Rett Syndrome Gene Therapy Cleared for Clinical Trial


NGN-401 is Neurogene’s second investigational gene therapy to enter clinical trials.

The FDA has cleared Neurogene’s investigational new drug application (IND) of NGN-401 and the company is planning to initiate a phase 1/2 clinical trial to evaluate intracerebroventricular (ICV) injection of the gene therapy in girls with Rett syndrome in 2023.

“Rett syndrome is a particularly challenging disorder for gene therapy because of the requirement to deliver therapeutic levels of MECP2, without also triggering significant side effects associated with too much gene expression,” Rachel McMinn, PhD, chief executive officer and founder, Neurogene, said in a statement. “We believe the preclinical profile for NGN-401 is highly compelling, with the strongest results generated to date across multiple animal models. FDA clearance of NGN-401 represents a significant milestone for Neurogene and the Rett syndrome community and underscores our commitment to turn devastating neurological diseases into treatable conditions, and to improve the lives of patients and families impacted by these rare diseases.”

NGN-401 is an adeno-associated virus (AAV) gene therapy that uses Neurogene’s proprietary gene regulation platform technology Expression Attenuation via Construct Tuning (EXACT) that was developed in collaboration with the University of Edinburgh. EXACT is meant to address toxicities and limitations with conventional gene therapy and is compatible with both viral and non-viral delivery methods. The therapy delivers the full-length human MECP2 gene, expression of which is regulated by EXACT to avoid overexpression-related toxicities.

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Preclinical data has shown ICV delivery of NGN-401 was well-tolerated and produced robust efficacy in mouse models of Rett syndrome, including a significant survival benefit and improvements in phenotypes compared to control animals. Expression data showed well-controlled MeCP2 protein levels in key affected brain regions.Conventional MECP2 gene therapy without EXACT regulation showed severe toxicity in mice and early signs of toxicity in non-human primates.

“Rett syndrome is a debilitating disease with a devastating impact on children and their families, with no disease-modifying treatments available,” Bernhard Suter, MD, Assistant Professor of Pediatrics and Neurology, Baylor College of Medicine and neurologist, Texas Children’s Hospital, added to the statement. “The upcoming clinical study of NGN-401, which has a mechanism of action aimed at addressing the root cause of disease, offers hope for improving the lives of those suffering from Rett syndrome.”

NGN-401 is Neurogene’s second investigational gene therapy to enter clinical trials, following NGN-101, which is currently being evaluated in a phase 1/2 clinical trial (NCT05228145) in children with CLN5 Batten disease. NGN-101 is a conventional gene therapy that does not use the EXACT platform. The company also has another conventional gene therapy in IND-enabling studies, NGN-201, for the potential treatment of Krabbe disease.

Neurogene announces FDA clearance of IND for NGN-401 gene therapy for children with Rett syndrome. News release. Neurogene. January 23, 2023.
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