Gene Therapy for Rett Syndrome
Recruiting in Palo Alto (17 mi)
+7 other locations
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.
12345What 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.
12678How 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.
12359Eligibility 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.
+1 more
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.
+2 more
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Low DoseExperimental Treatment1 Intervention
Dose Level 1
Group II: High DoseExperimental Treatment1 Intervention
Dose Level 2
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Montefiore Medical CenterNew York, NY
Rush University Medical CenterChicago, IL
Children's Hospital ColoradoAurora, CO
Boston Children's HospitalBoston, MA
More Trial Locations
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Who Is Running the Clinical Trial?
Neurogene Inc.Lead Sponsor
References
Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. [2019]To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design.
Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome. [2023]Rett syndrome is a rare genetic neurodevelopmental disease, affecting 1 in over 10,000 females born worldwide, caused by de novo mutations in the X-chromosome-located methyl-CpG-binding protein 2 (MeCP2) gene. Despite the great effort put forth by the scientific community, a therapy for this devastating disease is still needed. Here, we tested the therapeutic effects of a painless mutein of the Nerve Growth Factor, called human NGF painless (hNGFp), via a non-invasive intranasal delivery in female MeCP2+/- mice. Of note, previous work had demonstrated a broad biodistribution of hNGFp in the mouse brain by the nasal delivery route. We report that (1) the long-term lifelong treatment of MeCP2+/- mice with hNGFp, starting at 2 months of age, increased the chance of survival while also greatly improving behavioral parameters. Furthermore, when we assessed the phenotypic changes brought forth by (2) a short-term 1-month-long hNGFp-treatment, starting at 3 months of age (right after the initial presentation of symptoms), we observed the rescue of a well-known neuronal target population of NGF, cholinergic neurons in the medial septum. Moreover, we reveal a deficit in microglial morphology in MeCP2+/- mice, completely reversed in treated animals. This effect on microglia is in line with reports showing microglia to be a TrkA-dependent non-neuronal target cell population of NGF in the brain. To understand the immunomodulatory activity of hNGFp, we analyzed the cytokine profile after hNGFp treatment in MeCP2+/- mice, to discover that the treatment recovered the altered expression of key neuroimmune-communication molecules, such as fractalkine. The overall conclusion is that hNGFp delivered intranasally can ameliorate symptoms in the MeCP2+/- model of Rett syndrome, by exerting strong neuroprotection with a dual mechanism of action: directly on target neurons and indirectly via microglia.
Neurotrophic factors in cerebrospinal fluid and serum of patients with Rett syndrome. [2017]Rett syndrome is now considered to be a neurodevelopmental disease. Its cause is unknown, but it has been suggested that neuronal growth factors and neurotransmitters play important roles. We measured levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid, and nerve growth factor and brain-derived neurotrophic factor in serum in child and adolescent patients with Rett syndrome. Levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid were below the limit of sensitivity of the methods used. Serum levels of nerve growth factor and brain-derived neurotrophic factor did not differ from control values. In Rett syndrome, the normal serum levels of nerve growth factor together and previously reported low levels of the factor in cerebrospinal fluid indicate that the latter may reflect low levels of nerve growth factor in the central nervous system.
Trofinetide-a new chapter in rett syndrome's treatment. [2023]Trofinetide is the first drug approved by the FDA to treat Rett Syndrome in children aged 2 years or above. The drug significantly improved Rett syndrome behavioral scores Rett syndrome behavioral questionnaire in clinical studies. Although further research is needed to assess potential adverse events, Trofinetide's notable efficacy signifies a significant advancement in Rett syndrome treatment, offering a new therapeutic avenue with the potential to ameliorate the condition.
Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. [2023]Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.
A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. [2018]This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features.
Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. [2020]To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available.
Trofinetide in Rett syndrome: A brief review of safety and efficacy. [2023]Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 (MECP2) gene, leading to critical issues in normal brain function. The condition has a global prevalence of 5 to 10 cases per 100,000 females, and there is currently no cure for RTT. However, therapy is available to manage the symptoms and improve quality of life. Trofinetide, an insulin-like growth factor 1, was originally developed as a stroke medication and progressed to Phase II clinical trials, where it exhibited favorable safety and efficacy profiles by improving several core RTT symptoms. Recently, Trofinetide received the US Food and Drug Administration (FDA) approval and orphan drug designation for the treatment of RTT, making it the first approved drug for this rare genetic disorder. It has also shown to be safe, well-tolerated and with no known drug interactions. These findings suggest that Trofinetide is a promising treatment option for individuals with RTT.
Altered cholinergic function in the basal forebrain of girls with Rett syndrome. [2013]Rett syndrome (RS) is a neurodevelopmental disorder that is predominant in females and is associated with cortical atrophy, stereotyped hand movements and severe mental deficiency. Previous studies have demonstrated a significant decline in number of choline acetyltransferase (ChAT)-containing neurons throughout the forebrain of RS girls. The loss of these ChAT-positive cells may be caused by a lack of nerve growth factor (NGF). In the current study, cortical levels of NGF were normal in RS girls as compared to age-and sex-matched controls. The number of neurons within the basal forebrain that express the 75 kDa (p75) low-affinity receptor for NGF was unchanged. In contrast, the number of ChAT-positive neurons was significantly decreased. The results suggest that normal amounts of NGF are available for binding to the p75 receptor and for retrograde transport to forebrain cholinergic cells, however, these neurons do not respond by producing the ChAT protein that is necessary for the production of the neurotransmitter acetylcholine.