Gene therapy for guanidinoacetate methyltransferase deficiency restores cerebral and myocardial creatine while resolving behavioral abnormalities.

Autor:	Khoja S; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Lambert J; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Nitzahn M; Molecular Biology Institute, UCLA, Los Angeles, CA 90025, USA., Eliav A; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Zhang Y; Semel Institute for Neuroscience, UCLA, Los Angeles, CA 90025, USA., Tamboline M; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90025, USA.; Departments of Molecular and Medical Pharmacology, Universtiy of California, Los Angeles, CA 90025, USA., Le CT; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Nasser E; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Li Y; Departments of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90025, USA., Patel P; Department of Surgery, UCLA, Los Angeles, CA 90025, USA., Zhuravka I; Behavioral Testing Core, Department of Psychology, UCLA, Los Angeles, CA 90025, USA., Lueptow LM; Behavioral Testing Core, Department of Psychology, UCLA, Los Angeles, CA 90025, USA., Tkachyova I; Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Xu S; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90025, USA.; Departments of Molecular and Medical Pharmacology, Universtiy of California, Los Angeles, CA 90025, USA.; Jonsson Comprehensive Cancer Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA., Nissim I; Division of Metabolism and Human Genetics, Children's Hospital of Philadelphia, and the Department of Biochemistry and Biophysics, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Schulze A; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1X8, Canada.; Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Lipshutz GS; Department of Surgery, UCLA, Los Angeles, CA 90025, USA.; Molecular Biology Institute, UCLA, Los Angeles, CA 90025, USA.; Semel Institute for Neuroscience, UCLA, Los Angeles, CA 90025, USA.; Departments of Molecular and Medical Pharmacology, Universtiy of California, Los Angeles, CA 90025, USA.; Intellectual and Developmental Disabilities Research Center, UCLA, Los Angeles, CA 90025, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2022 Mar 28; Vol. 25, pp. 278-296. Date of Electronic Publication: 2022 Mar 28 (Print Publication: 2022).
DOI:	10.1016/j.omtm.2022.03.015
Abstrakt:	Creatine deficiency disorders are inborn errors of creatine metabolism, an energy homeostasis molecule. One of these, guanidinoacetate N -methyltransferase (GAMT) deficiency, has clinical characteristics that include features of autism, self-mutilation, intellectual disability, and seizures, with approximately 40% having a disorder of movement; failure to thrive can also be a component. Along with low creatine levels, guanidinoacetic acid (GAA) toxicity has been implicated in the pathophysiology of the disorder. Present-day therapy with oral creatine to control GAA lacks efficacy; seizures can persist. Dietary management and pharmacological ornithine treatment are challenging. Using an AAV-based gene therapy approach to express human codon-optimized GAMT in hepatocytes, in situ hybridization, and immunostaining, we demonstrated pan-hepatic GAMT expression. Serial collection of blood demonstrated a marked early and sustained reduction of GAA with normalization of plasma creatine; urinary GAA levels also markedly declined. The terminal time point demonstrated marked improvement in cerebral and myocardial creatine levels. In conjunction with the biochemical findings, treated mice gained weight to nearly match their wild-type littermates, while behavioral studies demonstrated resolution of abnormalities; PET-CT imaging demonstrated improvement in brain metabolism. In conclusion, a gene therapy approach can result in long-term normalization of GAA with increased creatine in guanidinoacetate N -methyltransferase deficiency and at the same time resolves the behavioral phenotype in a murine model of the disorder. These findings have important implications for the development of a new therapy for this abnormality of creatine metabolism. Competing Interests: G.S.L. has served as a consultant to Audentes Therapeutics and is on the scientific advisory board (SAB) of Taysha in areas unrelated to this work. A.S. has served as consultant to and has received research funds from Aeglea BioTherapeutics. He is on the SAB of and has received fellowship grants from the Association of Creatine Deficiencies. All of the other authors declare no competing interests. (© 2022 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu