Rett syndrome, a rare neurodevelopment disorder that primarily affects girls who develop normally until 6-18 months of age, is a gradual experience of progressive regression in acquired motor and verbal skills and the development of constant hand-wringing behavior. This syndrome leads to severe impairment, significantly affecting various aspects of their lives, including speech, walking, eating, and breathing.
As part of the ongoing first-in-human Phase I/II trial of a new investigational adeno-associated virus gene therapy, NGN-401, conducted by the clinical-stage company, Neurogene Inc., the Texas Children’s is currently the first clinical trial site to recruit and dose patients in the U.S. for the multicenter study.
In 1999, Dr. Huda Zoghbi’s team discovered that mutations in the MECP2 gene cause Rett syndrome. Now, 25 years later, a significant milestone is marked as the first gene therapy trial for Rett syndrome is underway at the same site, led by Dr. Bernhard Suter. Subsequent studies revealed that both insufficient and excessive MeCP2 protein levels lead to neurological issues. This underscores the importance of precise therapeutic strategies targeting MECP2 to achieve optimal protein levels for improving clinical outcomes and preventing toxicity.
Currently, there is only one specific treatment for Rett syndrome, but it does not address the underlying cause – the loss or alteration of MECP2. This highlights a notable gap in meeting the need for more effective treatments for this debilitating 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, M.D., principal investigator of this Phase I/II clinical trial.
To address these challenges, NGN-401 was specifically designed to enhance therapeutic efficacy while avoiding potential toxicities from transgene overexpression. Administered as a one-time treatment through the intracerebroventricular (ICV) route, it has demonstrated effective delivery of the therapeutic MECP2 gene to crucial areas of the brain associated with Rett syndrome. The procedure was conducted by Dr. Daniel Curry, M.D., director of Functional Neurosurgery and Epilepsy Surgery at Texas Children’s Hospital and professor of Neurosurgery and Surgery at Baylor College of Medicine.
“This gene therapy trial is an exciting step forward in finding an effective treatment for this difficult-to-treat genetic condition,” Dr. Zoghbi said.
NGN-401 has no serious side effects to date based on the first two treatment recipients. Rachel McMinn, Ph.D., founder and chief executive officer of Neurogene, expressed:
“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.”
The doctors in the Blue Bird Rett Center are hopeful that this treatment will fundamentally change the therapeutic landscape for these patients.
“All of us at Texas Children’s Hospital and Baylor College of Medicine are very grateful to all Rett patients and their families whose resilience, courage, and support drive our research efforts and inspire us,” Dr. Zoghbi added.
Xavier De Mollerat Du Jeu, Senior Director R&D at Thermo Fisher Scientific is accompanied by Gianluca Pettiti, Executive Vice President and President, Life Sciences Group at Thermo Fisher Scientific and Fred Parietti, Co-Founder and CEO at Multiply Labs for this Workshop at Advanced Therapies Week 2024.
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