Safety Profile Optimization of Glucose-Regulated Insulin Formulations

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DESCRIPTION (provided by applicant): SmartCells has developed Smartlnsulin, a once-a-day, injectable formulation of insulin for the treatment of diabetes. Unlike pump- and cell-based systems, Smartlnsulin is a "smart" hydrogel that self-assembles from two biomolecular building blocks: a glycosylated insulin-polymer conjugate (IPC) and a multimeric glucose-binding molecule (GBM). In SBIR Phase I of this grant, proof-of-concept efficacy and safety was demonstrated both in vitro and in vivo using a diabetic Sprague-Dawley rat model. SmartCells seeks Phase II funds to rigorously optimize the in vivo safety profiles of Smartlnsulin in non-diabetic Sprague Dawley (SD) rat models as a precursor to beginning IND-enabling preclinical studies on Smartlnsulin. With Phase II funds, SmartCells seeks to: 1. Identify PEG-Con A GBM candidates with minimal serum half-life that are chemically stable, such that no immunoreactive, non-PEGylated Con A is exposed in vivo. 2. Identify formulations with minimal local and systemic single-dose toxicity as measured by custom ELISAs, histology, and spleenocyte phenotyping. 3. Develop a hyperglycemic clamp to investigate Smartlnsulin pharmacokinetics in non-diabetic rats. 4. Confirm minimal local and systemic toxicity of daily injections following Smartlnsulin release under hyperglycemic clamp conditions in non-diabetic rats. The impacts on public health as a result of this project are potentially significant. Poor glycemic control has been shown to cause a host of diabetic complications which result in over $54 billion annually in medical costs. The landmark Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), have clinically proven that tighter glycemic control, as measured by lower glycosylated hemoglobin A1c (HbA1c) levels, significantly reduces the incidence of these complications. Thus, Smartlnsulin seeks to provide tighter glycemic control, lowered HbA1c levels, and decreased incidence of diabetic complications.