Neurogene Publishes Study on NGN-401 Gene Therapy for Rett Syndrome
Neurogene Inc. (Nasdaq: NGNE), a clinical-stage biotechnology company dedicated to developing transformative genetic medicines for patients suffering from rare neurological disorders, has announced the publication of a peer-reviewed study detailing its innovative EXACT™ transgene regulation technology. The study, featured in Science Translational Medicine, highlights the preclinical findings demonstrating the ability of EXACT to precisely regulate gene therapy expression, ensuring it remains within a safe and effective range. The results of this study have directly supported the initiation of Neurogene’s ongoing Phase 1/2 clinical trial of NGN-401, a gene therapy designed to treat Rett syndrome.
Neurogene was established with a mission to harness gene therapy’s potential for treating rare neurological conditions. “The development of EXACT was a pivotal breakthrough in our efforts to create gene therapies capable of treating disorders with narrow therapeutic windows, such as Rett syndrome,” stated Rachel McMinn, Ph.D., Founder and Chief Executive Officer of Neurogene. “NGN-401, which incorporates EXACT, was intentionally developed to maintain therapeutic and tolerable levels of MeCP2. The robust preclinical data we present today support EXACT’s ability to overcome traditional gene therapy limitations, not just for Rett syndrome, but for a broader range of severe neurological disorders.”
Rett syndrome is a devastating neurodevelopmental disorder caused by mutations in the MECP2 gene. While loss-of-function mutations in MECP2 lead to the condition, excessive levels of MeCP2 protein can also be toxic, posing a significant challenge for gene therapy approaches. Conventional, unregulated gene therapies often lead to inconsistent cellular uptake, potentially resulting in dangerously high levels of transgene expression. EXACT technology addresses this limitation by integrating a self-regulating circuit within the gene therapy construct. This circuit utilizes microRNA-based regulation to maintain transgene expression at therapeutically optimal and tolerable levels on a cell-by-cell basis.
“Gene therapies that incorporate transgene regulation hold immense promise for treating dosage-sensitive conditions that currently lack disease-modifying treatments,” explained Stuart Cobb, Ph.D., Chief Scientific Officer of Neurogene and Professor of Translational Neuroscience at the University of Edinburgh’s Simons Initiative in the Developing Brain and Centre for Discovery Brain Sciences. “EXACT was originally conceived to create a safer and more effective treatment for Rett syndrome, and its translation into NGN-401 represents a major milestone. I extend my gratitude to my colleagues at the University of Edinburgh, Edinburgh Innovations, and Neurogene for their dedication and support in developing this groundbreaking technology.”
Key Findings from the Preclinical Study
The published research presents a comprehensive series of preclinical investigations leading to the development of NGN-401. These studies demonstrate the superior safety and efficacy of NGN-401 compared to conventional gene therapy approaches:
- Design and Optimization: To develop a viable gene therapy candidate for Rett syndrome, researchers created multiple constructs with modified regulatory elements. Among these, NGN-401 emerged as the most effective, particularly in male knockout models, where it significantly extended median survival.
- Female Murine Model Results: In female mouse models, which exhibit mosaic MECP2 expression similar to human Rett syndrome patients, NGN-401 was well-tolerated at all tested doses. In contrast, conventional gene therapy resulted in severe toxicity due to uncontrolled transgene expression.
- Non-Human Primate Studies: To assess tolerability in a stringent model, NGN-401 was evaluated in non-human primates, which naturally express normal levels of MeCP2 in all cells. Across all administered doses, NGN-401 was well-tolerated. Conversely, conventional gene therapy led to highly variable and significantly elevated MECP2 mRNA levels in critical tissues.
These findings collectively validate the ability of EXACT to regulate transgene expression across both disease and large-animal models, mitigating the risks associated with unregulated gene therapy approaches.
Implications for the Future
The publication of these preclinical data marks an important milestone in advancing NGN-401 into clinical trials. The Phase 1/2 trial currently underway aims to assess the safety, tolerability, and initial efficacy of NGN-401 in human patients with Rett syndrome. Given the promising results seen in preclinical studies, Neurogene is optimistic that NGN-401 could provide a life-changing treatment for individuals affected by this severe disorder.
Beyond Rett syndrome, the EXACT transgene regulation platform holds potential for broader applications in treating other dosage-sensitive genetic conditions. The ability to fine-tune gene expression at a cellular level addresses a fundamental challenge in gene therapy, potentially expanding the applicability of this approach to numerous other neurological and genetic disorders.
The full research article, titled Self-regulating Gene Therapy for Overcoming Gene Dosage Sensitivity in Rett Syndrome, is available in Science Translational Medicine, a prestigious journal within the Science family of publications. This peer-reviewed study underscores the significance of Neurogene’s innovative approach and reinforces the potential of gene therapy as a transformative treatment modality for complex genetic diseases.
With a strong scientific foundation and an ongoing commitment to innovation, Neurogene continues to push the boundaries of genetic medicine. The company remains dedicated to developing breakthrough therapies that bring hope to patients and families affected by rare neurological disorders, leveraging cutting-edge research to address some of the most challenging medical conditions.
