Rett Gene Therapy NGN-401 Cleared to Advance to Clinical Trials

The treatment delivers full-length copies of the MECP2 gene

Joana Vindeirinho, PhD avatar

by Joana Vindeirinho, PhD |

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The U.S. Food and Drug Administration (FDA) has cleared Neurogene’s investigational new drug application for NGN-401, an experimental gene therapy for Rett syndrome.

This paves the way for the therapy to be tested in a planned Phase 1/2 clinical trial in girls with Rett syndrome, to begin later this year.

“We believe the preclinical profile for NGN-401 is highly compelling, with the strongest results generated to date across multiple animal models,” said Rachel McMinn, PhD, CEO and founder of Neurogene, in a press release. “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.”

Rett syndrome is mainly caused by mutations in the MECP2 gene, responsible for producing the MeCP2 protein, which is involved in processes that regulate the brain’s development and function. Because of MECP2’s location on the X chromosome, Rett syndrome occurs almost exclusively in girls. Affected males usually don’t survive infancy or have more symptoms since they don’t have a second X chromosome with a healthy MECP2 gene copy to compensate for mutations.

NGN-401 delivers full-length copies of the MECP2 gene using a harmless adeno-associated virus as a carrier.

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“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 [activity],” McMinn said.

To overcome this, NGN-401 uses Neurogene’s proprietary gene regulation technology Expression Attenuation via Construct Tuning (EXACT) to control the delivery of MECP2 gene copies. Unlike conventional gene therapy, where cells can be “overdosed” with too many copies, EXACT, developed with the University of Edinburgh, can be tuned to deliver a narrow range of gene expression levels.

Neurogene tested the effectiveness, tolerability, and toxicity of NGN-401 in preclinical studies. Administered into the cerebrospinal fluid, which surrounds the brain and spinal cord, it resulted in significant improvements in survival and disease burden in a Rett syndrome mouse model compared with untreated animals.

Treated animals showed well-regulated levels of MeCP2 in key brain regions in Rett, in contrast with conventional gene therapy, which yielded variable and too high protein levels. While NGN-401 was considered safe and well tolerated in mice and nonhuman primates, a comparable dose of conventional gene therapy caused severe toxicity in mice and early signs of toxicity in primates.

Neurogene is planning a Phase 1/2 trial to assess NGN-401’s safety, tolerability, and effectiveness in girls with Rett syndrome. The trial will be open-label and single-arm (without a placebo group), with participants receiving a single dose into the cerebrospinal fluid.

The trial design will incorporate feedback from the FDA, the Rett Syndrome Research Trust, and the International Rett Syndrome Foundation. Neurogene plans to open more than one recruitment center and for the trial to start this year.

“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,” said Bernhard Suter, MD, assistant professor of Pediatrics and Neurology at Baylor College of Medicine and neurologist at Texas Children’s Hospital.