RNA Therapy for Childhood Genetic Disorders
Our aim is to develop RNA-based or RNA-targeted therapeutics for rare childhood disorders, by using state-of-the-art nucleic acid technology, and to translate these experimental therapies to clinical applications. In addition to muscular dystrophies, we are now expanding this strategy to more genetic disorders in fields such as respiratory disorders, neurological conditions and metabolic diseases, in collaboration with groups across UCL and industries.
Our current focus is on developing novel therapeutic approaches using antisense oligonucleotides. This technology offers great potential as a gene-specific therapeutic strategy. Two classical neuromuscular disorders where antisense therapy has been successfully applied are Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). Together with Prof Francesco Muntoni at UCL GOSICH, we are now developing antisense therapy for another neuromuscular disorder, COL6-related congenital muscular dystrophy (COL6-CMD), by exploring different approaches for a number of recurrent common mutations in COL6A genes.
Gapmer antisense oligonucleotides decreased intracellular collagen VI retention and increased its extracellular matrix deposition in patient’s fibroblasts (Marrosu et al. 2017)
Current Funding: Wellcome Trust, Muscular Dystrophy UK, NIHR GOSH BRC
(A full list of publications can be found using the iris link below)
- Zhou H, Muntoni F. Morpholino-Mediated Exon Inclusion for SMA. Methods Mol Biol. 2018;1828:467-477. DOI:10.1007/978-1-4939-8651-4_29
- Marrosu E, Ala P, Muntoni F and Zhou H. Gapmer antisense oligonucleotides selectively suppress the mutant allele of COL6A3 gene in dominant Ullrich congenital muscular dystrophy and correct the disease phenotype. Molecular Therapy – Nucleic Acids 2017 Sep 15;8:416-427. DOI:10.1016/j.omtn.2017.07.006
- Sardone V, Zhou H, Muntoni F, Ferlini A and Falzarano MS. Antisense Oligonucleotide-based therapy for neuromuscular disease. Molecules. 2017 Apr 5;22(4). pii: E563. DOI:10.3390/molecules22040563
- Catapano F, Zaharieva I, Scoto M, Marrosu E, Morgan J, Muntoni F and Zhou H. Altered expression of microRNA-9, -206 and -132 in spinal muscular atrophy and the response to antisense oligonucleotide therapy. Molecular Therapy- Nucleic Acid. 2016 Jul 5; 5(7):e331. DOI:10.1038/mtna.2016.47
- Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Morgan J, Muntoni F and Zhou H. Histopathological defects in intestine in severe spinal muscular atrophy mice are improved by systemic antisense oligonucleotide treatment. PLoS One. 2016 May 10;11(5):e0155032. DOI:10.1371/journal.pone.0155032
- Zhou H, Meng J, Marrosu E, Janghra N, Morgan J and Muntoni F. Repeated low doses of morpholino antisense oligomer: an intermediate mouse model of spinal muscular atrophy to explore the window of therapeutic response. Hum Mol Genet. 2015 Nov 15;24(22):6265-77. DOI:10.1093/hmg/ddv329
- Zhou H, Janghra N, Mitrpant C, Dickinson R, K Anthony, L Price, I Eperon, S Wilton, J Morgan and F Muntoni. A novel Morpholino oligomer targeting ISS-N1 improves rescue of severe SMA transgenic mice. Hum Gene Therapy 2013; 24(3): 331-42. DOI:10.1089/hum.2012.211
- Zhou H, Owen N (co-first), Malygin AA, Sangha J, Smith LD, Muntoni F and Eperon IC. Design principles for bifunctional targeted oligonucleotide enhancers of splicing. Nucleic Acid Research 2011;39 (16): 7194-208. DOI:10.1093/nar/gkr152