NGN-401 / Neurogene - LARVOL DELTA

Expression Kinetics and Clinical Onset of Benefit Following Single-Stranded AAV Delivery of NGN-401 in Rett Syndrome (ESGCT 2026) - No abstract available

Clinical • Developmental Disorders • Movement Disorders

A Novel, Regulated Gene Therapy (NGN-401) Study for Females With Rett Syndrome (clinicaltrials.gov) - P3 | N=33 | Active, not recruiting | Sponsor: Neurogene Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Developmental Disorders • Gene Therapies • Movement Disorders

Gene Therapy Targeting CNS Diseases: ICV Administration as a Growing Standard for Delivery (ASGCT 2026) - "In the NGN-401 program, an AAV9-based gene therapy utilizing EXACT™ technology for regulated MeCP2 expression and delivered via ICV is being evaluated for Rett syndrome...These findings are aligned with other gene therapy clinical programs utilizing ICV ROA. ICV administration is emerging as a safe, feasible method for CNS gene therapy delivery."

Gene therapy • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Movement Disorders

From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies. (PubMed, Mol Diagn Ther) - "We discuss clinical-stage adeno-associated virus gene replacement programs, including TSHA-102 and NGN-401, highlighting their vector designs, regulatory elements, delivery approaches, and emerging clinical data. Beyond gene supplementation, we explore approaches that restore endogenous MECP2 regulation, such as reactivation of the inactive X chromosome, as well as DNA and RNA editing strategies. Collectively, these advances reflect a shift toward precision-regulated therapies for Rett syndrome that may provide a model for treating other dosage-sensitive neurodevelopmental disorders."

Journal • Review • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry

Neurogene Announces FDA Breakthrough Therapy Designation for NGN-401 Gene Therapy for Rett Syndrome (Businesswire) - "Breakthrough Therapy designation granted based on interim NGN-401 Phase 1/2 data demonstrating clinically meaningful, durable and multidomain functional improvements. On track to complete dosing in Embolden registrational trial of NGN-401 in second quarter of 2026. Plans to present additional interim Phase 1/2 clinical data in mid-2026."

Breakthrough therapy • P1/2 data • Trial status • CNS Disorders • Developmental Disorders

Disease-modifying therapies for Rett syndrome: a review for neurologists. (PubMed, Front Neurol) - "Until the recent approval of trofinetide, management relied exclusively on symptomatic treatment and multidisciplinary supportive care...TSHA-102 uses an intrathecally delivered miniMECP2 transgene regulated by a microRNA-based autoregulatory system, whereas NGN-401 delivers full-length MECP2 via intracerebroventricular administration using a synthetic expression-feedback circuit...Finally, we address key translational considerations such as optimal timing of intervention, dosing constraints, outcome measurement in severely impaired populations, long-term safety surveillance, and barriers to broad and equitable access. The RTT gene therapy experience serves as a model for precision medicine in other monogenic neurodevelopmental disorders, illustrating both the transformative promise and the substantial complexities of translating genetic science into meaningful clinical benefit."

Journal • Review • CNS Disorders • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics • Psychiatry • ADAR

A Novel, Regulated Gene Therapy (NGN-401) Study for Females With Rett Syndrome (clinicaltrials.gov) - P3 | N=33 | Recruiting | Sponsor: Neurogene Inc. | Phase classification: P1/2 ➔ P3 | N=14 ➔ 33

Enrollment change • Phase classification • Developmental Disorders • Gene Therapies • Movement Disorders

Route matters: intracerebroventricular (ICV) delivery of NGN-401 drives superior transgene expression to key areas of the brain when compared to intrathecal (IT-L) delivery at clinically relevant dose — implications for a one-time gene therapy for Rett syndrome (ESGCT 2025) - No abstract available

Clinical • Gene therapy • Developmental Disorders • Gene Therapies • Movement Disorders

Hemophagocytic Lymphohistiocytosis (HLH)/hyperinflammatory syndrome following high dose AAV9 therapy (ASGCT 2025) - "Byrne et al noted HLH cases, with a systemically administered AAV9 product at a similar dose, resolving with anakinra, an IL-1 receptor antagonist...Case summary: A 7-year-old female with classic RTT was treated with 3E15 vg (1.5E14 vg/kg) of NGN-401 via ICV administration with no procedure-related complications. Prophylactic immunosuppression included rituximab, sirolimus, and corticosteroids...A single dose of eculizumab was given as a precaution, without signs of thrombotic microangiopathy based on negative blood smear... High dose AAV has been linked to rare cases of HLH. Monitoring ferritin, complete blood count, and liver function frequently in the early post-dose period is warranted. Prompt treatment for suspected HLH should include high-dose corticosteroids, immunomodulation, and management by a multidisiplinary team."

