Safety Profile Optimization of Glucose-Regulated Insulin Formulations

描述(申请人提供)：SmartCells公司已经开发出Smartlnsulin，这是一种每天一次的可注射胰岛素配方，用于治疗糖尿病。与基于泵和细胞的系统不同，Smartlnsulin是一种“智能”水凝胶，由两个生物分子构建块自组装而成：糖基化的胰岛素-聚合物共轭化合物(IPC)和多聚体葡萄糖结合分子(GBM)。在这项赠款的SBIR第一阶段，通过使用糖尿病SpragueDawley大鼠模型，在体外和体内都证明了概念验证的有效性和安全性。SmartCells寻求第二阶段资金，以严格优化Smartlnsulin在非糖尿病SpragueDawley(SD)大鼠模型中的体内安全性，作为开始对Smartlnsulin进行IND支持的临床前研究的先导。有了第二阶段的资金，SmartCells寻求：1.确定具有最小血清半衰期且化学稳定的PEG-ConA GBM候选者，这样就不会有免疫活性的、非PEGylated ConA在体内暴露。2.通过常规ELISA、组织学和脾细胞表型检测，确定局部和全身单剂量毒性最小的制剂。3.建立高血糖钳夹，研究Smartlnsulin在非糖尿病大鼠体内的药代动力学。4.确定在高血糖钳夹条件下每日注射Smartlnsulin对非糖尿病大鼠的局部和全身毒性最小。这一项目对公众健康的影响可能是巨大的。血糖控制不佳已被证明会导致一系列糖尿病并发症，每年导致超过540亿美元的医疗费用。具有里程碑意义的糖尿病控制和并发症试验(DCCT)和英国前瞻性糖尿病研究(UKPDS)已经临床证明，以较低的糖化血红蛋白(HbA1c)水平衡量，更严格的血糖控制可以显著降低这些并发症的发生率。因此，Smartlnsulin寻求提供更严格的血糖控制，降低HbA1c水平，并减少糖尿病并发症的发生率。

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.