# mRNA Splicing Modulation in Familial Dysautonomia

> **NIH NIH R37** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $683,328

## Abstract

Familial dysautonomia (FD) is a hereditary sensory and autonomic neuropathy that is caused by a splice
mutation in the IKBKAP gene. The mutation results in variable skipping of exon 20 in IKBKAP mRNA, which
leads to a tissue-specific reduction of IKAP protein. We have shown that splicing is particularly poor in the
nervous system, resulting in dramatically reduced levels of IKAP protein. Despite the fact that FD is recessive,
patients retain the capacity to make both normal mRNA and protein, a discovery that offered an exciting, direct
approach towards the development of therapies via splicing modification. As part of an NINDS sponsored
Neurogeneration Drug Screening Consortium, we identified kinetin, a plant cytokinin, as a potent modulator of
mRNA splicing. This compound has remarkable efficacy and can restore normal IKAP protein levels in patient
cells within one week in culture. Recently, we have also demonstrated that kinetin can modify IKBKAP splicing
in vivo in both transgenic mice and in human FD carriers and patients. Over the past three years, we have
worked with the NINDS Blueprint Neurotherapeutics Network to perform medicinal chemistry and optimization
of kinetin, with the goal of developing a novel splicing modulator compound (SMC) as a therapy for FD. To
date, we have evaluated over 520 compounds and have identified more than 200 that have dramatically
improved potency and efficacy. The goal of this grant is to study, in detail, how our new class of SMCs modify
mRNA splicing. We will also perform a pre-clinical trial of one of our SMCs to determine, for the first time, if
increasing IKAP protein by modifying splicing in vivo will improve disease phenotypes in a new FD mouse
model. Lastly, we will identify critical disease-relevant networks. This will yield potential biomarkers for future
clinical studies, new targetable pathways for therapy, and will also shed light on the regulation of sensory and
autonomic nervous system development. Despite the fact that FD is a developmental disorder, patients are
plagued by continued, drastic neuronal degeneration throughout life. We believe that effectively increasing
IKAP levels early in life may support neuronal survival and prevent or delay the debilitating gait, sensory, and
cognitive decline seen in patients as they age. Successful completion of the Aims of this grant will allow us to
understand the mechanism of action of our SMCs, determine if their action is efficacious in a novel animal
model of the disease, and uncover gene networks that respond to a therapeutic increase in IKAP protein.
These are all fundamental steps as we continue the long climb towards the clinic.

## Key facts

- **NIH application ID:** 10133344
- **Project number:** 4R37NS095640-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Susan A Slaugenhaupt
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $683,328
- **Award type:** 4N
- **Project period:** 2016-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133344

## Citation

> US National Institutes of Health, RePORTER application 10133344, mRNA Splicing Modulation in Familial Dysautonomia (4R37NS095640-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133344. Licensed CC0.

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