Adeno-Associated Virus-Based Gene Therapy for Lafora Disease in-Deficient Mice.

Abstract

Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in theorgenes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption oforin mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues.andmice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carryingsignificantly improved pathology inmice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the humangene inmice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between- and-based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targetingmutations in Lafora disease.