# A CNS-Directed, AAV9 Gene Therapy Restores Expression and Biochemical Function of Guanidinoacetate Methyltransferase in Models of GAMT Deficiency

## TL;DR

A new gene therapy using AAV9 successfully restores creatine metabolism in models of GAMT deficiency, a rare genetic disorder affecting the brain.

## Contribution

This study introduces the first CNS-directed AAV9-based gene therapy for GAMT deficiency, demonstrating functional restoration in cellular and murine models.

## Key findings

- AAV9 gene therapy restored GAMT protein and mRNA expression in cellular models of GAMT-D.
- Treatment increased creatine levels and reduced GAA accumulation in the CNS and peripheral organs of mice.
- The therapy shows promise for future translation to human patients after further safety and efficacy studies.

## Abstract

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future.