My principal investigator was Dr. Muralidhar Hegde and my mentor was Joy Mitra. I conducted research in the Hegde Lab at the Center for Neurodegeneration, Department of Neurosurgery, Houston Methodist Research Institute.

TDP-43 is a protein essential for repairing damaged DNA in neurons, but in ALS it mislocalizes out of the nucleus, disabling its repair function and driving neuronal death. My research project investigated whether inhibiting a related protein, 53BP1, could redirect DNA repair through an alternative pathway to compensate for this defect. Using human tissue, patient-derived neural stem cells, and an AAV9 gene therapy approach in an ALS mouse model, we found that blocking 53BP1 with an engineered peptide, inh53, reduced genome instability and showed early signs of improving neuronal senescence.

ALS currently has no cure and few effective treatments, so a strategy that corrects the underlying DNA repair failure, rather than only managing symptoms, offers a unique therapeutic direction. Because inh53 is delivered using AAV9, a vector already used in approved gene therapies, this work also establishes a path toward clinical translation. As TDP-43 pathology is also found in frontotemporal dementia and related neurodegenerative diseases, this approach may extend beyond ALS to a broader class of disorders.