First Two Children Receive New Gene Therapy for Rett Syndrome

Texas Children’s Hospital is the first to deliver a novel gene therapy to treat Rett syndrome in pediatric patients. Two female patients with Rett syndrome were the first children worldwide to receive this promising treatment. This milestone is part of an ongoing first-in-human Phase 1/2 trial of a new investigational gene therapy, NGN-401, conducted by Neurogene Inc.

What are the symptoms of Rett syndrome?

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 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.

In 1999, a team led by Huda Zoghbi, MD, 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 (MECP2) causes Rett syndrome.

Subsequent preclinical studies by Zoghbi’s team revealed that too much MeCP2 protein also results in progressive neurological dysfunction in models, and studies by KU Leuven’s Hilde Van Esch, MD, PhD, 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, any therapeutic strategy that targets MECP2 must make just the right amount of MeCP2 protein to improve clinical outcomes and avoid toxicity.

An unmet clinical need

Presently, 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, MD, principal investigator of this Phase 1/2 clinical trial.

To address these issues, NGN-401 was strategically designed to maximize 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 maximize the delivery of the therapeutic MECP2 gene to key areas of the brain affected in Rett syndrome. Daniel Curry, MD, director, functional neurosurgery and epilepsy surgery at Texas Children’s Hospital and professor, neurosurgery and surgery at Baylor College of Medicine, performed the procedure to administer the gene therapy.

“This gene therapy trial is an exciting step forward in finding an effective treatment for this difficult-to-treat genetic condition,” Zoghbi said.

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 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.

- This press release was originally published on Neurogene Inc.’s website