Rescue of myocytes and locomotion through AAV2/9-2YF intracisternal gene therapy in a rat model of creatine transporter deficiency

Creatine deficiency syndromes (CDS), caused by mutations in GATM (AGAT), GAMT and SLC6A8, mainly affect central nervous system (CNS). CDS show brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. AGAT/GAMT-deficient patients lack brain creatine (Cr) synthesis but express the Cr transporter SLC6A8 at blood-brain barrier, and are thus treatable by oral supplementation of Cr. In contrast, no satisfactory treatment has been identified for Cr transporter deficiency (CTD), the most frequent of CDS. We used our Slc6a8Y389C CTD rat model to develop a new AAV2/9-2YF-driven gene therapy re-establishing the functional Slc6a8 transporter in rat CNS. We show, after intra-cisterna magna AAV2/9-2YF-Slc6a8-Flag vector injection of postnatal day 11 pups, the transduction of Slc6a8-Flag in cerebellum, medulla oblongata and spinal cord as well as a partial recovery of Cr in these brain regions, together with full prevention of locomotion defaults and impairment of myocytes’ development observed in Slc6a8Y389C/y male rats. While more work is needed to correct those CTD phenotypes more associated with forebrain structures, this study is the first demonstrating positive effects of an AAV-driven gene therapy on CTD and represents thus a very encouraging approach to treat the so far untreatable CTD.