HBI-002 to Treat Diabetic Retinopathy

项目摘要 糖尿病视网膜病变（DR）是糖尿病的神经血管并发症，是糖尿病视网膜病变的主要原因。 在美国，工作年龄的成年人和老年人失明，影响了大约420万糖尿病患者， 其中655，000人患有威胁视力的DR。迫切需要开发额外的 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， 有效性和实质性缺点。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）在各种疾病状态下的细胞保护特性，包括缺血- 相关疾病，如DR 迄今为止，吸入的CO气体（iCO）和与载体分子结合的CO（CORM）已经成为治疗的模式。 在大多数动物和所有临床研究中，选择低剂量 然而，预期iCO和CORMS不是药学上可接受的和可行的。 由于iCO存在因压缩CO而意外暴露的风险， 以及在控制剂量方面的困难，以及对于CORM，载体分子毒理学、稳定性和 CO释放特性已被证明是开发的实质性障碍。的目的 拟定项目是研究HBI-002，一种新型口服CO制剂，用于预防和治疗DR。 CO的安全性和耐受性已在25项成功的I期和II期临床研究中得到证实， 其他用于其他适应症，这些适应症得到了明确的临床前数据集的支持，这些数据集导致FDA批准 人体测试HBI-002包含含有精确量的CO的口服制剂，所述精确量的CO不与HBI-002结合。 载体分子（即不是CORM）。临床前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动物模型中有效，并更好地理解 行动上基于大量的文献，CO在保护缺血相关和 眼科疾病，我们的中心假设，将在这个项目中进行测试是：HBI-002将防止DR 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.