Developing a Novel Gene Therapy Approach to Treating Guanidinoacetate Methyltransferase Creatine Deficiency
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Authors
Binsfeld, Robyn Taylor
Date
2025-05-02
Type
thesis
Language
eng
Keyword
Gene therapy , Neuroscience , Creatine deficiency , GAMT , Rare disease , AAV , AAV9 , Immunosuppression , Gene replacement , Intellectual disability , Developmental delay , Creatine
Alternative Title
Abstract
Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, a small molecule that plays an important role in energy metabolism. The cerebral creatine deficiency syndromes are inborn errors of metabolism resulting in several neurological impairments including developmental delay, intellectual disability, and epilepsy, emphasizing the importance of creatine’s role in the brain. Endogenous synthesis of creatine takes place through the enzymatic function of arginine:glycine amidinotransferase (AGAT) to form guanidinoacetate (GAA) which is then converted to creatine by the GAMT enzyme. GAMT-deficiency is an autosomal recessive disorder resulting in little to no available intracellular creatine accompanied by an accumulation of the neurotoxic metabolite, GAA. Current treatments for GAMT-D focus on dietary intervention to supplement creatine and reduce GAA production, however this is slow to restore creatine especially in the brain, leaving many of the symptoms unattended. These collective works serve as an extensive pre-clinical investigation for a novel, CNS-directed adeno-associated virus-based gene therapy for the treatment of GAMT-D.
A proof-of concept study demonstrated that the scAAV9.hGAMT vector had the potential to restore expression and function of GAMT in cellular and murine models of GAMT-D following intrathecal administration. The ideal dosing window and durability of the vector was then carried out in mouse models. A dose-dependent increase in creatine and decrease in GAA accumulation was detected in several tissues and the serum of treated mice including the central nervous system. The vector established improvements that were detectable at 5-months post-treatment and stable long-term expression in the liver. Finally, we characterized the immunogenic profile of the GAMT transgene determining it was well-tolerated in treated mice regardless of immunosuppression. Additionally, we determined the use of immunosuppression can improve short-term biochemical outcomes and recommend its use in further pre-clinical and clinical studies. Overall, we have shown that scAAV9.hGAMT represents a promising therapeutic for the treatment of GAMT creatine deficiency and upon determining a full toxicological profile, it warrants translation to clinical investigation for use in human patients.
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