Preclinical validation of AAV9-TECPR2 gene therapy in a novel knock-in model of TECPR2-related disorder

Abstract TECPR2-related disorder is a rare, autosomal recessive neurodevelopmental and neurodegenerative disease characterized by early-onset motor dysfunction, sensory- and autonomic neuropathy, and progressive neurological decline with early mortality. Currently, there are no effective treatments for individuals affected by this debilitating condition. To advance our understanding of disease mechanisms and explore therapeutic strategies, we developed and then characterized a knock-in (KI) mouse model carrying the human TECPR2 c.1319delC frameshift mutation. TECPR2-KI mice exhibit a subset of disease-relevant phenotypes, most prominently abnormal gait, along with reduced body weight and altered tactile sensitivity. We additionally observe a reduction in acoustic startle responses, consistent with dysfunction of brainstem-associated sensorimotor pathways. Histopathological analyses reveal progressive accumulation of axonal spheroids in the dorsal column nuclei, together with abnormalities in autophagy-related markers, features previously reported in individuals with TECPR2-related disorder. To assess the therapeutic potential of gene replacement, we delivered TECPR2 via intracisternal infusion of AAV9/TECPR2 in neonatal KI mice. Gene therapy restored mechanosensory function, normalized gait and startle responses, maintain autophagic homeostasis, and partially reduced axonal pathology. These findings demonstrate that TECPR2-associated deficits are not only replicable in this new mouse model but are also amenable to postnatal intervention. Our study introduces a genetically accurate murine model of TECPR2 deficiency, identifies brainstem-associated phenotypes, and provides preliminary evidence supporting the feasibility of AAV9-mediated TECPR2 gene delivery, establishing a foundation for future translational research in a currently untreatable disease. One-Sentence Key Message TECPR2 deficiency disrupts brainstem sensory–motor circuits, impairing autophagy and tactile, gait, and startle function and is prevented by neonatal AAV9. Competing Interest Statement The authors have declared no competing interest. Footnotes The figures were blurred before, trying to fix it.