Development of a splicing modulator compound for familial dysautonomia

家族性自主神经功能障碍（FD），也称为HSAN III型或D-D综合征，是一种罕见的，致命的，先天性 由“渗漏”RNA剪接缺陷引起的感觉和自主神经病变， ELP 1蛋白主要存在于神经系统中。FD患者具有复杂的神经系统表型， 疼痛和温度感知减弱，肌张力反射减少或缺失，本体感受性步态共济失调， 和进行性视网膜退化在确定激动素是一种能够纠正ELP 1的小分子后， 剪接缺陷，我们作为NIH蓝图神经治疗网络的一部分， 激动素的功效，并产生一类新的剪接调节剂化合物（SMC）。2015年，我们与 PTC Therapeutics将进一步开发这些化合物，目标是为FD患者提供新药。后 经过四年的高度合作，PTC Therapeutics于2019年底取消了FD计划，原因是预算问题。 与开发用于这种罕见患者群体的药物相关的限制。这个目标 建议是完成我们的先导化合物PTC 680的IND使能研究，并进行I期 充分利用BPN顾问和承包商的专业知识和指导进行临床试验。PTC 680是 一个优秀的开发候选者：1）它是体外和体内ELP 1剪接的有效调节剂， 重要的是，导致小鼠所有组织（包括大脑）中功能性ELP 1蛋白的增加，2）发现 阶段性项目比较完整，并制定了合理的合成方案; 3）具有良好的 ADME特征，药物间相互作用的可能性有限，种属间蛋白结合相似。因此，我们认为， 临床前数据应及时转化为临床数据。该项目将进入开发阶段 并将利用NIH承包商的专业知识将PTC 680转移到诊所。在UG 3阶段，我们将执行 国家执行主任扶持性研究的筹备工作，包括进一步优化综合战略， 为拟议的研究提供足够的材料，并确定合适的配方。发展过程中 第三阶段（UH 3）将使用BPN CRO进行IND使能研究和I期临床试验， 个体在项目的这一阶段，我们将共同负责整个项目的管理 CDT、IND申请的组装和提交以及与FDA的所有通信。我们 我相信，在蓝图网络的支持下，我们将成功地实现我们的目标， 改善FD患者的病情。

Familial dysautonomia (FD), also known as HSAN type III or Riley-Day syndrome, is a rare, fatal, congenital sensory and autonomic neuropathy caused by a “leaky” RNA splicing defect that results in reduced levels of ELP1 protein mainly in the nervous system. Patients with FD have a complex neurological phenotype with diminished pain and temperature perception, decreased or absent myotatic reflexes, proprioceptive gait ataxia, and progressive retinal degeneration. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked as part of the NIH Blueprint Neurotherapeutics Network to optimize the potency and efficacy of kinetin and create a new class of splicing modulator compounds (SMCs). In 2015, we partnered with PTC Therapeutics to further develop these compounds with the goal of bringing a new drug to FD patients. After four years of highly collaborative work, PTC Therapeutics canceled the FD program in late 2019 due to budgetary constraints associated with the development of a drug for such a rare patient population. The goal of this proposal is to complete the IND-enabling studies for our lead compound, PTC680, and to conduct a Phase I clinical trial taking full advantage of the expertise and guidance of BPN consultants and contractors. PTC680 is an excellent development candidate: 1) It is a potent modulator of ELP1 splicing both in vitro and in vivo and, importantly, leads to an increase in functional ELP1 protein in mice in all tissues, including brain, 2) Discovery stage projects are complete and a reasonable synthesis scheme has been developed, and 3) It has a good ADME profile, limited potential for drug-drug interactions and similar protein binding across species. Therefore, preclinical data should promptly translate to the clinic. The proposed project will enter at the Development stage and will use the expertise of NIH contractors to move PTC680 to the clinic. In the UG3 phase, we will perform the preparatory work for the IND-enabling studies including further optimization of the synthesis strategy to produce enough material for the proposed studies, and determine a suitable formulation. During the development phase (UH3) will use the BPN CROs to conduct the IND-enabling studies and the Phase I clinical trial in healthy individuals. During this phase of the program, we will be responsible for overall project management together with the CDT, assembly, and submission of the IND application, and all communications with the FDA. We are confident that with the support of the Blueprint network, we will be successful in our quest to finally bring a disease-modifying therapy to FD patients.