Researchers have developed a pre-treatment strategy using antisense oligonucleotides, to increase the efficacy of gene therapy in Duchenne muscular dystrophy (DMD).
Muscular dystrophies are a group of inherited diseases of the muscle that are characterized by muscle degeneration and progressive muscle weakness. Duchenne muscular dystrophy (DMD) is the most common and devastating form of muscular dystrophy, and therefore the search for treatment for these conditions has focused mainly on this disease. Development of successful gene therapy face difficulties due to the size and complexity of the causative gene, dystrophin.
Several molecular strategies have been tried in mice models of DMD (mdx mice) and these include viral and non-viral-mediated gene transfer, exon skipping using antisense oligonucleotides etc. However, dystrophin restoration during adeno-associated viral (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles possibly due to alterations of the dystophic myofiber membranes.
To improve the membrane integrity of the dystrophic myofibers, a research study led by Prof. Stephanie Lorain (Sorbonne University UPMC, France) pre-treated mdx muscles with a single dose of peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides at the time of AAV-U7 injection. PPMO was shown to induce temporary dystrophin expression at the sarcolemma. Results showed that PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and increased dystrophin expression up to 10-fold and enhanced the efficacy of AAV-U7 therapy after six months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with the transfer of micro-dystrophin cDNA into muscles. The study is published in Human Molecular Genetics.
Thus, the study provides preclinical evidence to support the use of PPMO pre-treatment for efficient and long-term restoration of dystrophin in DMD patients. A phase I/II trial in the UK is monitoring the local intramuscular effects of a PMO aiming at exon 51 in children with DMD.
Source: Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles. Pecate C et al., Human Molecular Genetics July 2016. DOI