Unraveling the therapeutic potential of a new class of splicing modulators

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 DESCRIPTION (provided by applicant): The recent explosion of genomic sequence data generated from individual patients highlights the importance of mRNA splicing alterations in human disease. A large proportion of these mutations have been described in genes responsible for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Frontotemporal Dementia, Spinal Muscular Atrophy and Neurofibromatosis type 1. Our previous work has been focused on Familial Dysautonomia (FD), a congenital sensory and autonomic neuropathy caused by an mRNA splicing defect. Our work has led to the discovery that the plant cytokinin kinetin is a potent modulator of IKBKAP splicing and leads to a dramatic increase in the amount of functional IKAP protein. We also demonstrated that kinetin can modify splicing of NF1-causing mutations, suggesting that an appropriately targeted drug may prove efficacious in other genetic splicing disorders. Based on these findings, our FD program was selected to be part of the NINDS Blueprint Neurotherapeutics Network to develop a new drug for FD that targets disrupted splicing. Through this program, work is currently underway to optimize the potency and efficacy of kinetin and create a drug that can be used in patients. To date, we have created over 400 kinetin analogs and have in hand more than 50 splice modulator compounds (SMCs) with significantly improved potency, efficacy, and drug-like characteristics. The aim of the current R21 application is to determine if this new class of splicing modulators might be useful for other neurologic disorders. We have already shown that kinetin is able to modulate the splicing of human genes including IKBKAP, ABI2, BMP2K and NF1. Development of a drug to specifically target a precise molecular defect would be a major advance and would shift treatment paradigms not only for FD, but potentially for a number of other genetic diseases caused by mutations that alter mRNA splicing. Armed with our new class of splice modulator compounds, we will identify potential target genes and determine if our drugs can drive splicing modification in a gene-specific cell based assay.