NGN-401, a novel gene therapy approach, aims to address the underlying genetic cause of RTT by delivering a functional copy of MECP2 using an adeno-associated virus (AAV) vector.

Rett syndrome, predominantly affecting females, is characterized by early developmental regression, loss of purposeful hand use, gait abnormalities, and a range of motor, autonomic, and cognitive impairments. Current treatments are symptomatic, emphasizing the urgent need for disease-modifying therapies. Gene therapy offers a promising avenue, with NGN-401 at the forefront of this innovative therapeutic approach.

Mechanism of Action NGN-401 employs an engineered AAV9 vector to deliver a functional MECP2 transgene into neurons. The vector is designed to cross the blood-brain barrier (BBB), allowing systemic delivery to central nervous system (CNS) cells. To mitigate the risks of MECP2 overexpression, which can be neurotoxic, NGN-401 incorporates a regulated promoter system that mimics physiological expression levels. The key features include:

• Tropism: AAV9's natural affinity for neurons and glial cells ensures efficient targeting.

• Promoter Regulation: Fine-tuned expression under neural-specific promoters reduces risks of toxicity.

• Delivery Efficiency: Intrathecal or intravenous administration achieves widespread CNS distribution.

Preclinical Data Studies in MECP2-deficient mouse models demonstrated significant improvements in motor coordination, respiratory function, and longevity following NGN-401 administration. Key findings include:

1. Behavioral Recovery: Treated mice displayed enhanced exploratory behavior and motor skills.

2. Histological Findings: Restoration of MECP2 expression normalized dendritic spine morphology and synaptic density.

3. Safety Profile: Dose-escalation studies confirmed minimal off-target effects and no evidence of systemic toxicity.

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