Progress and Future Trends in Quality Control of Gene Therapy Products
ZHANG Jianping1,2#, ZHANG Yangyang1,2#, ZHANG Xiaobing1,2*
This review outlines an end-to-end QC (quality control) framework for gene therapies from development to clinic. For AAV (adeno-associated virus) and LV (lentiviral vector), CQAs (critical quality attributes) are synthesized: empty/full ratios, vector-genome integrity, ITR (inverted terminal repeat)-associated defects and exogenous DNA impurities for AAV; and genome-wide integration profiles, full-length integrant structures, and clonal dynamics for LV. Building on first-generation CRISPR clinical experience, detection and mitigation of offtargets and large deletions are addressed, extending to accuracy profiling and delivery strategies for BE (base editing) and PE (prime editing). Methodologically, a long-read sequencing-anchored paradigm integrated with ddPCR (droplet digital PCR), rFC (recombinant factor C assay)/MAT (monocyte activation test), functional readouts, and immunology/distribution assessments is advocated to establish a verifiable “methods-metrics-process-clinical outcomes” evidence loop. On the regulatory side, converging FDA/EMA/CDE expectations for deep molecular characterization and long-term follow-up are summarized. Looking forward, targeted LNP (lipid nanoparticle)/VLP (virus-like particle) for in-vivo programming, routine QC powered by long-read platforms and data intelligence, and the fusion of continuous manufacturing with online process analytical technologies are highlighted, enabling safer, auditable, and scalable gene therapy translation.
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