Abstract
Rett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized by severe impairment of motor and cognitive functions. The aim of this study was to investigate the impact of vector design, dosage, and delivery route on the efficacy and safety of gene augmentation therapy in mouse models of RTT. Our results show that AAV-mediated delivery of MECP2 to Mecp2 null mice by systemic administration, and utilizing a minimal endogenous promoter, was associated with a narrow therapeutic window and resulted in liver toxicity at higher doses. Lower doses of this vector significantly extended the survival of mice lacking MeCP2 or expressing a mutant T158M allele but had no impact on RTT-like neurological phenotypes. Modifying vector design by incorporating an extended Mecp2 promoter and additional regulatory 3′ UTR elements significantly reduced hepatic toxicity after systemic administration. Moreover, direct cerebroventricular injection of this vector into neonatal Mecp2-null mice resulted in high brain transduction efficiency, increased survival and body weight, and an amelioration of RTT-like phenotypes. Our results show that controlling levels of MeCP2 expression in the liver is achievable through modification of the expression cassette. However, it also highlights the importance of achieving high brain transduction to impact the RTT-like phenotypes.
Highlights
Rett syndrome (RTT; OMIM 312750) is a neurological disorder characterized by a constellation of clinical diagnostic and associated features and with overt onset occurring several months postnatally.[1]Typical RTT is almost exclusively caused by de novo germline mutations in the X-linked gene, MECP22
We identified particular challenges associated with the systemic delivery of a MECP2-bearing gene therapy vector in terms of a narrow therapeutic window driven by low brain transduction efficiency and the appearance of peripheral overexpression toxicity upon further dose escalation
We show that the vector has similar effectiveness in mice expressing the most common RTT-causing mutation, suggesting that the presence of existing mutant forms of MeCP2 is unlikely to be an obstacle to translational success
Summary
Rett syndrome (RTT; OMIM 312750) is a neurological disorder characterized by a constellation of clinical diagnostic and associated features and with overt onset occurring several months postnatally.[1]. Typical RTT is almost exclusively caused by de novo germline mutations in the X-linked gene, MECP22 (as reviewed elsewhere[3,4]). Several mouse models of RTT have been generated that harbor Mecp[2] deletions[5–7] or knocked-in mutations.[8–11]. Many of these models recapitulate the principal features that characterize RTT in humans, there are differences that reflect the phenotypic variability seen in patients.[12–14]. Despite the severity of RTT-like phenotypes, genetic reac- Several mouse models of RTT have been generated that harbor Mecp[2] deletions[5–7] or knocked-in mutations.[8–11] Many of these models recapitulate the principal features that characterize RTT in humans, there are differences that reflect the phenotypic variability seen in patients.[12–14] Despite the severity of RTT-like phenotypes, genetic reac-
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