Collectively, autoimmune diseases, such as multiple sclerosis (MS), psoriasis, rheumatoid arthritis and type 1 diabetes, are the third most prevalent cause of human morbidity and mortality in the United States. In these disorders, a failure in immune regulation results in T cell--mediated destruction of self-tissues. The pathologic role of T cells in driving autoimmune diseases has resulted in numerous therapies aimed at inactivating T cells. The induction of long-term, durable antigen-specific T-cell tolerance is the ideal therapy, but published 'tolerance-inducing' strategies such as T cell epitope--specific peptides, T cell--specific antibodies or co-stimulation blockade have not faired well clinically. These failures, in part, have been the result of individual treatment issues; however, many also involved concerns about safety and marginal efficacy. We previously reported that intravenous administration of soluble peptides cross-linked to syngeneic apoptotic splenic leukocytes using ethylene carbodiimide (ECDI) safely and efficiently induced antigen-specific immune tolerance effective for the prevention and treatment of T helper type 1 (TH1) cell-- and/or TH17 cell--mediated autoimmune diseases and overcame many of the drawbacks of the failed trials involving monoclonal antibodies and soluble peptides. We have recently described that this strategy is safe and demonstrated proof of efficacy for tolerance induction in a phase 1 clinical trial in MS patients. However, the manufacturing process is complex and expensive, involving isolation of isologous leukocytes and peptide coupling under good manufacturing practices (GMP) conditions. To overcome the cost and complexity of this cell-based approach, Drs. Miller and Getts established that myelin peptides associated with 500 nm carboxylated polystyrene (PS) or, more importantly, 'biodegradable' poly(lactide-co-glycolide) (PLGA) nanoparticles engineered to mimic apoptotic debris which are loaded with single antigenic peptides serve as an effective substitute capable of inducing potent antigen-specific tolerance for prevention and treatment of the experimental autoimmune encephalomyelitis (EAE) model of MS when administered at onset or at peak of acute disease, and, most importantly, minimize epitope spreading and subsequent disease relapses when administered during disease remission. To achieve broader autoepitope coverage, we have shown in the context of human MS that tolerogenic mixtures of myelin antigens can be employed. Therefore, this study is focused on completing preclinical studies to provide needed rationale for human testing of tolerogenic immune modifying nanoparticles (TIMP) that encapsulating a cocktail of myelin antigens to treat and reverse MS in relapsing-remitting MS patients by addressing the following aims: Specific Aim 1. Generate tolerogenic immune modifying nanoparticles (TIMP) containing a mixture of four EAE-associated encephalitogenic antigens (TIMPmix). Specific Aim 2. Test the ability of individual TIMPs vs. TIMPmix to induce antigen-specific preventative tolerance in the EAE model of MS. Specific Aim 3. Test the ability of TIMPmix administered at the peak of acute disease to induce therapeutic tolerance for prevention of clinical relapses and associated epitope spreading and safety in pre-primed mice. Specific Aim 4. Complete FDA-mandated in vitro and in vivo toxicology testing to promote clinical translation and enable first-in-man testing. Specific Aim 5. Complete first manufacturing run of human-specific TIMP containing MS-associated h
|Effective start/end date||1/1/15 → 3/31/18|
- Dr. Ralph and Marian Falk Medical Research Trust (Agr. 12/1/2014)
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