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. Analysis of tissue from FD patients shows significantly more exon skipping in neuronal tissue, and therefore lower IKAP levels. IKAP is a member of the human Elongator complex, which is required for efficient transcriptional elongation of a subset of genes. Studies have shown that depletion of IKAP leads to a defect in cell migration due to reduced expression of Elongator dependent genes, which might explain the neurodevelopmental defects seen in FD. Despite the fact that FD is recessive, we have shown that patients retain the capacity to make both normal mRNA and protein. This discovery offers an exciting, direct approach towards the development of therapies aimed at increasing levels of cellular IKAP via splicing modification. As part of the NINDS sponsored Neurogeneration Drug Screening Consortium, we found that treatment of cultured FD cells with kinetin, a plant cytokinin, enhances exon 20 inclusion and dramatically increases the amount of wild-type IKBKAP mRNA and IKAP protein in FD cells. Analysis of patient cell lines shows that within three days of kinetin treatment the level of normal IKAP is equivalent to that seen in normal cells. In order to develop kinetin as a therapy for FD, we have inserted the FD mutation into a human BAC and created several transgenic mouse lines. Importantly, transgene expression in these mouse lines shows that the human pattern of aberrant FD splicing is preserved. Moreover, analysis of several mouse tissues shows that aberrant splicing is significantly worse in the brain, modeling perfectly what we observe in FD patients. These mice will enable us to test kinetin in vivo to determine if the drug can increase levels of normal human IKAP. We have also recently shown that a complete loss of IKBKAP in mice leads to embryonic lethality. By rescuing the knock-out mouse with the transgene, we aim to create an accurate phenotypic model of FD for evaluating the efficacy of kinetin. Despite the fact that FD is a developmental disorder, patients are plagued by continued, drastic neuronal degeneration throughout life. Effectively increasing IKAP levels early in life may support neuronal survival and prevent or delay the debilitating gait, sensory, and cognitive decline seen in teenage patients.Familial dysautonomia is a severe neurodevelopmental disease that is caused by a mutation in the IKBKAP gene. This mutations leads to reduced protein expression in all tissues, but this reduction is variable and is most severe in neuronal tissue. We have identified a drug, kinetin, that can increase IKAP protein in patient cells and our goal is to develop this drug as a therapy for FD patients. The purpose of this grant is to test this drug to see if it works in mouse models of the disease. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Porter, John D
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Massachusetts General Hospital
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Axelrod, Felicia B; Liebes, Leonard; Gold-Von Simson, Gabrielle et al. (2011) Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr Res 70:480-3
Shetty, Ranjit S; Gallagher, Cary S; Chen, Yei-Tsung et al. (2011) Specific correction of a splice defect in brain by nutritional supplementation. Hum Mol Genet 20:4093-101