Scientist holding a DNA sample with the results on a computer screen in a laboratory
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Texas Children’s Hospital is the first, worldwide, to deliver a novel gene therapy to treat Rett syndrome in pediatric patients. 

Two girls received the treatment there as part of a Phase I/II trial (NCT05898620) of investigational gene therapy, NGN-401, conducted by Neurogene Inc. The two patients were dosed sequentially in the third and fourth quarter of 2023. Texas Children’s, which is affiliated with Baylor College of Medicine, is the first clinical trial site to recruit and dose patients in the U.S. for this multicenter study.

Rett syndrome is a rare neurodevelopmental disorder that primarily affects girls, most of whom develop normally until six to 18 months of age when they begin to experience progressive regression in acquired motor and verbal skills and develop constant hand-wringing behavior. Eventually, this condition causes severe impairments that affect nearly every aspect of their daily lives, including their ability to speak, walk, eat, and breathe. Presently, only one specific treatment exists for Rett syndrome, and that drug does not correct the root cause of the disease. 

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

Now, 25 years following that discovery, the first gene therapy trial for Rett syndrome is being led at Baylor by Bernhard Suter, MD, associate professor of Pediatrics and Neurology and medical director of the Blue Bird Circle Rett Center at Texas Children’s.

Subsequent preclinical studies by Zoghbi’s team revealed that too much MeCP2 protein also results in progressive neurological dysfunction in mice, and studies by KU Leuven’s Hilde Van Esch and team, led to the identification of MECP2 duplication syndrome in humans. Since too little MECP2 causes Rett syndrome and too much of it can cause MECP2 duplication syndrome, it is critical that any treatment that targets MECP2 must provide just the right amount of MECP2 protein to improve clinical outcomes and avoid toxicity.

“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 Suter.

Neurogen’s NGN-401 was purposefully designed to maximize therapeutic activity while averting toxicities due to transgene overexpression. Neurogene describes its EXACT gene regulation platform technology as “A self-contained transgene regulation platform that can be tuned to deliver a desired level of transgene expression within a narrow and therapeutically relevant range.”

NGN-401 is administered as a one-time treatment via the intracerebroventricular (ICV) route, which has been shown to maximize the delivery of the therapeutic MECP2 gene to key areas of the brain implicated in the disease. Daniel Curry, MD, professor, Neurosurgery and Surgery at Baylor College of Medicine, administered the gene therapy.

The gene therapy has had no serious side effects to date in either of these two patients. “We are encouraged by the tolerability profile observed in our first two pediatric 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,” Rachel McMinn, PhD, founder and chief executive officer of Neurogene, said.

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