Brain Targeted AAV1-GALC Gene Therapy Reduces Psychosine and Extends Lifespan in a Mouse Model of Krabbe Disease

Krabbe disease (KD) is a progressive and devasting neurological disorder that leads to the toxic accumulation of psychosine in white matter central nervous system (CNS). The condition inherited via biallelic, loss-of-function mutations galactosylceramidase (GALC) gene. To rescue GALC gene function CNS twitcher mouse model KD, an adeno-associated virus serotype 1 vector expressing murine under control chicken β-actin promoter (AAV1-GALC) was administered newborn mice by unilateral intracerebroventricular injection. AAV1-GALC treatment significantly improved body weight gain survival (n = 8) when compared with untreated controls 5). maximum after postnatal day 10 increased from 81% 217%. median lifespan extended 43 days 78 (range: 74–88 days) AAV1-GALC-treated group. Widespread expression protein alleviation KD neuropathology were detected treated examined at moribund stage. Functionally, elevated levels completely normalized forebrain region mice. In posterior region, which includes mid- hindbrain, reduced average 77% 53–93%) controls. Notably, this inversely correlated mice, suggesting degree viral transduction brain regions following ventricular injection determined efficacy on growth survivability, respectively. Overall, our results suggest delivery cerebroventricular can partially correct slower progression KD.