High-throughput transcriptome analyses from ASPIRO, a phase 1/2/3 study of gene replacement therapy for X-linked...

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• X-linked myotubular myopathy (XLMTM) is a severe congenital muscle disorder with no current approved therapies.
• Adeno-associated virus (AAV)-mediated gene replacement therapy is an investigational approach for XLMTM.

Purpose of the Study:

• To analyze transcriptomic changes in XLMTM patients treated with resamirigene bilparvovec (AT132).
• To identify potential RNA biomarkers correlating with therapeutic outcomes in XLMTM gene therapy.

Main Methods:

• RNA sequencing of muscle biopsies from 15 XLMTM participants at baseline, 24, and 48 weeks post-treatment.
• Differential gene expression analysis, gene co-expression analysis, and machine learning.

Main Results:

• MTM1 expression significantly increased post-treatment (p < 0.0001).
• Upregulated genes involved lipid metabolism and inflammation; downregulated genes involved cell adhesion and muscle development.
• Differential expression in inflammatory/immune pathways correlated with ventilator support reduction.
• Machine learning identified five genes, including MTM1, as potential RNA biomarkers.

Conclusions:

• Resamirigene bilparvovec treatment alters transcriptomic profiles in XLMTM muscle.
• Transcriptomic analysis provides insights into AAV gene therapy mechanisms and outcomes in XLMTM.
• Identified biomarkers may aid in monitoring XLMTM gene therapy progress.