Encouraging update from Neurogene NGN-401 Gene Therapy Clinical Trial
At the 2025 IRSF Rett Syndrome Scientific Meeting in Boston last week (June 9-11, 2025), Neurogene shared an encouraging progress update on its NGN-401 gene therapy program—a potential one-time treatment designed to address the underlying cause of Rett syndrome.
The company has since released a Community Letter which you can read here.
Here are the key takeaways for families:
All Planned Participants Now Dosed
Neurogene’s Phase 1/2 clinical trial is evaluating NGN-401 in girls and women aged 4 years and older.
- All 8 participants in the 4–10-year-old group have been dosed.
- 2 out of 3 participants in the 11+ age group have received the treatment, with the final participant expected to be dosed soon.
This means the initial dosing phase of this first-in-human study is nearly complete across both age groups.
Safety
The first priority of a phase 1 / 2 clinical trial is to assess safety.
Families may remember that in November 2024, Neurogene reported the death of one of the high dose participants in the clinical trial.
This very sad event came about because of a rare adverse reaction which is sometimes seen in a small subset of patients receiving high-dose AAV gene therapy, regardless of disease group and/or contents of the AAV9 vector (the virus which carries the gene therapy into the body).
Since this happened, Neurogene has dedicated tremendous resource to:
- Ensuring the safety of all participants in the NGN-401 clinical trial, first and foremost by terminating the higher dose (3e15 vg) part of the program.
- Putting in place enhanced HLH risk-mitigation strategies, including daily monitoring and a treatment plan should any symptoms appear.
No further patients on the trial have shown signs of this rare reaction.
The company is not aware of any case of Hemophagocytic Lymphohistiocytosis (HLH)/Hyperinflammatory Syndrome ever being reported at the low dose level (1E15 vg) now being used.
Neurogene has also dedicated significant resource to campaigning for monitoring for HLH to become standard in AAV therapy, demonstrating the company’s commitment to improving safety standards and enabling ongoing progress in AAV clinical trials and treatments across disease groups.
Life-Changing Functional Improvements Reported:
Neurogene also shared early signals of real-world improvement in patients’ development and daily function—progress not expected in Rett syndrome without intervention.
The company has only released efficacy data for the first 4 patients on the clinical trial.
As a reminder, these patients are in the 4-10 age group and were dosed one at a time, starting with patient 1 (15 months post dosing as of data cut off 17th October 2024).
This means that the progress being reported in different patients may be variable due to the time since they were dosed with this one-time treatment.
Across the first 4 treated patients (ages 4–10):
- All 4 showed at least a 2-point improvement on the Clinician Global Impression-Improvement (CGI-I) scale, rated as “much improved” compared to their baseline.
- Skills gained included:
- Improved hand use (like using a pincer grasp and self-feeding)
- Gross motor improvements (such as climbing stairs and walking more steadily)
- New or regained communication abilities (like waving, following commands, or tapping to request things)
For example:
- Patient 1 (15 months post-treatment): Now able to self-feed with a spoon and climb stairs—skills they did not have before.
- Patient 2 (12 months post-treatment): Gained the ability to stand independently and reach for objects.
- Patients 3 and 4: Showed early hand function improvements, such as picking up objects and using utensils.
These kind of gains are rarely seen in natural history studies of Rett syndrome, especially in this age group.
Here are some slides which were shown at the recent IRSF Scientific Meeting, showing CGI improvements and visual representations of the patients’ progress.
Patient 1: 15 months post-dosing
Patient 2: 12 months post-dosing:
Patient 3: 9 months post-dosing:
Patient 4: 3 months post-dosing:
What Happens Next?
Neurogene plans to:
- Share details this month about a larger, pivotal clinical trial—designed to gather the final data needed for potential approval by regulators like the FDA (US regulator), EMA (European regulator) and MHRA (UK regulator).
- Release additional clinical data from this Phase 1/2 trial in the second half of 2025.
These steps will help determine whether NGN-401 could become an approved, widely available therapy for people with Rett syndrome.
FDA Regulatory Momentum:
In 2024, Neurogene’s NGN-401 gene therapy program was selected to be part of the FDA’s START Pilot Program and the NGN-401 program also has RMAT designation, both of these initiatives allow for greater flexibility and more frequent regulatory interactions.
Where are the Neurogene clinical trials happening?
There are currently:
8 clinical trial sites, 5 in the USA, 1 in Australia and 2 in the UK.
Neurogene has already received the U.K. MHRA’s Innovative Licensing and Access Pathway designation which helps to accelerate the regulatory processes in the UK.
In Summary
These are very encouraging early results for the NGN-401 program:
✅ Safety: No further safety concerns, program moving forward at the low dose level.
✅ Function: Meaningful gains in real-world skills—motor, hand use, communication—seen in multiple participants.
✅ Momentum: Plans for a larger, pivotal trial to confirm these findings are underway.
While there is more to learn, our community can feel cautiously optimistic about NGN-401’s progress and its potential to significantly improve the lives of people with Rett syndrome moving forward.
We’ll keep following this program closely and share meaningful updates as they become available.
Thank you for your continued support.
Slides included in this article have come from a PDF shared on Neurogene’s website here.