# Development of a splicing modulator compound for familial dysautonomia

> **NIH NIH UH3** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $580,711

## Abstract

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.

## Key facts

- **NIH application ID:** 11009479
- **Project number:** 4UH3NS132462-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Susan A Slaugenhaupt
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,711
- **Award type:** 4N
- **Project period:** 2023-05-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009479

## Citation

> US National Institutes of Health, RePORTER application 11009479, Development of a splicing modulator compound for familial dysautonomia (4UH3NS132462-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11009479. Licensed CC0.

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