(W1336) IDENTIFYING PROTECTIVE FACTORS AND UNRAVELING THE MOLECULAR MECHANISMS THAT PRESERVE OCULOMOTOR NEURONS FROM DEGENERATION IN PATIENTS WITH SPINAL MUSCULAR ATROPHY
Mr The University of Hong Kong Hong Kong, Hong Kong
Abstract: Spinal Muscular Atrophy (SMA) is a neuromuscular degenerative disease caused by homozygous mutations or deletion of the survival motor neuron gene 1 (SMN1) gene, resulting in the loss of the ubiquitously expressed SMN1 protein. This leads to progressive and selective degeneration of spinal motor neurons and their innervation to the muscle fibers, causing muscular atrophy, immobility, and death. Although there are three FDA-approved treatments, Nusinersen, Zolgensma, and Risdiplam for restoration of SMN loss, they are not curative. Therefore, it is crucial to identify new therapeutic targets for effectively treating SMA. Interestingly, oculomotor neurons, responsible for eye movements, remain unaffected in SMA patients, implying a unique intrinsic mechanism to protect them from degeneration in response to the loss of SMN1. Previous studies revealed preferential expression of factors in oculomotor neurons of SMA mice but not in spinal motor neurons, suggesting their protective role. To investigate if similar factors are expressed in human ocular motor neurons, we utilized the expression of PHOX2A as a critical determinant of these neurons to generate a knock-in of the tdTomato reporter into its endogenous locus, enabling the enrichment of ocular motor neurons from induced pluripotent stem cells derived from healthy individuals- and SMA patients’ urine samples for transcriptomic profiling analysis. This approach holds promise for identifying protective factors in oculomotor neurons that confer resistance to SMA and may serve as new therapeutic targets to enhance the efficacy of SMA treatments.
Funding Source: Research Impact Fund R7018-23F IRB: UW 20-329; UW11-190 General Research Fund 17114619 Seed fund for collaborative research 2023-2024
