Development of a novel accurate therapy for multiple sclerosis

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PROJECT SUMMARY Multiple Sclerosis (MS) is the most common neurological disease of early adulthood and is mediated by autoimmune mechanisms that lead to demyelination and neuronal damage in the central nervous system, resulting in progressive neurological dysfunction. Up to date, there is no cure for this devastating disease and current available treatments focus on preventing future immunological attacks, primarily by suppressing the immune system, and this has adverse side effects that are often severe or fatal. Accordingly, there is a clear unmet need for the development of effective and well-tolerated therapies to arrest MS development. To reduce side effects, MS drugs should avoid immunosuppressive mechanisms and should be targeted to specific etiologies. This has been challenging because MS has multiple etiologies (>500 genes identified as risk factors for MS so far) and the molecular mechanisms underlying these etiologies are not well understood. Addressing this unmet need, we developed a personalized therapy that corrects a specific etiology of MS caused by elevated levels of the soluble form of the Interleukin 7 Receptor (sIL7R), which rises to pathogenic levels by aberrant exclusion of IL7R exon 6 during pre-mRNA splicing. Implicating sIL7R in the pathogenesis of MS and autoimmunity, it has been shown to: (i) be up-regulated by MS risk variants, (ii) exacerbate the severity of the disease in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS, and (iii) be elevated in patients from several autoimmune diseases, including MS, Type 1 diabetes, Rheumatoid arthritis and Systemic lupus erythematosus. Collectively, these findings support the scientific premise that a reduction in sIL7R would be therapeutic in MS and perhaps other autoimmune disorders where sIL7R is up-regulated. Given that sIL7R is generated by exclusion of exon 6 from IL7R RNAs, we developed antisense oligonucleotides (ASOs) that promote inclusion of this critical exon and reduce sIL7R expression (anti-sIL7R ASOs). By correcting this etiology of MS, anti-sIL7R ASOs are predicted to effectively prevent MS relapses while reducing side effects associated with immunosuppression. In our Phase I research, we optimized these ASOs ex vivo to efficiently reduce sIL7R secretion in human primary T cells with minimal cellular toxicity. In vivo efficacy studies of anti-sIL7R ASOs are limited to nonhuman primates (NHPs) because alternative splicing of IL7R exon 6 is observed exclusively in primates, of which macaques are the ideal model since they express sIL7R at levels equal to those observed in MS patients that suffer from this etiology. To advance pre-clinical development of anti-sIL7R ASOs as potential therapeutic drugs for MS, in this Phase II proposal we will assess the biodistribution, safety and therapeutic efficacy of lead anti-sIL7R ASOs in the highly relevant EAE model in cynomolgus macaques (Macaca fascicularis). This pivotal study will set the foundation for ensuing IND-enabling studies and clinical trials, and if successful, have the potential to provide a first-in-class precision medicine for MS.