A Novel Combinatorial Approach Targeting Neurodegeneration in Familial Dysautonomia

Familial dysautonomia (FD) is a neurodegenerative inherited disease caused by a splicing mutation in the Elongator acetyltransferase complex subunit 1 gene (ELP1) that results in variable skipping of exon 20, leading to a premature termination codon. This, in turn, leads to a drastic reduction of ELP1 protein, primarily in the central and peripheral nervous system. All FD patients possess at least one copy of the c.2204+6T>C mutation, with 99.5% of patients being homozygous for this mutation. Individuals with FD have a complex multisystemic neurological phenotype that includes diminished pain and temperature perception, decreased or absent myotatic reflexes, blood pressure instability, proprioceptive ataxia, and progressive retinal degeneration. Currently, no treatments are available to halt the continuous neuronal loss characteristic of this devastating disorder. In this proposal, we aim to develop a novel gene-editing strategy for FD and generate critical in vivo proof-of- concept data to evaluate the in vivo efficacy and synergy of a combinatorial therapy. This approach combines a small molecule splicing modulator compound (SMC), which rescues ELP1 mis-splicing, with a genome editing strategy that permanently corrects the FD mutation. Our goal is to assess the effectiveness of these combined treatments to significantly attenuate systemic disease manifestations in a humanized mouse model of FD, overcoming the limitations of currently explored single therapeutic options. Combining the two strategies leverages the rapid, systemic action of SMCs and the durable, long-term correction from gene editing. Additionally, a combinatorial strategy has the potential to reduce compound dosing, minimize toxicity, and synergistically enhance ELP1 splicing correction. In Aim 1, we will customize and optimize a base editing strategy to permanently correct the mutation in ELP1 causing FD. This innovative approach will overcome a major barrier in the field and holds promise for advancing base editing technology for other human genetic disorders. In Aim 2, we will perform an in-depth evaluation of off-target effects for both genome editing and SMC strategies. These experiments are crucial for providing a comprehensive analysis of the specificity of our approaches and for ensuring the successful translation of our combinational strategy to the clinic. In Aim 3, we will assess the therapeutic effectiveness of our combinatorial approach in rescuing disease manifestations in a humanized mouse model of FD. The significance of this proposal lies in developing a novel combinatorial approach to address the complex and multisystemic disease manifestations characteristic of FD. More importantly, this R01 proposal aligns with our long-term goals of leading a translational research program toward a durable therapeutic strategy to correct the ELP1 splicing defect in FD patients. Project Number: 1R01NS142225-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Elisabetta Morini | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $642,454 | Activity Code: R01 | Study Section: Therapeutic Approaches to Genetic Diseases Study Section[TAG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295670