SUMMARY:
UCLA researchers in the Departments Molecular & Medical Pharmacology and Surgery in the David Geffen School of Medicine have developed a novel and tissue-specific gene therapy treatment for Guanidinoacetate methyltransferase (GAMT) deficiency.
BACKGROUND:
Guanidinoacetate Methyltransferase (GAMT) deficiency is caused by a mutation in the GAMT gene that is necessary for the production of creatine. Specifically, GAMT converts the intermediate guanidinoacetate (GAA) into creatine. With the loss of GAMT, there’s an accumulation of GAA and low levels of creatine, which is critical to sustaining the high energy levels needed for brain and muscle development. In addition to its role in energy formation, recent studies also demonstrate creatine functioning as a neuromodulator of circuit activity. Consequently, patients with GAMT deficiency develop an intellectual disability, seizures, and muscle weakness in early infancy. The current treatments for GAMT deficiency are typically oral supplements to increase levels of creatine in the body. However, these treatments require routine monitoring to detect possible creatine-associated kidney disease, and only help to alleviate some of the symptoms; this present-day therapy is often not completely effective. Furthermore, the addition of dietary creatine does not address the buildup of GAA in the body which has been shown to increase the potential for seizures which are a continual concern.
INNOVATION:
Researchers at UCLA have developed a novel therapeutic strategy for GAMT deficiency. To address the cause of creatine deficiency, the Lipshutz group conceptualized the use of gene therapy to restore the function of the GAMT gene. Using adeno-associated viral vector (AAV), human cDNA of GAMT can be introduced under the control of a liver-specific promoter. Conferring control of the process to the liver is a fundamental important detail of the technology and for the treatment of the disease, as the liver is the site of GAMT’s GAA conversion to creatine and subsequent distribution to different tissues via circulation. GAMT deficient mice when intravenously treated with this novel AAV show normalized decreased GAA levels in the plasma and produce healthy levels of creatine in the blood resulting in increased body weight and normal brain/behavioral activity and function.
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ADVANTAGES:
DEVELOPMENT-TO-DATE:
Related Papers (from the inventors only): Mol Ther Methods Clin Dev. 2022 Mar 28;25:278-296. doi: 10.1016/j.omtm.2022.03.015.