Phase 1/2 trial of Rett syndrome gene therapy to dose 3rd patient

NGN-401 appearing to be safe and well tolerated in first two treated girls

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A Phase 1/2 clinical trial has been cleared to infuse NGN-401, a one-time investigational gene therapy, to a third girl with Rett syndrome, its developer, Neurogene, reports.

The green light given by the Data Safety Monitoring Board overseeing the clinical trial’s progress was based on data indicating to date that the gene therapy appears to be well tolerated.

Two girls with Rett syndrome were treated with a single dose of NGN-401 in the second half of 2023, without serious side effects or signs of overexpression-related toxicity, a problem that may arise when too much protein is produced from the delivered gene.

The open-label clinical trial (NCT05898620) still is enrolling an estimated five girls with Rett syndrome, ages 4 to 10, at sites in Houston and Boston. A third site, Children’s Hospital Colorado, in Aurora, is set to open for recruitment.

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While the company plans to include a larger number of participants and a higher dose in the clinical trial, pending regulatory clearance, interim results from a first group of treated patients are expected toward the end of the year.

“We remain on track to deliver interim results for our potentially best-in-class Rett syndrome gene therapy program in the fourth quarter of 2024,” Rachel McMinn, PhD, Neurogene’s founder and CEO, said in a company press release.

Neurogene also received clearance from U.K. regulatory authorities to expand the trial to include girls with Rett syndrome living in that country.

Most Rett syndrome cases are caused by mutations in the MECP2 gene, which codes for a protein needed for the brain to develop properly. Disease symptoms range from problems with growth to seizures and loss of the ability to speak.

NGN-401 is designed to deliver a working, full-length version of the MECP2 gene to the body. The MECP2 gene is packaged aboard a viral vector that is engineered to be harmless and acts as a delivery vehicle. The viral vector used in NGN-401 is derived from AAV9.

Given as an intracerebroventricular infusion directly into the fluid-filled cavities of the brain, NGN-401 allows cells to start producing the MeCP2 protein coded by the gene on their own. This is expected to increase the protein’s levels, helping to ease symptoms.

To control how much of the protein is produced, NGN-401 uses the company’s EXACT technology. By delivering consistent levels of protein, EXACT protects the cells against the overexpression-related toxicity that sometimes occurs with conventional gene therapy.

In a mouse model of Rett syndrome, a single dose of NGN-401 extended the animals’ lifespan and eased disease burden. The gene therapy also appeared to be safe when given early in life to nonhuman primates.

Neurogene was cleared in the U.S. to move NGN-401 into a Phase 1/2 clinical trial, which now is testing the gene therapy’s safety when given at a total dose of 1E15 vector genomes. Side effects will be monitored for up to five years.