Researchers Identify Optimized AAV9 Vector for Long-Term Treatment of Fatal Neuromuscular Disorders SMARD1 and CMT2S

January 5, 2026- A pivotal study led by the Pagliari research group and published in the Journal of Biomedical Science has established a new benchmark for treating the rare, life-altering genetic conditions Spinal Muscular Atrophy with Respiratory Distress 1 (SMARD1) and Charcot-Marie-Tooth Disease type 2S (CMT2S). The research demonstrates that optimized adeno-associated virus serotype 9 (AAV9) vectors can provide sustained therapeutic benefits while maintaining a superior long-term safety profile in preclinical models.

Advancing the AAV9 Delivery Platform

SMARD1 and CMT2S are caused by mutations in the IGHMBP2 gene, leading to progressive motor neuron loss and respiratory failure. While gene therapy has long been viewed as a potential cure, the challenge has been finding a delivery vehicle that can safely reach the central nervous system and remain effective for years.

AAV9 has emerged as the vector of choice for these conditions due to its unique ability to cross the blood-brain barrier and transduce non-dividing cells like neurons. The Pagliari study meticulously compared different AAV9 variants, focusing on:

• Durability: Ensuring the therapeutic gene remains active as the patient ages.

• Immunogenicity: Minimizing the risk of the body’s immune system rejecting the viral vector.

• Safety: Analyzing off-target effects and systemic tolerance over extended periods.

Key Highlights:

• Therapeutic approach: Intracerebroventricular (ICV) delivery of two AAV9-IGHMBP2 constructs using different promoters (CBA vs. P546) was evaluated in a SMARD1 mouse model.

• Efficacy: Both constructs significantly extended survival, improved body weight and motor function, and preserved motor neurons and neuromuscular junctions.

• Neuroinflammation insight: For the first time, spinal cord inflammatory signatures were identified in SMARD1 and shown to resolve following gene therapy, including reductions in astrogliosis and microgliosis.

• Comparative outcome: The P546 promoter construct demonstrated superior long-term efficacy and a more favorable safety profile compared to the CBA-driven vector.

• Translational relevance: These findings support ICV AAV9-based gene therapy as a viable strategy for SMARD1 and related neuromuscular disorders, with construct design playing a key role in durability and safety.

A Critical Shift Toward Clinical Translation

The research highlights that the selection of specific vector components—such as the promoter that “switches on” the gene—is critical for success. The team identified an optimized AAV9 construct that enabled prolonged therapeutic effects, effectively slowing the progressive degeneration characteristic of these diseases.

“The significance of vector selection cannot be overstated,” the report notes. The study’s systematic approach to safety assessments, including the tracking of immune responses, provides a robust data set that will be essential for navigating the complex regulatory pathway toward human clinical trials.