HBI-002 to Treat Diabetic Retinopathy

项目总结 糖尿病视网膜病变(DR)是糖尿病的一种神经血管并发症，是糖尿病的主要病因。 工作年龄成年人和老年人失明，影响到美国约420万糖尿病患者， 其中655,000名有视力威胁的医生迫切需要开发更多的 预防和治疗糖尿病视网膜病变的方法，因为目前的治疗干预措施有限 有效性和实质性缺陷。在多项临床前研究中，我们和其他人已经证明了 低剂量一氧化碳(CO)在不同疾病状态下的细胞保护特性，包括在缺血- 相关疾病，如DR 到目前为止，吸入的CO气体(ICO)和与载体分子(球茎)结合的CO一直是 在大多数动物和所有临床研究中进行的选择，以研究Low的潜在好处 剂量CO。然而，ICO和球茎预计不会在药学上被接受和可行 由于ICO存在因存在压缩CO而意外暴露的风险，因此可选择治疗方案 以及控制剂量的困难，对于球茎，载体分子毒理学，稳定性，以及 CO发布的特性已被证明是开发的重大障碍。该计划的目标是 拟议的项目是研究新型口服一氧化碳药物产品HBI-002，以预防和治疗DR。 一氧化碳的安全性和耐受性已在25项成功的1期和2期临床研究中得到证实 其他适应症，由定义明确的临床前数据集支持，导致FDA批准 人体测试。HBI-002包含一种口服配方，含有精确数量的CO，不与 载体分子(即不是球茎)。临床前的体内药代动力学研究证明- 概念可行性、耐受性和生物利用度。开发的下一步是证明HBI-002 在临床相关的DR动物模型中是有效的，并更好地理解DR的潜在机制(S) 行动。基于大量文献，一氧化碳在保护缺血相关和 眼科疾病，我们将在这个项目中检验的中心假设是：HBI-002将防止DR。 通过减少氧化应激和炎症。

PROJECT SUMMARY Diabetic retinopathy (DR) is a neurovascular complication of diabetes mellitus and the leading cause of blindness in working age adults and elderly, affecting approximately 4.2 million diabetes patients in the US, of which 655,000 have vision-threatening DR. There is an urgent need for the development of additional approaches to prevent and treat diabetic retinopathy, as the current therapeutic interventions have limited efficacy and substantial drawbacks. In multiple preclinical studies, we and others have demonstrated the cytoprotective properties of low dose carbon monoxide (CO) in various disease states, including in ischemia- associated diseases such as DR To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies carried out to study the potential benefit of low dose CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. The objective of the proposed project is to investigate HBI-002, a novel oral CO drug product, to prevent and treat DR. The safety and tolerability of CO has been demonstrated in 25 successful Phase 1 and 2 clinical studies by others in other indications supported by well-defined preclinical data sets that led to approval by the FDA for human testing. HBI-002 comprises an oral formulation containing precise amounts of CO that are not bound to a carrier molecule (i.e. not a CORM). Preclinical in vivo pharmacokinetic studies demonstrated proof-of- concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of DR and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in protecting against ischemia-associated and ophthalmologic disease, our central hypothesis that will be tested in this project is: HBI-002 will prevent DR by reducing oxidative stress and inflammation.