Mouse study shows gene therapy can correct creatine deficiency disorder


A new study in mice reveals that a gene therapy developed by a UCLA researcher appears to correct a rare creatine deficiency disorder that typically results in intellectual disabilities, speech problems, involuntary movements and recurrent seizures. The treatment could potentially represent an improvement over the treatment available for the inherited disorder, known as guanidinoacetate methyltransferase (GAMT) deficiency.

The researchers found that their gene therapy approach increased creatine in treated mice to normal levels and reduced toxic levels of guanidinoacetic acid (GAA), which is implicated in the pathology of the disease.


Creatine plays an important role in regulating the body’s energy, especially in the muscles and the brain. GAMT is one of several creatine deficiency disorders, and it occurs in approximately 1 in 114,000 to 1 in 250,000 live births. The only therapy currently available for GAMT patients is high-dose dietary creatine therapy, which often has limited efficacy and leaves some patients at risk for recurrent attacks and other symptoms.


The researchers modified a gene therapy viral vector system to carry a normal copy of GAMT, which was administered intravenously to mice genetically modified to have GAMT deficiency. The researchers studied the mice for a year to understand how the therapy changed their biochemistry, brain metabolism and behavior.


Creatine levels and GAA levels were normalized in the blood of treated mice within 30 days. Tests performed during the study period revealed that the mice had normal creatine levels in the tissues and organs studied by the researchers. GAA levels were normal in all but the kidneys and brain, although brain GAA was reduced by approximately 60%. Behavioral tests revealed that brain function in treated mice was normalized compared to untreated mice. Brain metabolism was also normalized, which was not found with currently available diet-based therapy when examined in mice.

“What we were able to demonstrate is that adult mice treated with this therapy now have normal cognitive activity, which was abnormal before gene therapy,” said study corresponding author Gerald S. Lipshutz. , MD, from UCLA. Department of Surgery and Center for Research on Intellectual and Developmental Disabilities at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA. “Although the human brain and learning are more complex than those of the mouse, we hope that permanently reducing GAA toxin levels in the brain will lead to the correction of cognitive and behavioral abnormalities in human patients.”

The researchers plan to refine their gene therapy approach in an effort to achieve a lower dose for effective treatment, which could translate to greater safety for affected patients.


Other authors: Suhail Khoja, Jenna Lambert, Matthew Nitzahn, Adam Eliav, YuChen Zhang, Mikayla Tamboline, Colleen T. Le, Eram Nasser, Yunfeng Li, Puja Patel, Irina Zhuravka, Lindsay M. Lueptow, Ilona Tkachyova, Shili Xu, Itzhak Nissim and Andreas Schulze.


The study is published in Molecular Therapy: Methods & Clinical Development.

Quote: “Gene therapy for guanidinoacetate methyltransferase deficiency restores brain and myocardial creatine while resolving behavioral abnormalities”



Funding was provided by NIH grant R01NS110596, and additional funding was provided by the Association for Creatine Deficiency.

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