2 girls with Rett dosed in Phase 1/2 trial of NGN-401 gene therapy

Data so far indicates Neurogene's experimental treatment is well tolerated

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Two young girls with Rett syndrome have been dosed with Neurogene‘s gene therapy candidate NGN-401 in a Phase 1/2 clinical trial, with data so far indicating that the treatment has been well tolerated.

Another patient is expected to be dosed in the first months of 2024, with interim efficacy data from multiple participants planned for the end of next year.

Meanwhile, this first in-human study (NCT05898620) is still enrolling up to five girls with Rett syndrome, ages 4-10, at sites in Houston and Boston. A third site, Children’s Hospital Colorado, in Aurora, has not yet started recruitment.

“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 CEO of Neurogene, said in a company press release.

“We remain on track to report preliminary clinical data from the first cohort of patients in this trial in the fourth quarter of 2024, with additional data from an expanded number of patients expected in the second half of 2025,” McMinn added.

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Rett gene therapy candidate delivers patients working MECP2 gene version

Mutations in the MECP2 gene are the cause of most cases of Rett syndrome. The protein it encodes, known as MeCP2, is involved in regulating the activity of other genes — playing an especially critical role in brain development and function. As such, patients experience a range of neurological symptoms including problems with cognition, emotional control, and motor skills, as well as seizures.

NGN-401 is a gene therapy designed to deliver patients a working version of the MECP2 gene, enabling cells to produce a healthy and functional MeCP2 protein. It is packaged into a viral carrier called an adeno-associated virus (AAV) to help it be taken up inside a person’s cells.

The therapy was specifically designed with Neurogene’s proprietary technology to avoid overexpression toxicity, a problem known to arise with traditional gene therapies in which too much of the lab-made gene (transgene) is delivered to some cells.

In the case of Rett syndrome, too much MECP2 gene activity, or expression, means that too much MeCP2 protein will be produced. Preclinical studies show that this is toxic and can cause neurological dysfunction. The amount of MECP2 activity thus must be optimal for the treatment to be therapeutic.

“While gene therapy has proven to be a powerful tool in the treatment armamentarium 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 in Rett syndrome,” noted Bernhard Suter, MD, the principal investigator of the ongoing trial and an associate professor of pediatrics and neurology at Baylor College of Medicine and Texas Children’s Hospital, both in Houston.

NGN-401 is expected to provide controlled and consistent transgene expression. It’s administered directly into the fluid-filled cavities of the brain via an intracerebroventricular, or ICV, infusion, which helps target the treatment where it is most needed.

According to McMinn, “delivering robust transgene expression in these areas is essential for enabling a clinically meaningful benefit.”

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Preclinical studies showed that when administered at clinically relevant doses, NGN-401 extended survival and eased disease burden without signs of overexpression toxicity in a mouse model of Rett syndrome.

Early this year, the U.S. Food and Drug Administration (FDA) cleared NGN-401 for in-human testing. The regulatory agency also has granted NGN-401 orphan drug, rare pediatric disease, and fast track designations, all of which offer various incentives intended to speed a therapy’s development toward approval.

All participants in the Phase 1/2 trial are receiving a single dose of NGN-401 (1 x 10E15 vector genomes) via ICV infusion. The study’s main goal is to monitor safety and tolerability over several years following treatment.

The first two girls were dosed this year at Texas Children’s Hospital. The therapy thus far has been well tolerated by these two patients, with no serious treatment-emergent side effects associated with the treatment or the procedure, according to Neurogene. There’s also been no evidence of overexpression toxicity.

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


If an upcoming review from an independent Data and Safety Monitoring Board is successfully completed, a third patient will be dosed. While the trial initially plans to enroll five patients, Neurogene expects this may expand pending trial data and regulatory authorization.

“This gene therapy trial is an exciting step forward in finding an effective treatment for this difficult-to-treat genetic condition,” Huda Zoghbi, MD, a professor at Baylor, founding director of the Duncan Neurological Research Institute at Texas Children’s Hospital, and Howard Hughes Medical Institute investigator, said in a separate press release.

Zoghbi’s team at Texas Children’s made the discovery that MECP2 mutations cause Rett syndrome about 25 years ago. They also identified too much MECP2 as being toxic.

“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,” Zoghbi added.