Precision Medicine for the Peripheral Nervous System Disorder Familiar Dysautonomia

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Project summary/Abstract Familial Dysautonomia represents a rare, particularly devastating form of a peripheral nervous system (PNS) disorder. Defective development and degeneration of the sensory and autonomic nervous system in FD patients leads to symptoms including decreased sensitivity to pain and difficulty regulating blood pressure or heart rate. Some FD patients can have very severe symptoms, while others have much milder symptoms. Interestingly, this is the case despite the fact that 99.5% of all patients carry a homozygous mutation in the gene ELP1 (previously IKBKAP). ELP1 protein is involved in transcriptional elongation and tRNA modification, amongst other functions, and the mutation specifically affects PNS tissues. There are no approved drugs for FD available and patients’ symptoms are merely managed. There is a critical need for a deeper understanding of the mechanistic underpinning of FD for the development of precise and effective treatments. To understand why there is this discrepancy of severity in FD, we employed the human pluripotent stem cell (hPSC) technology and successfully recapitulated phenotypes in vitro that captured varying disease severity seen in patients. For example, decreased sensation of pain was captured by the development of decreased numbers of sensory neurons derived from severe FD PSCs. This model further allowed us to identify three potential modifier mutations in LAMB4, KIAA1211 and FAT2, an extra cellular matrix (ECM) protein, actin regulator and cadherin, respectively. These were present in severe FD patients only and were absent in mild patients. Thus, we established the basis for a new paradigm in FD research that FD may consist of two genetically distinct sub-diseases. In preliminary studies, we were able to employ this model to conduct a chemical screen that allowed us to identify a compound called genipin that was able to rescue the severe FD phenotype. Here, we propose to expand on our previous discoveries and define the molecular mechanism behind severe FD. In Aim 1, we aim to understand the molecular mechanism underlying severe FD. In Aim 2, we investigate the mode of action of genipin and how it may aid us in understanding the mechanism of severe FD as well as be developed as a potential future treatment option for FD patients. We believe our studies may enable us to move the field closer toward precision medicine for FD patients and provide deep molecular insights into the understanding of other PNS disorders.