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.

Public Health Relevance

We have developed a new class of mRNA splicing modulator drugs and the goal of this grant is to determine their mechanism of action, evaluate their efficacy in a new mouse model of familial dysautonomia, and identify disease-specific gene networks that are altered by increasing IKAP expression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Gwinn, Katrina
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Massachusetts General Hospital
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Donadon, Irving; Pinotti, Mirko; Rajkowska, Katarzyna et al. (2018) Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model. Hum Mol Genet 27:2466-2476