Gene Therapy for Rett Syndrome

Recruiting at 12 trial locations

Overseen By Contact Center

Age: Any Age

Sex: Female

Trial Phase: Phase 3

Sponsor: Neurogene Inc.

Must be taking: Anti-epileptics

Disqualifiers: Normal hand function, Other conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, NGN-401, to determine its safety for females with typical Rett syndrome, a rare genetic condition affecting brain development. Researchers focus on the treatment's tolerability in two groups: younger children and adolescents/adults. Individuals with Rett syndrome who have stable anti-epileptic medication and a specific genetic mutation may qualify for this trial. Participants must also reside near the study center for a few months. This trial offers an opportunity to explore a new treatment option for Rett syndrome. As a Phase 1/Phase 2 trial, the study aims to understand how NGN-401 works in people and assess its effectiveness in a smaller group.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but your anti-epileptic drug regimen must be stable for at least 12 weeks before joining. You may start taking trofinetide after the gene therapy, with your doctor's support.

Is there any evidence suggesting that NGN-401 is likely to be safe for humans?

Research has shown that the experimental gene therapy NGN-401 is safe in early tests. Initial results suggest that participants have tolerated both low and high doses of NGN-401 well. However, a serious side effect occurred in the high-dose group, raising concerns. In contrast, the low-dose group has not experienced any major safety issues.

The trial is in its early stages, focusing on testing the treatment's safety. Participants are closely monitored for any side effects. If NGN-401 had already been approved for another condition, it might offer more safety assurance, but that is not the case here. While the current safety data is promising, it remains under development. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Rett syndrome?

Researchers are excited about NGN-401 because it offers a unique approach to treating Rett Syndrome through gene therapy. Unlike current treatments that mainly focus on managing symptoms with medications like anticonvulsants or supportive therapies, NGN-401 aims to address the root cause by delivering a therapeutic gene to correct the underlying genetic defect. This innovative method has the potential to significantly improve neurological function and quality of life for those affected by Rett Syndrome, offering hope for a more effective long-term solution.

What evidence suggests that NGN-401 might be an effective treatment for Rett syndrome?

Research has shown that NGN-401, a gene therapy for Rett syndrome, has promising early results. An initial study with four children receiving a low dose demonstrated improvements in their behavior. Specifically, their scores on a behavior questionnaire for Rett syndrome increased from 28% to 52%, indicating better symptom management. The trial will include a Pediatric 1e15 vg dose arm for children aged 4-10 years and an Adolescent/Adult 1e15 vg dose arm for participants aged 11 years and above. This therapy targets the brain and nervous system, showing effectiveness in early tests. However, the high-dose group experienced serious side effects, leading to the discontinuation of that dose level. Overall, NGN-401 shows potential, but further studies are needed to confirm its safety and effectiveness. ^{1 2 3 5 6}

Who Is on the Research Team?

Julie Jordan, MD

Principal Investigator

Neurogene Inc.

Are You a Good Fit for This Trial?

This trial is for female children with typical Rett syndrome who have a specific mutation in the MECP2 gene. They should be on a stable anti-epileptic drug regimen for 12 weeks and live close to the study center. Those with normal hand function, other significant conditions, or certain neurological disorders are excluded.

Inclusion Criteria

I have Rett syndrome with a confirmed MECP2 gene mutation.

My epilepsy medication has not changed for the last 12 weeks.

I and my caregiver live within 2 hours of the study center and can stay for 3 months post-treatment.

Exclusion Criteria

I do not have any health conditions that prevent me from receiving treatments directly into my brain or using anesthesia.

My child had significant developmental delays in the first 6 months.

My hands function normally or almost normally.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NGN-401 via intracerebroventricular delivery under general anesthesia

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and preliminary efficacy after treatment

5 years

Long-term follow-up

Participants are expected to enroll in a long-term follow-up study

10 years

What Are the Treatments Tested in This Trial?

Interventions

• NGN-401

Trial Overview The trial is testing NGN-401, an investigational gene therapy designed specifically for Rett syndrome. It aims to evaluate how safe this treatment is when given to young girls suffering from this condition.

How Is the Trial Designed?

Group I: Pivotal Cohort Experimental Treatment 1 Intervention

Dose Level 1 for ages 3 and above

Group II: Pediatric 3e15 vg dose (discontinued) Experimental Treatment 1 Intervention

Dose Level 2 for ages 4-10 years (discontinued)

Group III: Pediatric 1e15 vg dose (fully enrolled) Experimental Treatment 1 Intervention

Dose Level 1 for ages 4-10 years

Group IV: Adolescent/Adult 1e15 vg Dose (fully enrolled) Experimental Treatment 1 Intervention

Dose Level 1 for ages 11 years \& above

Who Is Running the Clinical Trial?

Neurogene Inc.

Lead Sponsor

Trials

6

Recruited

150+

Published Research Related to This Trial

In Rett syndrome, despite normal levels of nerve growth factor (NGF) in the brain, there is a significant loss of choline acetyltransferase (ChAT)-containing neurons, which are crucial for producing the neurotransmitter acetylcholine.

