Chemically ligated guide RNA (LgRNA) is highly compatible with the Individualized Feature Space (IFS) framework in the FDA’s October 2026 draft guidance. By joining a short, readily purified crRNA segment (~32 nt) to a constant scaffold via non-nucleotide linkers, LgRNA confines sequence variation to a single, high-purity oligonucleotide. Consequently, introducing a new product variant within the IFS requires only synthesis and purification of a new spacer-containing crRNA, not resynthesis of a full-length guide. This modular architecture eliminates the sequence-dependent impurity profiles, chromatographic challenges, and extensive method re-validation that accompany both continuous solid-phase and chemoenzymatic production of full-length sgRNA. At the same time, chemical ligation remains fully tolerant of therapeutic modifications and unrestricted in split-site selection, delivering product free of detectable truncated spacers and enabling robust, predictable CMC control across the entire IFS.
FDA. Individualized Human Genome Editing Products: Considerations for BLA Submission and Postapproval Management (Draft Guidance). October 2026. FDA-2026-D-11783.
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