Genetic therapies

Gene therapy and genetic therapies are direct treatments for the underlying genetic cause of a disease. Various methods are in development in academic and commercial centres worldwide involving intervention at a molecular level to modify or replace the defective gene and restore its function. Most of these are at an early stage in preclinical development, but some have progressed to the clinic. Antisense oligonucleotides have recently been approved for the treatment of SMA and amyloid neuropathies. Gene replacement using viral vectors is in clinical development for several neuromuscular diseases including DMD, SMA and myotubular myopathy.

Our current research focuses on gene therapy using viral vectors in animal models of DMD such as the mdx mouse and the DMD pig. We have developed small dystrophin genes to fit into AAV vectors and tested their functionality.

Wild-type and DMD piglets climbing a step

Relevant publications

Dominov, JA, Uyan, Ö, McKenna-Yasek, D, Nallamilli, BRR, Kergourlay, V, Bartoli, M et al.. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. Ann Clin Transl Neurol. 2019.6 (4)642-654 PMID:31019989

Lourbakos, A, Yau, N, de Bruijn, P, Hiller, M, Kozaczynska, K, Jean-Baptiste, R et al.. Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne. Sci Rep. 2017.7 (1)17888 PMID:29263366

Meng, J, Counsell, JR, Reza, M, Laval, SH, Danos, O, Thrasher, A et al.. Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy. Sci Rep. 2016.6 19750 PMID:26813695

Coenen-Stass, AM, McClorey, G, Manzano, R, Betts, CA, Blain, A, Saleh, AF et al.. Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics. Sci Rep. 2015.5 17014 PMID:26594036

Walter, MC, Bernert, G, Zimmermann, U, Müllner-Eidenböck, A, Moser, E, Kalaydjieva, L et al.. Long-term follow-up in patients with CCFDN syndrome. Neurology. 2014.83 (15)1337-44 PMID:25186864

Greer, KL, Lochmüller, H, Flanigan, K, Fletcher, S, Wilton, SD. Targeted exon skipping to correct exon duplications in the dystrophin gene. Mol Ther Nucleic Acids. 2014.3 e155 PMID:24643206

Dick, E, Kalra, S, Anderson, D, George, V, Ritso, M, Laval, SH et al.. Exon skipping and gene transfer restore dystrophin expression in human induced pluripotent stem cells-cardiomyocytes harboring DMD mutations. Stem Cells Dev. 2013.22 (20)2714-24 PMID:23829870

Schinkel, S, Bauer, R, Bekeredjian, R, Stucka, R, Rutschow, D, Lochmüller, H et al.. Long-term preservation of cardiac structure and function after adeno-associated virus serotype 9-mediated microdystrophin gene transfer in mdx mice. Hum. Gene Ther. 2012.23 (6)566-75 PMID:22248393

Moll, J, Barzaghi, P, Lin, S, Bezakova, G, Lochmüller, H, Engvall, E et al.. An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature. 2001.413 (6853)302-7 PMID:11565031

Lochmüller, H, Petrof, BJ, Pari, G, Larochelle, N, Dodelet, V, Wang, Q et al.. Transient immunosuppression by FK506 permits a sustained high-level dystrophin expression after adenovirus-mediated dystrophin minigene transfer to skeletal muscles of adult dystrophic (mdx) mice. Gene Ther. 1996.3 (8)706-16 PMID:8854096