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While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches. Small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies effectively reduce TTR production and have demonstrated promising clinical outcomes, though their use in cardiac amyloidosis remains investigational. CRISPR-Cas9 therapies represent a paradigm shift, offering a potential one-time treatment by permanently silencing the TTR gene. Recent clinical trials have shown significant TTR reduction and stabilization of disease biomarkers, although long-term safety and efficacy require further evaluation. Despite the lack of direct comparisons among these modalities, their emergence highlights a promising future for ATTR-CM management. This review discusses the pathogenesis of ATTR-CM, mechanisms of novel gene-modulating therapies, clinical evidence, challenges, and the future outlook for advancing treatment options.<\/jats:p>","DOI":"10.1007\/s10741-025-10502-5","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T04:12:23Z","timestamp":1741407143000},"page":"759-770","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy"],"prefix":"10.1007","volume":"30","author":[{"given":"Song Peng","family":"Ang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Ee","family":"Chia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debabrata","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"10502_CR1","doi-asserted-by":"crossref","unstructured":"Writing Committee; Kittleson MM, Ruberg FL, Ambardekar AV, Brannagan TH, Cheng RK et al (2023) 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology Solution Set Oversight Committee. 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