UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Developing RNA-targeted therapy for collagen VI-related congenital muscular dystrophy

Supervisors: Professor Francesco Muntoni, Dr Haiyan Zhou

The aim of this project is to develop a novel antisense oligonucleotide therapy for collagen VI-related congenital muscular dystrophy.

Collagen VI-related congenital muscular dystrophies (COL6-CMD) are a group of muscular dystrophies caused by recessive and dominant mutations in the three Collagen VI genes (COL6A1, COL6A2 and COL6A3).  COL6-CMDs have a wide clinical spectrum ranging from the severe early-onset Ullrich muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). There is no cure available for COL6-CMD at present.[1,2]

Antisense oligonucleotide (AON) can interfere with gene splicing or induce gene silencing. They are under active development for a number of neuromuscular conditions with a substantial contribution of our group on Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA).[3,4] We have recently explored the therapeutic application of AON allele-specific silencing approach in selected dominant UCMD mutations and achieved very encouraging results.[5] Based on this promising proof-of-principle study, we here propose to expand the AON therapy to target more dominant collagen 6 mutations, including those representing the most frequent genetic defects in COL6-CMD.

This PhD student project includes two work packages. The first one will be the identification of lead AON compounds in selectively silencing the mutant transcripts in vitro in cellular models. The second work package will be functional assessment in vitro in cellular models and in vivo where mouse models are available. These studies are essential to take AON approaches closer to therapeutic applications for dominant COL6-CMD.

The student has great opportunities to gain a broad experience and benefit in the following areas: knowledge in antisense oligonucleotide design principle; national and international collaborations with active involvement in the UK muscular dystrophy exon-skipping (MDEX) consortium and international COL6-CMD consortium; engagement with patients groups and charities; working with cell culture and animal models; quantitative expression analyses at the protein and mRNA levels.  

1.   Bonnemann. Nat Rev Neurol 7: 379-390 (2011).
2.   Foley et al.  Brain 136:3625-33 (2013).
3.   Zhou et al. Hum Gene Ther 24(3):331-42 (2013).
4.   Sardone et al. Molecules 5: 22(4) (2017).
5.   Marrosu et al. Mol Ther–Nuc Acid 8:416-427 (2017).