Tolerogenic Nanotherapy to Delay Type I Diabetes

Abstract Type 1 diabetes (T1D) is an endocrine disorder characterized by the autoimmune destruction of pancreatic β islet cells with onset most often occurring in children. T1D is on the rise, especially among Hispanic, African American, and Asian pediatric populations in the United States. The only treatment for T1D is a lifetime prescription for exogenous insulin. Adverse events and side effects are commonplace, and patients face the risk of life-threatening hypoglycemic episodes, which can result in accidents and death. Long-term complications of T1D include neuropathy and microvascular disease resulting in amputation and blindness. T1D increases the risk of cancer (+25%) and cardiovascular disease (+200%). Thus, there is a great need for a preventative treatment to stop T1D onset in susceptible populations. The laboratory of Dr. Scott (PI at Northwestern University and founder and CEO of SNC Therapeutics Inc. (SNC)), previously demonstrated that subcutaneous (SC) administration of rapamycin-loaded vesicular nanoparticles, a.k.a. polymersomes (PS), induces antigen-specific tolerance (AST) in recipients of fully major histocompatibility complex (MHC)-mismatched islet grafts for T1D treatment in mice. Preliminary study results were published in Nature Nanotechnology. SNC’s rapamycin-loaded polymersomes (rPS) target antigen-presenting cells (APCs), increasing MHC II expression and decreasing coreceptor expression. This results in a unique CD4+ T cell costimulation blockade and upregulation of CD8+ regulatory T cells (Tregs). Preliminary results show rPS delay T1D onset in nonobese diabetic (NOD) mice. AST against multiple antigens is uniquely elicited by rPS without co-administration or even prior identification of the relevant autoantigens. SNC is developing rPS for selective delivery to APCs to avoid global lymphocyte suppression. Furthermore, while many current immunomodulatory drugs require costly intravenous infusions, rPS is administered via a short-term SC injection regimen to lower costs and increase compliance. Redosing is not associated with an adverse immune response. This STTR will validate and optimize rPS as a subcutaneously administered treatment to delay T1D onset. Preliminary preclinical data shows that rPS does not directly modify T cells and induces tolerance without systemic immunosuppression, which will be verified for T1D onset delay as well. The overall goal of this project is to develop rPS for an investigational new drug (IND). To this end, the team will complete the following Aims: Aim 1: Optimize rPS dosing for T1D onset delay in the NOD mouse model and benchmark against anti-CD3 Ab therapy (i.e. Tzield) and Aim 2: Scale up polymer synthesis and rPS formulation using Good Laboratory Practices (GLP). The proposed studies will build on SNC’s initial data to demonstrate the therapeutic and IND potential of rPS for T1D onset delay and ultimately prevention while avoiding side effects. In parallel, the company will optimize production scale-up. SNC anticipates the success of Phase I will support a Phase II to advance rPS to clinical trials for T1D onset delay. SNC will position rPS as a direct competitor to Tzield.