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2 US girls become world’s first to get gene therapy for genetic brain disorder

A team of US doctors have in a world first delivered a novel gene therapy to treat Rett syndrome — a rare genetic brain disorder — in two girls. They became the first children worldwide to receive the promising treatment as part of the first-in-human Phase I/II trial of a new investigational gene therapy, NGN-401, developed by US-based Neurogene.

Rett syndrome is a rare neurodevelopmental disorder that primarily affects girls, most of whom develop normally until 6-18 months of age when they begin to experience progressive regression in acquired motor and verbal skills and develop constant hand-wringing behaviour.

Eventually, this condition causes severe impairments that affect nearly every aspect of their daily lives, including their ability to speak, walk, eat, and breathe.

In 1999, a team led by Dr. Huda Zoghbi, a distinguished service professor at Baylor College of Medicine, founding director of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and Howard Hughes Medical Institute investigator, made the transformational discovery that mutations in methyl cytosine binding protein 2 (MECP2) gene causes Rett syndrome.

About 25 years following the discovery, Baylor College and Texas Children’s has become the first trial site for the gene therapy. At present, only one specific treatment exists for Rett syndrome, and that drug does not correct the root cause of the disease, which is the loss or alteration of MECP2.

There is, therefore, a significant unmet need to develop better treatments for this devastating condition.

“While gene therapy has proven to be a powerful tool in the treatment arsenal for a number of devastating genetic conditions, the highly variable transgene expression associated with conventional gene therapies has limited its application in many complex neurological disorders, especially Rett syndrome in which MECP2 transgene overexpression is toxic,” said Bernhard Suter, principal investigator of the Phase I/II clinical trial and Associate Professor of Pediatrics and Neurology at Baylor College.

To address these issues, NGN-401 was purposefully designed to maximise the therapeutic activity while averting toxicities due to transgene overexpression.

It is administered as a one-time treatment via the intracerebroventricular (ICV) route, which has been shown to maximise the delivery of the therapeutic MECP2 gene to key areas of the brain implicated in Rett syndrome.

Based on the first two treatment recipients, NGN-401 has no serious side effects to date.

“We are encouraged by the tolerability profile observed in our first two paediatric patients, and look forward to collecting sufficient follow-up data on a larger number of patients to inform the therapeutic potential of NGN-401, which we believe could serve as a best-in-class therapy,” said Rachel McMinn, founder and chief executive officer of Neurogene.

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