Recent advancements in understanding transthyretin amyloid cardiomyopathy (ATTR-CM) are transforming its treatment landscape, according to a review article published recently in the Polish Heart Journal.
ATTR-CM, a progressive condition caused by deposits of misfolded transthyretin protein in the heart, has traditionally relied on limited therapeutic options such as tafamidis to stabilize transthyretin tetramers.
What is ATTR-CM?
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare progressive disease of the heart muscle that leads to congestive heart failure. It occurs when the transthyretin protein produced by the liver is unstable. Symptoms include fatigue; shortness of breath; irregular heart rate or palpitations; swelling of the legs, ankles and stomach; brain fog; wheezing; and dizziness. It often goes underdiagnosed because of a lack of awareness and knowledge of the disease. There is currently no cure for ATTR-CM.
But the emergence of RNA-silencing technologies, gene-editing methods and innovative stabilization therapies has brought new hope for managing this challenging disease. Patients may benefit from these breakthroughs, which promise to slow disease progression and enhance quality of life.
Read more about ATTR-CM therapies
“By integrating advanced therapies and innovative approaches, the future of ATTR-CM management looks increasingly promising,” the article authors said.
Therapies to treat ATTR-CM share similarities with those of other amyloid-related disorders, such as their reliance on understanding protein misfolding and the mechanisms of deposition. Therapies now in development aim to address the disease at multiple stages.
For example, RNA-silencing treatments such as vutrisiran and eplontersen target the production of transthyretin protein at its source, reducing its synthesis in the liver. Clinical trials, such as HELIOS-B and CARDIO-TTRansform, are evaluating these approaches, offering patients a potential reduction in amyloid burden with improved cardiac outcomes.
Gene-editing technologies, particularly CRISPR/Cas9, have garnered attention for their groundbreaking ability to modify the genetic code responsible for ATTR-CM. This technique has shown promise in preclinical studies and clinical trials, including the MAGNITUDE study with NTLA-2001. Single-dose treatments aim to halt disease progression by editing the genes responsible for transthyretin production, potentially offering lasting benefits for patients.
In addition to prevention, therapies targeting amyloid degradation and removal are under investigation. Monoclonal antibodies such as ALXN2220, alongside other agents such as doxycycline and green tea-derived epigallocatechin-3-gallate, show potential for breaking down amyloid deposits. These treatments could complement existing approaches by addressing established cardiac damage caused by protein accumulation.
“A personalized approach is essential for optimizing outcomes in ATTR-CM,” the authors said.
Patients may soon benefit from next-generation stabilizers such as acoramidis, which demonstrated success in the ATTRibute-CM trial. Unlike earlier options, these therapies target transthyretin with improved precision and efficacy.
Researchers are also exploring novel therapies including seeding inhibitors and molecular tweezers to prevent amyloid formation before it begins.
While the advances bring optimism, challenges remain, such as ensuring safety and accessibility for patients. As clinical trials progress, the potential for transformative outcomes grows, signaling a new era of hope for those living with ATTR-CM.
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