies not within the muscle fibre, but in the surrounding support matrix. By enhancing delivery strategies, we aim to increase the therapeutic potential of these ASOs.
This collaboration marks a major step forward in precision delivery of nucleic acid therapeutics—and offers hope for patients with COL6-CMD who have long gone without effective options.
Learn more about the partnership driving this project: Muscular Dystrophy UK and LifeArc £1M CMD collaboration
Learn more about the ASO identified by UCL: Exon-Skipping Oligonucleotides Restore Functional Collagen VI (Aguti et al., 2020)