Data demonstrate EXACT has potential to overcome limitations of conventional gene therapy for dosage-sensitive disorders
Findings published in Science Translational Medicine
NEW YORK, April 02, 2025--(BUSINESS WIRE)--Neurogene Inc. (Nasdaq: NGNE), a clinical-stage company founded to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, today announced a peer-reviewed publication on its EXACT™ transgene regulation technology. The preclinical studies demonstrate EXACT’s ability to regulate gene therapy expression to a tolerable and therapeutic level, including in preclinical models of Rett syndrome. These data, published in Science Translational Medicine, supported the initiation of Neurogene’s ongoing Phase 1/2 clinical trial with NGN-401 gene therapy for Rett syndrome.
"Neurogene was founded to extend the promise of gene therapy to rare neurological disorders, and EXACT was critical to enabling gene therapy treatment for Rett syndrome, a disorder with a narrow therapeutic window that requires transgene regulation," said Rachel McMinn, Ph.D., Founder and Chief Executive Officer of Neurogene. "NGN-401 gene therapy for Rett syndrome is our first product candidate incorporating EXACT, which was intentionally developed to deliver therapeutic and tolerable MeCP2 levels. The preclinical data published today and the translation of the platform into the clinic support the proposition that EXACT has the potential to overcome the limitations of conventional gene therapy to address Rett syndrome and other devastating disorders."
Rett syndrome is caused by loss of function variants in the MECP2 gene; however, high levels of MeCP2 can lead to toxicity. Conventional, unregulated gene therapy leads to variable cellular uptake that can result in toxic levels of transgene expression. EXACT is a self-regulating circuit contained within a gene therapy cassette and enables therapeutic and tolerable transgene expression on a cell-by-cell basis through regulation by microRNA.
"Gene therapy with transgene regulation holds the potential to treat a variety of dosage-sensitive disorders that currently have no disease-modifying options available," said Stuart Cobb, Ph.D., Chief Scientific Officer of Neurogene, and Professor of Translational Neuroscience at Simons Initiative in the Developing Brain and Centre for Discovery Brain Sciences at the University of Edinburgh. "The development of a potential treatment option for Rett syndrome was the impetus for creating EXACT, and its translation to NGN-401 is a major advancement. I would like to thank my colleagues at the University of Edinburgh, Edinburgh Innovations and Neurogene for their support in the development of EXACT."
Overview of Data
The publication today details a series of preclinical studies that led to the development of NGN-401 and demonstrate more promising safety and efficacy compared to conventional gene therapy:
To design a gene therapy to move forward into clinical testing for Rett syndrome, a series of constructs were designed by modifying individual regulatory elements. In the male knockout model of Rett syndrome that has no MeCP2 expression, NGN-401 was the most effective construct and extended median survival the longest.
In the female murine model of Rett syndrome that has mosaic MeCP2 expression, similar to human females with Rett syndrome, NGN-401 was well-tolerated across all doses evaluated; in comparison, conventional gene therapy resulted in severe toxicity.
In non-human primates, which express normal levels of MeCP2 in all cells and are therefore the most conservative model to evaluate tolerability, all doses of NGN-401 were well-tolerated. Conventional gene therapy resulted in more variable and several-fold higher MECP2 mRNA levels in key tissues compared to NGN-401.
Together, these data provide evidence that EXACT regulates expression across disease and large animal models. The peer-reviewed article, "Self-regulating Gene Therapy for Overcoming Gene Dosage Sensitivity in Rett Syndrome," was published in Science Translational Medicine, a member of the Science family of journals. The article can be accessed from Neurogene’s website at https://ir.neurogene.com.
About Neurogene
The mission of Neurogene is to treat devastating neurological diseases to improve the lives of patients and families impacted by these rare diseases. Neurogene is developing novel approaches and treatments to address the limitations of conventional gene therapy in central nervous system disorders. This includes selecting a delivery approach to maximize distribution to target tissues and designing products to maximize potency and purity for an optimized efficacy and safety profile. The Company’s novel and proprietary EXACT transgene regulation platform technology allows for the delivery of therapeutic levels while limiting transgene toxicity associated with conventional gene therapy. Neurogene has constructed a state-of-the-art gene therapy manufacturing facility in Houston, Texas. CGMP production of NGN-401 was conducted in this facility and will support pivotal clinical development activities. For more information, visit www.neurogene.com.
About NGN-401
NGN-401 is an investigational AAV9 gene therapy being developed as a one-time treatment for Rett syndrome. It is the first clinical candidate to deliver the full-length human MECP2 gene under the control of Neurogene’s EXACT™ transgene regulation technology. EXACT technology is an important advancement in gene therapy for Rett syndrome, specifically because the disorder requires a treatment approach that enables targeted levels of MECP2 transgene expression without causing overexpression-related toxic effects associated with conventional gene therapy.
NGN-401 was selected by the U.S. Food and Drug Administration (FDA) for its START Pilot Program and has also received Regenerative Medicine Advance Therapy (RMAT) designation, orphan drug designation, Fast Track designation and rare pediatric designation from the FDA. Neurogene was previously granted an INTERACT meeting with the FDA regarding the EXACT technology. NGN-401 also received Priority Medicines (PRIME) designation, orphan designation and advanced therapy medicinal product designation from the European Medicines Agency (EMA) and the Innovative Licensing and Application Pathway (ILAP) designation from the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA).
Statements in this press release which are not historical in nature are intended to be, and hereby are identified as, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or financial condition, or otherwise, based on current expectations and beliefs of the management of Neurogene, as well as assumptions made by, and information currently available to, management of Neurogene, including, but not limited to, statements regarding: the therapeutic potential and utility, efficacy and clinical benefits of the EXACT transgene technology generally and specifically in NGN-401; the safety, tolerability and efficacy of NGN-401; and the potential applications of the EXACT transgene technology for future uses, including in potential additional preclinical product candidates. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "anticipate," "plan," "likely," "believe," "estimate," "project," "intend," "on track," and other similar expressions or the negative or plural of these words, or other similar expressions that are predictions or indicate future events or prospects, although not all forward-looking statements contain these words. Forward-looking statements are based on current beliefs and assumptions that are subject to risks, uncertainties and assumptions that are difficult to predict with regard to timing, extent, likelihood, and degree of occurrence, which could cause actual results to differ materially from anticipated results and many of which are outside of Neurogene’s control. Such risks, uncertainties and assumptions include, among other things: risk related to the Company’s ability to obtain regulatory approval for, and ultimately commercialize, its product candidates, including NGN-401; the Company’s ability to successfully create future product candidates using EXACT; the ability to successfully advance any product candidates using EXACT through pre-clinical and clinical development and obtain regulatory and marketing approvals of these product candidates; the potential for competitors to create other therapies that compete with EXACT; and other risks and uncertainties identified under the heading "Risk Factors" included in Neurogene’s Annual Report on Form 10-K for the year ended December 31, 2024, filed with the Securities and Exchange Commission (SEC) on March 24, 2025, and other filings that the Company has made and may make with the SEC in the future. Nothing in this communication should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that the contemplated results of any such forward-looking statements will be achieved. Forward-looking statements in this communication speak only as of the day they are made and are qualified in their entirety by reference to the cautionary statements herein. Except as required by applicable law, Neurogene undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise.
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