The study indicates that while NGF is available to bind to its receptors, the ChAT-positive neurons in the basal forebrain fail to respond appropriately, suggesting a dysfunction in the signaling pathway necessary for their survival and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered cholinergic function in the basal forebrain of girls with Rett syndrome. Wenk, GL., Hauss-Wegrzyniak, B.[2013]

Long-term treatment with human NGF painless (hNGFp) in MeCP2+/- mice significantly increased survival rates and improved behavioral outcomes, indicating its potential as a therapeutic option for Rett syndrome.

hNGFp treatment not only rescued cholinergic neurons but also reversed microglial morphology deficits, suggesting a dual mechanism of action that provides neuroprotection directly to neurons and indirectly through microglial modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome. Tiberi, A., Borgonovo, G., Testa, G., et al.[2023]

In patients with Rett syndrome, levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid were undetectable, suggesting a potential deficiency in these important growth factors.

Serum levels of nerve growth factor and brain-derived neurotrophic factor were normal, indicating that while these factors are present in the bloodstream, they may not be effectively reaching the central nervous system in individuals with Rett syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotrophic factors in cerebrospinal fluid and serum of patients with Rett syndrome. Vanhala, R., Korhonen, L., Mikelsaar, M., et al.[2017]

In a phase 3 study involving 187 females with Rett syndrome, trofinetide showed significant improvement in core symptoms compared to placebo, with a notable reduction in Rett Syndrome Behaviour Questionnaire scores (LSM change of -4.9 vs -1.7, P=0.0175).

While trofinetide was effective, it also had a high incidence of mild to moderate diarrhea (80.6% in the trofinetide group vs 19.1% in placebo), indicating the need for monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Neul, JL., Percy, AK., Benke, TA., et al.[2023]

Trofinetide is the first FDA-approved drug for Rett syndrome (RTT), a rare genetic disorder affecting girls, and has shown favorable safety and efficacy in improving core symptoms during Phase II clinical trials.

The drug is well-tolerated with no known drug interactions, making it a promising treatment option for managing RTT symptoms and enhancing the quality of life for affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trofinetide in Rett syndrome: A brief review of safety and efficacy. Singh, A., Balasundaram, MK., Gupta, D.[2023]

Trofinetide was found to be well tolerated and generally safe in a phase 2 study involving 56 adolescent and adult females with Rett syndrome, indicating its potential as a therapeutic option for this condition.

At the higher dose of 70 mg/kg, trofinetide showed promising efficacy compared to placebo, suggesting it may lead to clinically meaningful improvements in key symptoms of Rett syndrome, despite the study's short duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. Glaze, DG., Neul, JL., Percy, A., et al.[2018]

In a double-blind crossover study involving 30 girls with Rett syndrome, mecasermin (rhIGF-1) did not show significant improvement in symptoms compared to placebo, and some measures indicated worsening of symptoms.

While the treatment was generally safe with mostly mild to moderate adverse events, serious adverse events were reported, and EEG parameters also showed deterioration, suggesting caution in its use for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. O'Leary, HM., Kaufmann, WE., Barnes, KV., et al.[2019]

Trofinetide was found to be safe and well-tolerated in a phase 2 study involving 82 female children and adolescents with Rett syndrome, with no significant adverse effects reported across all dose levels.

At a dosage of 200 mg/kg twice daily, trofinetide showed statistically significant improvements in key symptoms of Rett syndrome compared to placebo, indicating its potential as a treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Glaze, DG., Neul, JL., Kaufmann, WE., et al.[2020]

Trofinetide is the first FDA-approved drug for treating Rett Syndrome in children aged 2 years and older, marking a significant milestone in the management of this condition.

Clinical studies have shown that Trofinetide significantly improves behavioral scores in children with Rett Syndrome, indicating its efficacy as a new treatment option, although further research is needed to evaluate potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trofinetide-a new chapter in rett syndrome's treatment. Furqan, M.[2023]

Citations

1. ir.neurogene.com ir.neurogene.com/news-releases/news-release-details/neurogene-reports-positive-interim-efficacy-data-first-four-low

Release Details Neurogene reports positive interim efficacy data from first four low-dose pediatric participants in NGN-401 gene therapy clinical trial for Rett syndrome.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05898620

A Novel, Regulated Gene Therapy (NGN-401) Study for ... This study will evaluate the safety profile of the investigational gene therapy, NGN-401, in females with typical Rett syndrome. Detailed Description. The study ...

3. ir.neurogene.com ir.neurogene.com/static-files/53a3302a-93d4-4de6-b94d-f1e73e6d23c4

NGN-401 Gene Therapy for Rett Syndrome Clinical Program NGN-401's intracerebroventricular (ICV) route of delivery has been shown in preclinical models to have the broadest targeting of brain and nervous system ...

4. reverserett.org reverserett.org/news/articles/neurogene-announces-interim-data-from-clinical-trial-of-ngn-401-gene-therapy-for-rett/

Neurogene Announces Interim Results from Gene Therapy ... Today Neurogene hosted a webcast to share preliminary results on their pediatric clinical trial of NGN-401 gene therapy for Rett syndrome.

5. cgtlive.com cgtlive.com/view/neurogene-rett-syndrome-gene-therapy-ngn-401-demonstrates-efficacy-in-low-dose-cohort-but-serious-adverse-event-in-high-dose-group-raises-concerns

Neurogene's Rett Syndrome Gene Therapy NGN-401 ... In addition, the patients improved from 28% to 52% from baseline on the caregiver-completed Rett Syndrome Behavior Questionnaire. Neurogene ...

6. ir.neurogene.com ir.neurogene.com/static-files/51d2d22f-5f21-4af2-86eb-b4d3d031d4c9

Preliminary Safety Results from the Ph1/2 Study of NGN- ... High-dose NGN-401 has been well-tolerated thus far with an early favorable safety profile. • Interim efficacy data are expected fourth quarter ...