Clinical grade insulin-producing iPSCs encapsulated with durable hyaluronic acid for long-term treatment of type 1 diabetes

Abstract For those with type 1 diabetes, the wait for a cell therapy to control blood glucose without systemic immunosuppression has been long and disappointing. While recent commercial acquisitions for such cell therapies offer hope that the field is finally advancing, there will be a need for numerous options, much like the approach to the COVID vaccine. Likarda holds multiple patents surrounding our novel microplates used for differentiation of induced pluripotent stem cells into insulin-producing cells and around our unique encapsulation technology that allows us to use biocompatible hydrogels that are not available to traditional microencapsulation approaches. We have differentiated clinically-appropriate human pluripotent cells into insulin-producing cells (Insulin-Producing induced Pluripotent Stem Cells – IPiPSCs) using our 5-step protocol that incorporates few growth factors compared to published protocols and can reverse diabetes in immune-compromised mice. We have encapsulated islets in a PEG-based hydrogel and reversed diabetes in immune-competent rats for their lifespan without immunosuppression or exogenous insulin. However, the IPiPSCs did not function well in the PEG- based hydrogel. Preliminary data indicates that a new hydrogel formulation we have created based on thiolated hyaluronic acid (ThHA) is a better match for the IPiPSCs. The purpose of this project is to examine the ability of ThHA to durably reverse diabetes in rats with a pilot trial in diabetic dogs. The specific aims are: 1) Identify genetic stability of the IPiPSCs after encapsulation and implantation into diabetic rats; 2) Determine whether implantation of ThHA-encapsulated human IPiPSCs in diabetic rats and beagles arrests the clinical signs of diabetes; 3) Identify biomarkers of a possible foreign body reaction in the surrounding tissue at 2 wks, 3 and 9 mos post-transplant int diabetic rats and 6 mos in diabetic dogs. Once we confirm the optimal hydrogel formulation for the IPiPSCs, we will incorporate them into our ribbon device, a retrievable device that maintains the large surface area and low diffusion barrier characteristics of microspheres while delivering retrievability for regulatory requirements. At the completion of this Phase I feasibility study, we will undergo Phase II studies in spontaneously diabetic dogs, which are an optimal model for human T1D due to parallel clinical presentation, similar autoantibodies, pathology and complications. Promising long-term results in spontaneously-diabetic dogs would offer strong preclinical data for human clinical trials.The key to a successful treatment of type 1 diabetes requires both insulin-producing cells and a way to protect them from immune rejection by the recipient’s body. We have both clinically appropriate stem cells that we have differentiated into insulin-producing cells and a hydrogel to coat the cells so that they are protected from the immune system. This proposal will test the combination of the two in diabetic rats and dogs to determine whether they can reverse hyperglycemia and the clinical signs of diabetes without insulin shots and without immunosuppression.