Gene Therapy for Rett Syndrome

Recruiting at 7 trial locations

Overseen By Contact Center

Age: < 18

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Neurogene Inc.

Must be taking: Anti-epileptics

Disqualifiers: Normal hand function, Other conditions, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests NGN-401, a gene therapy using a virus to deliver a healthy gene, in female children with Rett syndrome. It aims to improve brain cell function by providing the correct version of a missing or faulty gene.

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.

What data supports the effectiveness of the drug NGN-401 for treating Rett Syndrome?

The research on a similar treatment, Trofinetide, which is related to insulin-like growth factor 1, shows significant improvement in Rett syndrome symptoms in clinical studies. This suggests that treatments targeting similar pathways, like NGN-401, may also be effective. ^{1 2 3 4 5}

What safety data exists for gene therapy treatments like NGN-401 for Rett Syndrome?

There is no specific safety data available for NGN-401 in the provided research articles. However, Trofinetide, a similar treatment for Rett Syndrome, has been shown to be safe and well-tolerated in clinical trials, with no known drug interactions. ^{1 2 6 7 8}

How does the drug NGN-401 differ from other treatments for Rett syndrome?

NGN-401 is unique because it is a gene therapy specifically targeting the genetic cause of Rett syndrome, which is a mutation in the MeCP2 gene. Unlike other treatments that may focus on managing symptoms, NGN-401 aims to address the underlying genetic defect, potentially offering a more direct and long-term solution. ^{1 2 3 5 9}

Research Team

Julie Jordan, MD

Principal Investigator

Neurogene Inc.

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• NGN-401 (Gene Therapy)

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.

Participant Groups

Group I: Low Dose Experimental Treatment 1 Intervention

Dose Level 1

Group II: High Dose Experimental Treatment 1 Intervention

Dose Level 2

Who Is Running the Clinical Trial?

Neurogene Inc.

Lead Sponsor

Trials

6

Recruited

150+

Findings from Research

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]

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]

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]

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 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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Neurotrophic factors in cerebrospinal fluid and serum of patients with Rett syndrome. [2017]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. [2020]

8. Japan pubmed.ncbi.nlm.nih.gov

Trofinetide in Rett syndrome: A brief review of safety and efficacy. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Altered cholinergic function in the basal forebrain of girls with Rett syndrome. [2013]