A review article recently published in Heart Failure Reviews details the mechanisms, risks and benefits of gene-modulating therapies for transthyretin amyloid cardiomyopathy (ATTR-CM). Although none of the drugs have received approval by the U.S. Food & Drug Administration (FDA) for use in ATTR-CM yet, several have entered clinical trials, with positive outcomes reported.
Gene‑modulating therapies treat disease by changing the expression of a gene. “Gene-modulating therapies represent a transformative advancement in the management of ATTR-CM, offering disease-modifying strategies that target the root cause of the disease,” the authors wrote.
Antisense oligonucleotides (ASOs) are one group of therapies that work by binding to transthyretin messenger RNA, preventing the mutated gene from being translated into protein.
Inotersen, an ASO drug, was approved by the FDA and the European Commission in 2018 for use in patients with hereditary transthyretin amyloid polyneuropathy (hATTR-PN), but has since been removed from the market due to a lack of sales. Eplontersen, another ASO therapy, received approval for use in hATTR-PN and has shown promise in ATTR-CM. Challenges of ASOs include the potential for off-target effects, though advancements have been made to minimize these effects.
Read more about ATTR-CM therapies
The study also covered small interfering RNA (siRNA), a double-stranded RNA molecule that binds to transthyretin messenger RNA and marks it for degradation. A clinical trial studying the efficacy of revusiran was terminated due to elevated mortality as a result of heart failure. Patisiran and vutrisiran, on the other hand, have shown favorable outcomes compared to a placebo in clinical trials. Like ASOs, though, siRNA therapies face challenges related to tissue specificity and delivery.
Lastly, the authors discussed CRISPR-Cas9 technology, an approach that directly edits the transthyretin gene itself. One therapy, nex-z, entered a Phase 1 trial and was shown to be effective and well-tolerated. CRISPR-Cas9 gene editing raises questions surrounding ethics, long-term safety and the potential for irreversible off-target effects, though.
“The dynamic evolution of ATTR-CM therapies highlights the potential for more effective treatments, paving the way for improved patient outcomes in this population,” the study concluded.
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