IO biomarker • Acute Kidney Injury • CNS Disorders • Developmental Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Hepatology • Hypotension • Immunology • Infectious Disease • Liver Failure • Movement Disorders • Nephrology • Oncology • Psychiatry • Rare Diseases • Renal Disease • Respiratory Diseases • Thrombocytopenia

Neurogene's experience with the START Pilot Program in advancing their NGN-401 product for Rett Syndrome (ASGCT 2025) - "Supported by the Regulatory Affairs Committee"

Developmental Disorders • Movement Disorders

Neurogene Announces Upcoming Oral Presentation on Monitoring and Treatment to Reverse Rare Complication of High Dose Gene Therapy at the ASGCT Annual Meeting (Businesswire) - "Neurogene...today announced an oral presentation and participation in a fireside chat and panel discussion on critical gene therapy topics during the American Society for Gene and Cell Therapy (ASGCT) 28th Annual Meeting on May 13-17, 2025 in New Orleans. The oral presentation will include approaches for monitoring and managing hemophagocytic lymphohistiocytosis (HLH), a rare, severe hyperinflammatory syndrome that has been associated with systemic exposure to high doses of adeno-associated virus (AAV) gene therapy....'In our ongoing clinical trial of NGN-401 gene therapy for Rett syndrome, we have implemented early monitoring and a treatment plan into our protocol, and we encourage others to do the same.'"

Clinical data • Clinical protocol • CNS Disorders • Hemophagocytic lymphohistiocytosis • Inflammation

Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome. (PubMed, Sci Transl Med) - P1/2 | "NGN-401 was also well tolerated by female Mecp2+/- mice and healthy juvenile nonhuman primates, in contrast with a conventional construct, which caused toxicity. The results from these studies underpin a first-in-human pediatric trial of NGN-401 in RTT (ClinicalTrials.gov, NCT05898620)."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics

Preliminary Safety Results from the Ph1/2 Study of NGN-401, a Novel Regulated Gene Therapy for Rett Syndrome (ASGCT 2024) - P1/2 | "NGN-401 given via one-time ICV administration has been generally well tolerated, with an adverse event profile consistent with AAV9 administration. No clinical evidence of MeCP2 overexpression was observed in three pediatric female subjects with differing pathogenic mutations of classic RTT, including one predicted to result in residual MeCP2 function."

Clinical • Gene therapy • CNS Disorders • Developmental Disorders • Gastrointestinal Disorder • Gene Therapies • Movement Disorders • Pediatrics • Psychiatry

Neurogene Announces Upcoming Presentation of Safety Data from Phase 1/2 Trial of NGN-401 Gene Therapy for Rett Syndrome at ASGCT Meeting (Businesswire) - P1/2 | N=16 | NCT05898620 | Sponsor: Neurogene Inc. | "Neurogene...announced that initial safety and tolerability data from its ongoing Phase 1/2 gene therapy clinical trial for Rett syndrome will be presented at the American Society for Gene and Cell Therapy (ASGCT) Annual Meeting. The data show that the NGN-401 gene therapy candidate has been generally well-tolerated, and there have been no treatment-emergent or procedure-related serious adverse events or signs of MeCP2 overexpression-related toxicity observed in any patient, including a patient with a mild variant predicted to result in residual MeCP2 function....'We believe it is important to share this safety update at the ASGCT Meeting, in advance of our expected fourth quarter 2024 interim efficacy read-out, as we have multiple months of data from three patients showing NGN-401 has been generally well-tolerated'."

P1/2 data • CNS Disorders • Developmental Disorders

A Novel, Regulated Gene Therapy (NGN-401) Study for Female Children With Rett Syndrome (clinicaltrials.gov) - P1/2 | N=5 | Recruiting | Sponsor: Neurogene Inc.

Trial completion date • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics

A Novel, Regulated Gene Therapy (NGN-401) Study for Female Children With Rett Syndrome (clinicaltrials.gov) - P1/2 | N=5 | Recruiting | Sponsor: Neurogene Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Gene therapy • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics

A Novel, Regulated Gene Therapy (NGN-401) Study for Female Children With Rett Syndrome (clinicaltrials.gov) - P1/2 | N=5 | Not yet recruiting | Sponsor: Neurogene Inc.

Gene therapy • New P1/2 trial • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics

Preclinical Safety Assessment of NGN-401, a Clinical-Stage Gene Therapy Product for Rett Syndrome (ASGCT 2023) - "Overall, the totality of data generated in multiple preclinical models demonstrated that NGN-401 allowed for MeCP2 expression that provided therapeutic benefit while mitigating the risk of overexpression toxicity, supporting FDA clearance to initiate a first-in-human pediatric clinical study."

Gene therapy • Preclinical • CNS Disorders • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics