Research Insights

Familial Dysautonomia (FD) is a severe genetic disorder affecting children, with no specific treatment. It involves neurodevelopmental defects at birth and progressive sensory and autonomic neuropathy. Symptoms include progressing loss of pain and temperature sensation, gait ataxia, and blindness. FD is caused by a mutation in the ELP1 gene, reducing the Elp1 protein in peripheral neurons specifically; but decades of research on ELP1 have not yet yielded a treatment. Especially important, a post-birth treatment is needed to prevent further neuron loss. Thus, exploration of alternative treatments, like targeting the extracellular matrix (ECM) are crucial. This R01 renewal application follows a successful project that assessed the molecular mechanistic basis of disease severity in FD and aimed at personalized therapies for FD. There, we discovered genipin, a compound of a Traditional Chinese Medicine, which has shown promise in preventing neurodevelopmental defects and sensory neuron death in FD by crosslinking ECM proteins. Our goal is to investigate genipin’s mechanism of action and its potential to prevent FD-related peripheral neuropathy in human and mouse models. Using transcriptomics and proteomics analysis, we found the ECM and glycosaminoglycans (GAGs) downregulated and growth factors upregulated in FD, possibly a compensation mechanism. Here, we will test if the ECM and GAGs are aberrant in FD, using deep disaccharide analysis. We will assess if this consequently leads to aberrant growth factor presentation and signaling issues, preventing proper development of sensory neurons — and whether genipin’s crosslinking action rescues that (Aim 1). We will assess genipin’s ability to prevent neurodegeneration in a human FD stem cell model, focusing on axon growth, cytoskeletal, and energy issues (Aim 2). Finaly, we will evaluate genipin’s effect on the FD mouse model, testing for phenotype reversal and sensory neuron preservation (Aim 3). The outcomes could position genipin as a treatment for FD and other peripheral neuropathies, as there are currently no FDA-approved drugs targeting these conditions.

Funder: NIH 

Amount: $2,950,014 

PI: Nadja Zeltner, Franklin College of Arts and Sciences, Department of Biochemistry and Molecular Biology