Cerebral creatine deficiency syndromes: New in vivo AAV approaches to treat SLC6A8 deficiency

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A new approach to treating genetic disease Deficiency of the creatine transporter SLC6A8 is linked to intellectual disabilities, including a marked impairment of speech acquisition and several other neurological symptoms in infants. Researchers are developing a new approach to treat this genetic disease, as Professor Olivier Braissant and Dr Cristina Cudalbu explain. A type of

naturally occurring organic compound, creatine plays an important role in recycling adenosine triphosphate (ATP) and storing high-energy phosphates within cells in the human body. While it was previously thought that the brain’s creatine needs were met primarily from peripheral sources, recent research by Professor Olivier Braissant has shown otherwise. “A few years ago we discovered in my group that the brain probably needs its own creatine synthesis – it is not sufficient to take creatine from the periphery,” he says. The blood-brain barrier (BBB) – which protects the brain from the periphery – has a very low permeability for creatine, and so the brain itself expresses the two enzymes that enable the synthesis of creatine. “These two enzymes are called AGAT and GAMT, while the brain also expresses the creatine transporter SLC6A8,” explains Professor Braissant. “Creatine can enter the brain through the BBB with the means of the

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creatine transporter – but it is very inefficient. The brain needs its own creatine synthesis to ensure it has enough creatine for its own needs, and the creatine transporter also appears essential to this.”

transporter deficiency in the brain. “We have designed an in vivo model of creatine transporter deficiency. This is a knock-in rat, which harbours a single nucleotide mutation that has been described in patients with

We hope to re-establish this activity of creatine uptake by brain cells. We have done preliminary experiments with a Green Fluorescent Protein (GFP), under the same promoter that we will use for the creatine transporter. Creatine transporter deficiency A deficiency in this transporter is known to cause intellectual disabilities, a topic of great interest to Professor Braissant, a specialist in inborn errors of metabolism (IEM) based at Lausanne University Hospital in Switzerland. As the Principal Investigator of a new SNSFfunded research project, Professor Braissant is investigating the factors behind creatine

creatine transporter deficiency,” he outlines. This model is representative of the genome of patients with creatine transporter deficiency, now researchers are using it to investigate the disease in great depth. “The first part of the project involved characterising this rat model, to see whether it had a phenotype that we could relate to the disease,” says Professor Braissant. “In the second part of the project, we want to

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