RNA-Biopolymer Nanostructures for Smart Insulin Delivery

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。真正的血糖控制需要提供血糖调节的胰岛素替代治疗。Smartlnsulin以临床相关的方式感知并响应变化的血糖水平，直接满足了这一需求。与基于泵和细胞的系统不同，Smartlnsulin是一种“智能”纳米结构材料，由两个生物分子构建块自组装而成：糖基化胰岛素聚合物共轭化合物(IPC)和多聚体葡萄糖结合分子(GBM)。在这项提议中，我们试图通过以下具体目标，用一种更安全的、非免疫原性的、由基于核糖核酸(RNA)的适体构建的合成GBM来取代我们的概念验证配方： -开发抗核酸酶的基于RNA的适体，与葡萄糖结合 -使用自组装过程从单体结构合成多聚体RNA适配子 -证明RNA适配子与IPC形成凝胶，并在生理上相关的葡萄糖浓度下溶解。 这一项目对公众健康的影响可能是巨大的。血糖控制不良已被证明会导致一系列糖尿病并发症，包括视网膜病变、神经病变、肾病以及心脏病和中风的发病率增加，这导致每年超过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. True glycemic control requires treatments that provide plasma glucose-regulated insulin replacement. Smartlnsulin, which senses and responds to altered serum glucose levels in a clinically relevant way, directly addresses this need. Unlike pump- and cell-based systems, Smartlnsulin is a "smart" nanostructured material that self-assembles from two biomolecular building blocks: a glycosylated insulin polymer conjugate (IPC) and a multimeric glucose-binding molecule (GBM). In this proposal, we seek to replace our proof-of-concept formulation with a safer, non-immunogenic, synthetic GBM constructed from ribonucleic acid (RNA)-based aptamers through the following specific aims: -Develop nuclease-resistant RNA-based aptamers that bind glucose -Synthesize multimeric RNA aptamers from monomeric constructs using a self-assembly process -Demonstrate that RNA aptamers form gels with IPCs and dissolve at physiologically relevant glucose concentrations. 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 including retinopathy, neuropathy, nephropathy, and increased prevalence of heart disease and stroke, 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.