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

Details

Serval ID
serval:BIB_350EDEDB3B0D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Rescue of myocytes and locomotion through AAV2/9-2YF intracisternal gene therapy in a rat model of creatine transporter deficiency.
Journal
Molecular therapy. Methods & clinical development
Author(s)
Fernandes-Pires G., Azevedo M.D., Lanzillo M., Roux-Petronelli C., Binz P.A., Cudalbu C., Sandi C., Tenenbaum L., Braissant O.
ISSN
2329-0501 (Print)
ISSN-L
2329-0501
Publication state
Published
Issued date
13/06/2024
Peer-reviewed
Oui
Volume
32
Number
2
Pages
101251
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Creatine deficiency syndromes (CDS), caused by mutations in GATM (AGAT), GAMT, and SLC6A8, mainly affect the central nervous system (CNS). CDS show brain creatine (Cr) deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. AGAT/GAMT-deficient patients lack brain Cr synthesis but express the Cr transporter SLC6A8 at the 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 Slc6a8 <sup>Y389C</sup> 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 myocyte development observed in Slc6a8 <sup>Y389 C/y</sup> 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 thus represents a very encouraging approach to treat the so-far untreatable CTD.
Keywords
Slc6a8, adeno-associated virus, brain, creatine transporter deficiency, gene therapy, locomotion, muscle, SLC6A8
Pubmed
Open Access
Yes
Create date
16/05/2024 16:14
Last modification date
17/05/2024 6:57
Usage data