Science advancesJan 2, 2026

Using a highly precise and widely compatible Cas9 variant to target transthyretin

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A redesigned SpCas9 variant, SpCas9-Mut5, may improve the fidelity of TTR genome editing while preserving on-target activity.

Evidence

This genome-editing platform study systematically compared SpCas9-based TTR editing, designed structural variants, and tested SpCas9-Mut5 with nuclease and adenine base editor systems for off-target edits, translocations, and editing-window effects.

Caveat

The abstract reports editing performance rather than clinical treatment outcomes for ATTR amyloidosis, so therapeutic safety and efficacy remain unproven.

Simplified

Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down thegene by CRISPR-Cas9 represents a promising strategy for treating ATTR amyloidosis, its efficiency and safety remain to be further investigated. Here, we report a systematic investigation of SpCas9-basedediting. Besides the target site, wild-type SpCas9 and the reported variants induced extensive off-target edits. To improve the fidelity, we performed structural analysis and designed a series of SpCas9 variants. Studies demonstrated that SpCas9-Mut5 is an ultrahigh-fidelity variant, which induces extremely low levels of off-target edits and translocations without substantial impairment of on-target editing activity. SpCas9-Mut5 is compatible with the adenine base editor (ABE) system, markedly reducing off-target edits and narrowing the editing window. In conclusion, our study suggests that SpCas9-Mut5 is an excellent candidate forgene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases. TTR TTR TTR

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Using a highly precise and widely compatible Cas9 variant to target transthyretin

Abstract

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