Potential applications of antisense oligonucleotides (AOs) vary from a research tool to therapeutic compounds now in the clinic. Advances in AO chemistry have addressed some of the issues that hindered clinical applications and led to FDA approval of three antisense drugs in recent years. Our laboratory has extensive experience in designing splice switching AOs that can specifically redirect pre-mRNA processing to induce selected exon/intron combinations. Recently the FDA gave accelerated approval to a phosphorodiamidate morpholino oligomer (PMO) developed in our laboratory to reframe the disrupted dystrophin mRNA and restore some dystrophin expression in a subgroup of individuals with Duchenne muscular dystrophy. We are now extending the application of PMO-based splice switching therapies to other diseases and present a novel strategy for multiple sclerosis (MS).

MS is a neurodegenerative disease characterized by chronic inflammation in the central nervous system (CNS) that damages the protective myelin sheath around the neurons and causes disrupted communication in the CNS. The etiology is unknown and current therapies focus on minimizing the severity and frequency of relapses and attacks. Natalizumab, a humanized monoclonal antibody directed to integrin alpha 4 (ITGA4), present on the surface of lymphocytes, is currently one of the most potent drugs for the treatment of relapsing remitting multiple sclerosis. Natalizumab inhibits the interaction between ITGA4 and vascular cell adhesion molecule 1 (VCAM-1) of endothelial cells, thereby reducing lymphocyte migration across the blood brain barrier and into the CNS. This treatment reduces relapses and stabilizes disease progression in many MS patients.

As with many other antibody based therapies, frequent side effects and development of neutralizing antibodies are serious limitations. We have developed an alternative therapy for MS using exon skipping AOs to induce specific isoforms and disrupt normal expression of the ITGA4 transcript. ITGA4 exon skipping AOs were first designed with 2’-O-methyl modified bases on a phosphorothioate backbone and transfected into normal human fibroblasts. The most effective splice switching sequences were re-synthesized as PMOs. Lymphocytes treated with these PMOs showed reduced ITGA4 expression, affinity for VCAM-1 and altered cell migration patterns. In vivo assessment of these compounds is ongoing in models of MS. With an excellent safety profile, the PMO developed for the validated target, ITGA4, could offer a safe and effective alternative therapy for MS patients.