Neurogene Announces Peer-Reviewed Publication Demonstrating Gene Therapy Candidate NGN-401 with EXACT™ Technology Regulates Transgene Expression in Preclinical Models of Rett Syndrome
Data demonstrate EXACT has potential to overcome limitations of conventional gene therapy for dosage-sensitive disorders
Findings published in Science Translational Medicine
“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
Overview of Data
The publication today details a series of preclinical studies that led to the development of
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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 toNGN-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
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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
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Company Contact:
Cara Mayfield
Vice President, Corporate Affairs
cara.mayfield@neurogene.com
Investor Contact:
Melissa Forst
Argot Partners
Neurogene@argotpartners.com
Source: Neurogene Inc.