December 11, 2023

Technology Development

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Neurogene Announces New Development Program in Rett Syndrome Utilizing Novel EXACT Technology Platform

NEW YORK–(BUSINESS WIRE)–Neurogene Inc., a company founded on the vision to push the boundaries of genetic medicine to address complex and devastating neurological diseases, announced the addition of NGN-401 for Rett syndrome to the Company’s development pipeline. NGN-401 is Neurogene’s first product candidate using the Expression Attenuation via Construct Tuning (EXACT) gene regulation platform technology, and has shown in preclinical models to deliver efficacious levels of MeCP2, while avoiding toxicity observed with conventional MECP2 gene therapy. EXACT is a self-regulating gene therapy platform technology that can be tuned to deliver a desired level of transgene expression within a narrow range, and is compatible with viral and non-viral delivery platforms.

Preclinical efficacy and safety data for NGN-401 were presented today at the 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Washington, D.C., in an oral presentation of the abstract entitled, “A Self-regulating Gene Therapy for Rett Syndrome.” NGN-401 delivers a full-length human MECP2 transgene, which is under the control of Neurogene’s EXACT self-regulating technology.

“Rett syndrome is a complex disorder not readily addressable by conventional gene therapy because the MECP2 gene is toxic if expressed at high levels. As someone who has been working in Rett syndrome research for more than 15 years, I am pleased that NGN-401, our lead program utilizing EXACT technology, has demonstrated a significant survival benefit and reduced disease burden in a robust preclinical Rett model,” said Stuart Cobb, Ph.D., Neurogene’s Chief Scientific Officer and a Simons Fellow and Reader in Neuroscience at the Patrick Wild Centre and Centre for Discovery Brain Sciences, at the University of Edinburgh. “These data, along with a substantial body of additional preclinical data are foundational to advancing NGN-401 to the clinic for Rett syndrome.” Dr. Cobb’s laboratory has been collaborating with the Rett Syndrome Research Trust (RSRT) and numerous researchers in the field to develop a gene therapy with a strong profile to advance to the clinic.

Neurogene is grateful for RSRT’s support in advancing the scientific knowledge for the treatment of Rett syndrome, which ultimately enabled the early development of the EXACT technology. Neurogene is also appreciative of the broader Rett syndrome patient community, including the International Rett Syndrome Foundation and Reverse Rett (UK).

Monica Coenraads, CEO of the Rett Syndrome Research Trust (RSRT) shared, “We are thrilled that NGN-401 has demonstrated promising preclinical results. RSRT’s long-term support of Dr. Cobb’s laboratory at the University of Edinburgh demonstrates our commitment to drive innovation in research for Rett Syndrome. We hope this novel approach will continue to advance in its development and ultimately provide a much-needed treatment option for families impacted by Rett syndrome.”

ASGCT Presentation Details

NGN-401 showed a significant improvement in survival and disease clinical score at both doses that were evaluated in a Rett male mouse model. Cohorts treated with either 1E11vg or 3E11vg of NGN-401 had a median survival of approximately 23 weeks and 37 weeks, respectively, compared to untreated mice with a median survival of approximately 9 weeks. Moreover, mice treated with comparable doses of conventional gene therapy, lacking the EXACT technology, showed significant toxicity and early mortality.

In a separate study using the mosaic female Rett mouse model, NGN-401 treated cohorts showed a normal phenotype with no toxicity at comparable doses employed in the male study. In contrast, conventional gene therapy treated female mice at these doses led to significant toxicity and early death.

Taken together, these data demonstrate that NGN-401 treatment led to a clear efficacy benefit in the severe Rett male knock out mouse model while demonstrating safety in the female model.

About Rett Syndrome

Rett syndrome is an X-linked, progressive, neurodevelopmental disorder. Rett syndrome has an estimated incidence of 1 in 10,000 live female births, making it one of the most common genetic causes of developmental and intellectual impairment in females. The incidence in males is currently unknown.

Rett syndrome is caused by a mutation in the MECP2 gene that leads to deficiency of the methyl cytosine binding protein 2 (MeCP2), an important protein responsible for normal neural development and signaling in the brain and other parts of the nervous system. Females with Rett syndrome typically acquire early gross motor skills such as rolling and sitting with support up until 6-18 months of age. However, females then experience rapid regression of previously acquired milestones including speech, gross and fine motor skills, and develop stereotypical, repetitive hand movements that prevent them from purposeful hand movement or function. Over time females may develop muscle contractures, rigidity, and debilitating scoliosis, along with periods of recurrent seizures, burdensome gastrointestinal abnormalities, breathing abnormalities and cognitive decline.

Currently, there are no approved disease-modifying therapies, and treatment for Rett syndrome includes symptom management and supportive care.

About Neurogene Inc.

Neurogene’s mission is to turn devastating neurological diseases into treatable conditions to improve the lives of patients and families impacted by these rare diseases. Neurogene is working on cutting edge science to address limitations of conventional gene therapy in CNS disorders by selecting a delivery approach to maximize distribution to target tissues, designing products to maximize potency and purity for an optimized efficacy and safety profile, and using the company’s novel EXACT gene regulation platform technology for complex disorders to deliver therapeutic levels while limiting transgene toxicity associated with conventional gene therapy. For more information, visit