Neurogene Announces Peer-Reviewed Publication Demonstrating Gene Therapy Candidate NGN-401 with EXACT™ Technology Regulates Transgene Expression in Preclinical Models of Rett Syndrome

Rhea-AI Summary

Neurogene (NASDAQ: NGNE) has published peer-reviewed data in Science Translational Medicine demonstrating the effectiveness of its EXACT™ transgene regulation technology in preclinical models of Rett syndrome. The study supports their ongoing Phase 1/2 clinical trial of NGN-401, their gene therapy candidate.

The research shows EXACT's capability to regulate gene therapy expression to therapeutic and tolerable levels, addressing a key challenge in treating Rett syndrome, which requires careful regulation of MeCP2 levels. The technology is designed to overcome limitations of conventional gene therapy, which can result in toxic levels of transgene expression.

In preclinical studies, NGN-401 demonstrated:

• Extended median survival in male knockout models
• Good tolerability across all doses in female murine models
• Well-tolerated results in non-human primates
• More controlled MECP2 mRNA levels compared to conventional gene therapy

Positive

• Successfully demonstrated regulated gene therapy expression in preclinical models
• Ongoing Phase 1/2 clinical trial for NGN-401
• Superior safety profile compared to conventional gene therapy in animal models
• Publication in prestigious peer-reviewed journal validates technology

Negative

• Technology still in early clinical stages with unproven human efficacy
• Requires careful dosing control to avoid MeCP2 toxicity

Insights

Biotechnology Research Analyst

Neurogene has achieved a significant milestone with the publication of preclinical data for NGN-401 in Science Translational Medicine, validating their EXACT™ transgene regulation technology for Rett syndrome. This peer-reviewed validation represents a material scientific advancement in gene therapy technology.

The data demonstrates a critical technological differentiation - EXACT™ solves the fundamental challenge of dosage sensitivity in gene therapy by enabling precise transgene expression regulation on a cell-by-cell basis. For Rett syndrome specifically, the technology maintains therapeutic levels of MeCP2 protein while avoiding toxicity that occurs with overexpression.

The publication highlights three compelling advantages versus conventional gene therapy approaches:

• Extended median survival in male knockout models lacking MeCP2
• Superior tolerability across all doses in female murine models with mosaic MeCP2 expression
• Well-tolerated administration in non-human primates with normal MeCP2 levels

Most importantly, these preclinical results have already translated into clinical development, supporting Neurogene's ongoing Phase 1/2 trial for NGN-401. Beyond Rett syndrome, this platform technology potentially expands Neurogene's addressable market to other dosage-sensitive disorders currently considered unsuitable for conventional gene therapy approaches.

Genetic Medicine Specialist

The Neurogene publication represents a potentially significant breakthrough in addressing one of gene therapy's most persistent challenges - the inability to precisely control transgene expression levels. The EXACT™ technology employs microRNA-based regulation to create a self-regulating circuit within the gene therapy vector itself, essentially enabling each transduced cell to adjust its own expression levels.

For Rett syndrome, this approach tackles a fundamental biological constraint. While the disorder results from MECP2 loss-of-function variants, excessive MeCP2 protein is equally problematic due to narrow therapeutic window. Conventional gene therapy approaches face a classic Goldilocks problem: too little protein maintains disease, too much causes toxicity.

The preclinical data demonstrates three crucial technical achievements:

• Cell-autonomous regulation that adjusts expression based on individual cellular context
• Reduced expression variability compared to conventional approaches
• Maintenance of therapeutic efficacy while eliminating dose-limiting toxicities

The translation to non-human primates is particularly noteworthy, as these models express normal MeCP2 levels, creating the highest risk for overexpression toxicity. The tolerability in this model suggests potential clinical safety for human translation. This publication validates years of technological development work and positions Neurogene's platform as potentially applicable to multiple genetic disorders where precise dosage control is essential.

Data demonstrate EXACT has potential to overcome limitations of conventional gene therapy for dosage-sensitive disorders

Findings published in Science Translational Medicine

NEW YORK--(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).

Cautionary Note Regarding Forward-Looking Statements

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.

This communication contains hyperlinks to information that is not deemed to be incorporated by reference into this communication.

View source version on businesswire.com: https://www.businesswire.com/news/home/20250402886880/en/

Company Contact:

Cara Mayfield

Vice President, Corporate Affairs

cara.mayfield@neurogene.com



Investor Contact:

Melissa Forst

Argot Partners

Neurogene@argotpartners.com

Source: Neurogene Inc.

FAQ

What are the key findings of Neurogene's (NGNE) EXACT technology in Rett syndrome treatment?

EXACT technology demonstrated regulated gene therapy expression to therapeutic levels, showing better safety and efficacy than conventional gene therapy in preclinical models, with extended survival in male models and good tolerability across all doses in female models.

How does Neurogene's NGN-401 differ from conventional gene therapy for Rett syndrome?

NGN-401 uses EXACT technology to self-regulate transgene expression on a cell-by-cell basis, preventing toxic levels of MeCP2, while conventional gene therapy leads to variable cellular uptake and potential toxicity.

What results did NGNE's NGN-401 show in non-human primate studies?

NGN-401 demonstrated good tolerability across all doses in non-human primates and showed more controlled MECP2 mRNA levels compared to conventional gene therapy.

Where was Neurogene's (NGNE) EXACT technology research published?

The research was published in Science Translational Medicine in a peer-reviewed article titled 'Self-regulating Gene Therapy for Overcoming Gene Dosage Sensitivity in Rett Syndrome.'