Development of a splicing modulator compound for familial dysautonomia

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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.