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Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA\u2010targeting therapeutics ALN\u2010CC5, ARO\u2010C3, and IONIS\u2010FB\u2010LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.<\/jats:p>","DOI":"10.1111\/imr.13149","type":"journal-article","created":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T08:45:10Z","timestamp":1668242710000},"page":"402-419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway"],"prefix":"10.1111","volume":"313","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5904-0961","authenticated-orcid":false,"given":"Anna K","family":"Dreismann","sequence":"first","affiliation":[{"name":"Gyroscope Therapeutics Limited  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M","family":"Hallam","sequence":"additional","affiliation":[{"name":"Gyroscope Therapeutics Limited  London 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