Molecular Mechanisms and Treatment Of Autoimmunity In Man And Animal Models

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

In this project, we are developing new diagnostic and therapeutic approaches to immune dysregulatory diseases. First, we have pursued novel therapeutic approaches focusing on multiple sclerosis (MS) as well as new immunological diseases for which we have determined the genetic basis. Our principle approach is to use antigen itself to program the specific cognate T cells to die through apoptosis via a process termed restimulation-induced cell death (RICD). The death is clonally specific and represents a way to eliminate disease-causing T cells by using antigen. Additionally, depending on the molecular and genetic mechanism of disease, we will also investigate using other small molecules or protein-based therapeutics. The key is to precisely tailor the therapy to the pathophysiological mechanism of the disease so that it will be highly effective. This is the overarching goal of "precision" medicine. At the present time, we have chosen to focus on developing new, highly effective therapeutics against MS using immunological and genetic approaches. Evidence suggests that myelin proteins antigens are targets of the autoimmune attack, but how the specificities determine disease outcome in progressive and relapsing-remitting MS is unclear. By programming the T cells that recognize such antigens to die, the effect of eliminating these cells on the disease can be demonstrated. Although twin studies show that there is a significant genetic component to MS susceptibility, there is little concrete knowledge about the genes or pathways involved. Genome-wide association studies (GWAS) have unearthed a variety of single nucleotide polymorphisms (SNPs) that are statistically associated with disease. The International MS Genetics Consortium has performed numerous GWAS but the number of identified SNPs with strong association with MS has been much lower than anticipated. However, these studies that the correlated SNPs are in or around mainly immune genes rather than central nervous system genes. Nonetheless, the implication of specific pathways in various subtypes of MS has not been achieved. Therefore, we have concluded that approaching the problem by searching for Mendelian or de novo genetic variants may provide more definitive information about pathogenesis. Using next generation sequencing (NGS) techniques such as whole exome sequencing (WES) and whole genomic sequencing (WGS) we are now capable of identifying causal genes in rare and severe disorders that do not have enough fitness to be inherited broadly in the population and detected by GWAS. Moreover, these highly penetrant and deleterious variants likely contribute strongly to de novo and Mendelian forms of autoimmune disease as well as susceptibility to common autoimmune diseases. Identification of rare genetic variants generally provides key information about disease mechanisms, biological pathways, and novel avenues for clinical treatments. We have established a collaboration with investigators at the University of British Columbia, Canada who have assembled a DNA biobank of nearly 14,000 samples, including over 450 Multiplex MS families: 1. Families with 3 or more affected members with MS (400 families); 2. Families with index cases with age of onset < 12 years old (extremely rare and available under this study). Approximately 35% of the samples are from affected patients, and most were diagnosed with MS between the ages of 21 and 40 years old, with the average age of onset being 31.4 years old. These patients, family members, and relatives will be subjected to WES through a collaboration with the Regeneron Sequencing Center. We expect that gene variants found by NGS in these patients, particular in the first two categories, will unveil major pathogenic pathways for MS. We have also pursued the direction of therapeutics particularly for a unique disorder we have discovered called "p110delta activating mutations causing Senescent T cells, Lymphadenopathy, and Immunodeficiency" (PASLI) disease. We studied the germline, heterozygous, dominant, gain-of- function mutations in the p110delta catalytic subunit of PI3K in nine patients from seven unrelated families and also families with severe mutations in the regulatory subunit of PI3K. We investigated specific p110delta enzyme inhibitors in PASLI patients and entered into a Cooperative Research and Development Agreement with Novartis to carry out a clinical trial testing their inhibitor of p110delta, a compound called leniolisib (CDZ173), in the NIH Clinical Center. Preliminary evidence showed that leniolisib is a potent and selective inhibitor of p110delta and can inhibit the wild-type as well as overactive forms of the enzyme thereby potently suppressing disease with few or no side effects. We completed a phase III of a larger triple-blinded, randomized, placebo-controlled study. We found that patients who received leniolisib achieved a significant benefit over placebo with respect to the co-primary endpoints, reducing lymphadenopathy and increasing the percentage of naive B cells, and was well tolerated in patients suffering from PASLI. This resulted in FDA-approval of leniolisib for treatment of PASLI disease.