Developing peptide-conjugated antisense oligonucleotide therapy for COL6-related congenital muscular dystrophy
Awardee: Haiyan Zhou
Institution: University College London
Grant Amount: $70,133.00
Funding Period: February 1, 2024 - January 31, 2025
Summary:
Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are one of the most common types of CMDs. There is no curative treatment available. In the last few years, we have provided strong proof-of-concept evidence that experimental oligonucleotide therapy is a promising approach for the treatment of this fatal neuromuscular condition. My group has tested antisense oligonucleotide (ASO) therapeutic strategies in skin cells cultured from COL6-CMD patients and have already identified the lead ASO compounds able to correct the common disease mutations. However, for ASOs to work efficiently in humans, it is essential they target the skeletal muscle interstitial fibroblasts (MIFs), the major cell population producing collagen VI protein in muscle. So far, MIFs targeting has proved to be challenging to the field and has clearly obstructed the therapeutic development in COL6-CMDs. My group has recently identified a series of short protein fragments (peptides) that specifically bind to a cell surface receptor of MIFs, while also promoting the cellular internalization that will be needed when an oligonucleotide is attached to the peptide. Crucially, our data also demonstrated that some of these peptides efficiently target fibroblasts in a preferential manner, an important finding to avoid the accumulation of oligonucleotides in unwanted cell types. Here we propose a project aiming to further develop this exciting approach by using optimized MIF targeting peptides as a strategy to enhance the uptake of therapeutic ASOs to MIFs specifically, with an ultimate aim of developing a new therapy for COL6-CMD. The experiment plan includes: 1) To optimize the peptide sequences by testing alternative amino acids to improve the binding affinity, increase internalization and endosomal escape and reduce any potential cytotoxicity. 2) To validate the conjugates, for exon-skipping strategy in targeting MIFs, using cultured patients’ fibroblasts. 3) To generate a pilot in vivo biodistribution profile of pep-ASO conjugates, in wild-type mice. By the end of this project, we expect to identify the optimal peptide-ASO conjugates ready for further in vivo validation in the available humanized mouse model of COL6-CMD and to promote the future clinical translation of ASO therapy in COL6-CMD.