Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing; Draft Guidance for Industry

Diane Castillo, an independent scientist, argues that the proposed guidance is too permissive and fails to account for the stochastic and unpredictable nature of genome editing. She advocates for requiring single-cell long-read whole genome sequencing (scLRWGS) to detect large structural variants and off-target events that current short-read and targeted methods miss.

SeQure, a contract research organization, supports the draft guidance and suggests specific improvements regarding minimum sensitivity for off-target confirmation, the inclusion of optical genome mapping for structural variations, and the recommendation of insertion site analysis for certain payloads. They also advocate for high-throughput biochemical assays to account for human genetic variation and editor-specific nomination strategies.

Dr. Kristiina Vuori, a physician-scientist and professor at the Sanford Burnham Prebys Medical Discovery Institute, supports the draft guidance but recommends explicitly including Optical Genome Mapping (OGM) as an orthogonal method. She argues that OGM provides essential capabilities for detecting large structural variants and chromosomal rearrangements that Next-Generation Sequencing (NGS) may miss.

The commenter supports the FDA's draft guidance on genome editing safety assessments but requests that the final document explicitly include Optical Genome Mapping (OGM) as a recommended orthogonal tool. They argue that OGM is superior to Next-Generation Sequencing (NGS) for detecting large-scale structural variants and maintaining chromosomal integrity.

James Adams supports the draft guidance but urges the FDA to include Optical Genome Mapping (OGM) as a complementary methodology to Next-Generation Sequencing (NGS). He argues that OGM is necessary to detect large-scale structural variations and maintain genomic integrity that NGS might miss.