Advancing age and sex modulate antidyskinetic efficacy of striatal CaV1.3 gene therapy in a rat model of Parkinson’s disease

Abstract

We previously demonstrated that viral vector-mediated striatal Ca_V1.3 calcium channel downregulation in young adult (3mo) male parkinsonian rats provides uniform, robust protection against levodopa-induced dyskinesias (LID). Acknowledging the association of PD with aging and incidence in male and female sexes, we have expanded our studies to include rats of advancing age of both sexes. The current study directly contrasts age and sex, determining their impact on efficacy of intrastriatal AAV-Ca_V1.3-shRNA to prevent LID induction, removing the variable of levodopa-priming. Considering both sexes together, late-middle-aged (‘aged’; 15mo) parkinsonian rats receiving AAV-Ca_V1.3-shRNA developed significantly less severe LID compared control AAV-scramble(SCR)-shRNA rats, however therapeutic benefit was significantly less robust than observed in young males. When considered separately, females showed significantly less therapeutic benefit than males. Furthermore, aged non-cycling/proestrous-negative female rats were refractory to LID induction, regardless of vector. This study provides novel insight into the impact of age and sex on the variable antidyskinetic responses of Ca_V1.3-targeted gene therapy, highlighting the importance of including clinically relevant age and sex populations in PD studies.