{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:29:34Z","timestamp":1790792974031,"version":"4.1.0"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"1","funder":[{"name":"Key Research and Development Project of China","award":["2023YFC2307104"],"award-info":[{"award-number":["2023YFC2307104"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>\n                    Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down the\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    gene 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-based\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    editing. 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 for\n                    <jats:italic toggle=\"yes\">TTR<\/jats:italic>\n                    gene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adu6505","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T18:59:44Z","timestamp":1767380384000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6831-0289","authenticated-orcid":true,"given":"Sixian","family":"Qi","sequence":"first","affiliation":[{"name":"CSPC Pharmaceutical Group Limited, Shijiazhuang, PR China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3789-3979","authenticated-orcid":true,"given":"Lifan","family":"Wei","sequence":"additional","affiliation":[{"name":"CSPC Pharmaceutical 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