AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model.

Summary

In a SMARD1 murine model, two AAV9-IGHMBP2 constructs (CBA and P546 promoters) both rescued survival, weight, motor function, and preserved motor neurons/neuromuscular junctions. RNAseq and histopathology revealed inflammatory changes in SMARD1 spinal cord that normalized after treatment; the P546-promoter vector showed superior long-term efficacy and safety.

Key Findings

• Both AAV9-IGHMBP2 constructs (CBA and P546) rescued survival, body weight, motor function, and preserved motor neurons and neuromuscular junctions.
• Histopathology and RNA sequencing uncovered spinal cord inflammatory marker alterations in SMARD1 for the first time; these normalized after gene therapy.
• The P546-promoter AAV9 construct demonstrated superior long-term efficacy and a better safety profile compared with the CBA-promoter construct.

Clinical Implications

Supports prioritizing promoter-optimized AAV constructs (P546) for translational development toward clinical trials in SMARD1; suggests monitoring and targeting spinal cord inflammation as a biomarker/outcome in future trials.

Limitations

• Preclinical murine model—translation to humans requires larger-animal safety and regulatory studies.
• Exact sample sizes and detailed duration metrics are not provided in the abstract; full-text needed for power assessment.

Future Directions

Proceed to dose-ranging and large-animal safety studies, define immunogenicity and biodistribution of P546 construct, and design first-in-human trial with inflammation biomarkers as endpoints.