Organocatalysis for the treatment of sickle cell disease

描述（由申请人提供）：镰状细胞病（SCD）是一种全球性健康问题，影响约10万美国人和全球1300多万人。这种疾病的复杂性决定了可能需要一种多模式治疗方法。SCD在镰状危象的急性事件期间在生理上表现为扭曲的红细胞阻碍血液流动，引起生理损伤和剧烈疼痛。SCD通常以分子疾病为特征，与炎症和再灌注损伤的病理生理学表现出许多相似之处。因此，各种形式的抗氧化剂疗法正被积极寻求作为治疗SCD的新方法。没有商业治疗可用于治疗或避免急性危机事件，因为开发已被有效性所需的高（和毒性）浓度所扼杀。急性事件目前仅用止痛药管理。产品和长期目标：Nanometics开发了一种新型的多模式治疗药物，称为AIC- 6020，作为一种小分子药物，可供患者在发病或镰刀危机期间服用。AIC-6020直接修饰血红蛋白（HbS）， 并释放已知的抗氧化剂以通过抗氧化/抗炎机制帮助减弱微循环中的氧化应激事件。AIC-6020将是第一个用于治疗急性事件的商业治疗药物，也是第一个用于SCD的多模式治疗药物。技术创新：Nanometics开发了一种新的多模式治疗方法来治疗镰状细胞病，将两种不同的治疗机制整合到一种化合物中。铅治疗剂通过独特的transaldimination机制与化学计量浓度的HbS反应。第一阶段假设和具体目标：第一阶段假设是AIC-6020比5-羟甲基-2-糠醛（5 HMF）更有效，毒性更低。该假设在体外、离体和体内（小鼠）中成功验证，其中AIC-6020的有效浓度比5 HMF的有效浓度低>50%。第二阶段目标：II期研究的目标是：1）优化AIC方法，以在AIC-6020的最低可能浓度下抑制镰状化，（2）确定AIC-6020的生物利用度，并确定其毒理学和组织病理学特征，以及（3）检查AIC-6020对减轻镰状细胞病病因微循环事件的影响。商业机会：仅在美国，每年就有约190，000例因急性危机事件寻求治疗的患者到急诊室就诊，其中约42%需要住院治疗 平均5天。此外，每年约有30万婴儿出生时患有镰状细胞病，随着发展中国家婴儿死亡率的下降，预计未来20年患者的目标市场将大幅增加。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a global health issue that affects ~100,000 Americans and over 13 million people worldwide. The complexity of the disease dictates that a multimodal approach to treatment will likely be needed. SCD is manifested physiologically during acute events of sickle crisis as the distorted red blood cells impede blood flow, causing physiological damage and severe pain. Generally characterized as a molecular disease, SCD exhibits many similarities with the pathophysiology of inflammation and reperfusion injury. As such, various forms of antioxidant therapies are being actively pursued as a new approach to treat SCD. No commercial therapeutic is available to treat or avert acute events of crisis, as the development has been stifled by the high (and toxic) concentration required for efficacy. Acute events are currently only managed with pain medication. Product and Long-Term Goal: Nanometics has developed a new type of multimodal therapeutic, termed AIC- 6020, as a small-molecule medication to be taken by patients at the onset or during sickle crisis. AIC-6020 directly modifies hemoglobin (HbS) to both inhibit sickling and to release a known antioxidant to help attenuate oxidative stress events in the microcirculation by antioxidant/anti-inflammatory mechanisms. AIC-6020 will be the first commercial therapeutic useful to treat acute events and the first multimodal therapeutic for SCD. Technical Innovation: Nanometics has developed a new class of multimodal therapeutics to treat sickle cell disease that incorporates two distinct therapeutic mechanisms into one chemical compound. The lead therapeutic reacts with HbS at stochiometric concentrations by a distinct transaldimination mechanism. Phase I Hypothesis and Specific Aims: The Phase I hypothesis was that AIC-6020 would be more effective and less toxic than 5-hydroxymethyl-2-furfural (5HMF). This hypothesis was successfully validated in vitro, ex vivo and in vivo (mice) where the efficacious concentration of AIC-6020 was >50% lower than that of 5HMF. Phase II Objectives: The Phase II objectives will be to 1) optimize the AIC approach to inhibit sickling at the lowest possible concentrations of AIC-6020, (2) establish the bioavailability of AIC-6020 and determine its toxicological and histopathological profile, and (3) examine the impact of AIC-6020 to attenuate events in the microcirculation that are etiologic to sickle cell disease. Commercial Opportunity: In the US alone, there are ~190,000 emergency room visits annually by patients seeking treatment for acute events of crisis, and ~42% of these visits required hospitalization for an average of 5 days. Additionally, there are ~300,000 babies born each year with sickle cell disease, and as infant death rates in developing countries decrease, the target market of patients is expected to rise dramatically over the next 20 years.