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Development of a novel accurate therapy for multiple sclerosis

开发一种针对多发性硬化症的新型精确疗法

基本信息

批准号：
10384985
负责人：
Gaddiel Galarza-Munoz
金额：
$ 100万
依托单位：
AUTOIMMUNITY BIOLOGIC SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-22 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10384985
关键词：
Address Advanced Development Affect Alternative Splicing Animals Antisense Oligonucleotide Therapy Antisense Oligonucleotides Autoimmune Diseases Autoimmune Process Autoimmunity Back Biodistribution Biological Response Modifier Therapy Brain CD4 Positive T Lymphocytes CNS Demyelinating Autoimmune Diseases Cell model Clinical Clinical Trials Coupled Demyelinations Development Diagnostic tests Disease Disease Progression Dose Drug Kinetics Economic Burden Etiology Evaluation Event Exclusion Exons Experimental Autoimmune Encephalomyelitis Foundations Future Genes Genetic Predisposition to Disease Goals Harvest Heart Human IL7R gene Image Immune mediated destruction Immune system Immunodeficiency and Cancer Immunologics Immunomodulators Immunosuppression In Vitro Individual Insulin-Dependent Diabetes Mellitus Interleukin 7 Receptor Kidney Lead Liver Lung Macaca Macaca fascicularis Magnetic Resonance Imaging Maximum Tolerated Dose Mediating Modeling Molecular Monitor Morbidity - disease rate Multiple Sclerosis Mus Myelin Sheath Nerve Degeneration Neuraxis Neurologic Deficit Neurologic Dysfunctions Neurons Outcome Pathogenesis Pathogenicity Pathology Patients Pharmaceutical Preparations Phase Primates RNA RNA Splicing Relapse Relapsing-Remitting Multiple Sclerosis Research Rheumatoid Arthritis Risk Factors Safety Severity of illness Societies Spinal Cord Spleen Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Thymus Gland Time Tissues Toxic effect Toxicology Treatment Efficacy base cancer immunotherapy cancer therapy cellular targeting curative treatments disability drug candidate efficacy study efficacy testing emerging adult immune function immunoregulation in vivo lymph nodes mRNA Precursor mortality motor impairment mouse model multiple sclerosis patient multiple sclerosis treatment nervous system disorder nonhuman primate novel novel therapeutics personalized medicine precision medicine preclinical development preclinical study prevent primary endpoint receptor expression receptor function reduce symptoms risk variant side effect socioeconomics targeted treatment young adult

项目摘要

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.

项目总结