Development of An Oral, Brain/Eye penetrating, Second Generation TTR Stabilizer for The Treatment of Transthyretin Amyloidoses

TTR淀粉样病变（ATTR）是一种罕见的、进行性的、最终致命的疾病，它损害多个器官的功能，引起广泛的衰弱的临床症状。ATTR是由四聚体转甲状腺素（TTR）蛋白解离引起的，导致释放的单体错误折叠和聚集，形成有毒的低聚物，随后组织沉积为生理上不溶性淀粉样蛋白原纤维（淀粉样蛋白形成）。虽然循环中的TTR主要在肝脏合成，但眼睛和大脑中的TTR分别由视网膜色素和脉络膜丛上皮细胞局部合成。常染色体显性遗传病是由123种种系不稳定的TTR突变之一引起的，这种突变表现出一系列疾病表型，包括多发性神经病、心肌病、眼部病理、局灶性中枢神经发作和痴呆。散发性衰老相关性老年性系统性淀粉样变性（SSA），其中野生型TTR是淀粉样蛋白前体，主要表现为心脏和腕管综合征表型。目前治疗ATTR的选择是基于1)通过肝移植（LT）或mRNA降低剂（如patsiran和intertersen）介导的TTR基因治疗来消除加速疾病的TTR突变体的产生；2)防止循环TTR解离，这限制了与小分子TTR动力学稳定剂他法米底的聚集速度，他法米底选择性地结合并稳定天然四聚体TTR，从而有效地阻止疾病进展。Tafamidis已获得约40个国家的监管机构批准，用于治疗由TTR突变引起的家族性淀粉样变性多发性神经病；在最近的一项III期研究中，他非他胺还能显著降低SSA患者的全因死亡率和心脏住院率。尽管可以显著延长寿命和健康寿命，但LT、基因下调和他法米地并不能阻止与局部合成TTR相关的眼部和中枢神经系统（CNS）症状的发生或进展（系统给药的他法米地在这些组织中不能达到治疗浓度）。由于动态稳定剂如他法底斯可显著减缓外周退行性疾病的进展，因此在ATTR患者的大脑和眼睛中开发一种有效水平的动态稳定剂可能会满足迫切的医疗需求。为了实现这一目标，我们将开展一个完整的药物发现项目，包括先导物鉴定、SAR引导优化、体外和体内药代动力学研究（见初步数据），以产生在眼睛和/或中枢神经系统中达到足够水平的TTR动力学稳定剂，以减缓疾病进展。Tafamidis是由我们的团队成员（Kelly和labaudini<e:1>）发明和开发的，消除了第二代动态稳定器策略的风险。这里提出的努力将与我们专有的早期诊断和治疗反应生物标志物策略相结合，促进候选药物的产生，为临床前和ind研究做好准备。

The TTR Amyloidoses (ATTR) are rare, progressive, ultimately fatal diseases that compromise the function of multiple organs, causing a wide range of debilitating clinical symptoms. ATTR is caused by the dissociation of the tetrameric transthyretin (TTR) protein, leading to misfolding and aggregation of the released monomers with toxic oligomer formation and subsequent tissue deposition as physiologically insoluble amyloid fibrils (amyloidogenesis). While circulating TTR is synthesized predominantly in the liver, TTR in the eye and the brain is made locally by retinal pigment and choroid plexus epithelial cells, respectively. Autosomal dominant disease is caused by one of 123 germ-line destabilizing TTR mutations that exhibit a spectrum of disease phenotypes including polyneuropathy, cardiomyopathy, ocular pathology, focal central neurologic episodes and dementia. Sporadic aging-associated Senile Systemic Amyloidosis (SSA), in which wild type TTR is the amyloid precursor, displays a primarily cardiac and carpal tunnel syndrome phenotype. Current treatment options for ATTR are based on 1) eliminating production of the disease-accelerating TTR mutants through TTR gene therapy mediated by liver transplantation (LT) or mRNA lowering agents, such as patisiran and inotersen; and 2) preventing circulating TTR dissociation, which is rate-limiting for aggregation with the small molecule TTR kinetic stabilizer, tafamidis, which selectively binds and stabilizes native tetrameric TTR, thereby effectively halting disease progression. Tafamidis has received regulatory agency approval in ~40 countries for the treatment of Familial Amyloidotic Polyneuropathy caused by TTR mutations; in a recent phase III study, tafamidis also significantly reduced all-cause mortality and cardiac hospitalizations in patients with SSA. Despite achieving significant increases in lifespan and health span, LT, gene knockdown, and tafamidis do not prevent the well documented onset or progression of ocular and central nervous system (CNS) symptoms related to locally synthesized TTR (systemically administered tafamidis does not attain therapeutic concentrations in these tissues). Since kinetic stabilizers such as tafamidis dramatically slows peripheral degenerative disease progression, it is likely that developing a kinetic stabilizer with effective levels in the brain and eyes of ATTR patients will meet an urgent medical need. To achieve that goal, we will conduct a full-fledged drug discovery program including lead identification, SAR guided optimization, in vitro and in vivo pharmacokinetic studies (see preliminary data) to generate a TTR kinetic stabilizer achieving sufficient levels in the eye and/or CNS to slow disease progression. Tafamidis was invented and developed by members of our team (Kelly and Labaudinière), de-risking the 2nd generation kinetic stabilizer strategy. The effort proposed here will be combined with our proprietary early diagnostic and response-to-therapy biomarker strategies, facilitating the generation of a drug candidate ready for pre-clinical, IND-enabling studies.