Amyloid Transthyretin (ATTR) Cardiomyopathy (CM) is a progressive and fatal disease caused by a variant in the transthyretin (TTR) gene that results in the misfolded protein. TTR protein is primarily synthesized in the liver as a tetrametric protein. In ATTR-CM, TTR tetramers become less stable and dissociate into monomers and fragments that misfold and aggregate into pathogenic amyloid deposits in multiple sites in the body, predominantly in peripheral nerves and the heart. Misfolded proteins can be deposited as amyloid fibrils resulting in amyloid TTR amyloidosis (ATTR) Continued accumulation of amyloid deposits leads to progressive thickening of myocardial walls, impaired diastolic function, heart failure, and death. There are two types of ATTR-CM, hereditary (hATTR-CM) that is caused by an inherited mutation in the TTR gene that causes amyloids to build up and wild type (WT) ATTR-CM that is spontaneous and occurs for no reason. Early diagnosis is the key. Several noninvasive screening methods are available in combination with laboratory testing for the diagnosis of ATTR cardiomyopathy. Multimodality cardiac imaging such as Echocardiography, Electrocardiography and Cardiac MRI are commonly used. A single screening result cannot establish a diagnosis but may be a warning sign of ATTR-CM. Genetic testing could determine if it is hereditary (hATTR) to check the possibility that family members may be affected.



Early therapeutic interventions included inhibition of hepatic synthesis of TTR via pharmacological agents, stabilizing the tetramer or disrupting the amyloid fibrils. These medications can help manage the condition to help prevent heart failure. Attruby (acoramidis) is an FDA approved drug that is a novel TTR stabilizer used in the treatment of ATTR-CM. Acoramidis binds the tetrameric form of TTR and prevents its dissociation into dimers and monomers. VYNDAMAX® is a medication that can slow the buildup of faulty proteins, helping to prevent heart failure.







Advancements in gene editing technologies such as CRISPR-Cas9 and RNA therapeutics such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO) that block the liver TTR expression are being tested in several clinical trials. An investigational therapy, NTLA-2001 in Phase I trials is being evaluated targeting the TTR gene via gene editing strategy. Intellia Therapeutics designed NTLA-2001 based on CRISPR/Cas9 technology to inactivate the TTR gene, thereby preventing the production of harmful protein. Delivered systemically via a proprietary non-viral LNP platform, NTLA-2001 has demonstrated consistent, deep, and long-lasting reductions in TTR protein levels in interim Phase 1 clinical data. Importantly, re-dosing with CRISPR has shown an additive effect, further highlighting the potential of this approach. NTLA-2001 is currently being evaluated in patients with both ATTR-CM and ATTRv-PN (polyneuropathy).



The clinical landscape for ATTR-CM is rapidly evolving, with RNA interference technologies driving a new wave of mRNA-targeted therapies into clinical trials.





RNAi (interference) is emerging as a new class of medicines to silence or turn-off specific genes at RNA level. RNAi is a revolutionary approach that leverages the body's natural gene silencing mechanism. This biological process involves small interfering RNAs (siRNAs), short double-stranded RNA molecules that target and destroy specific messenger RNAs (mRNAs). These mRNAs carry genetic instructions from DNA, ultimately directing protein synthesis. Within cells, siRNAs are incorporated into the RNA-induced silencing complex (RISC). This complex unwinds the siRNA, retaining a single strand that acts as a guide to locate and bind to complementary disease-causing mRNAs. Once bound, RISC functions like molecular scissors, cleaving the target mRNA, thereby preventing the production of the corresponding harmful protein. Importantly, a single siRNA-loaded RISC can degrade multiple mRNA copies, making this a highly efficient and catalytic process for gene silencing and a promising avenue for developing novel disease treatments. Based on this technology Alnylam Pharmaceuticals developed 'Vutrisiran' an investigational RNAi therapy that is showing promising results for ATTR-CM in Phase III clinical trials.



Apart from gene editing and RNA interference, novel antibody therapies are being developed for ATTR-CM to target the disease at protein level. Antibody therapies are designed to specifically target and remove the misfolded, disease-causing forms of the transthyretin (TTR) protein. Currently in clinical trials, these therapies aim to address the underlying cause of ATTR-CM by depleting these harmful amyloid deposits.



The development of ATTR-Cardiomyopathy therapies is a testament to the power of modern medicine. By harnessing cutting-edge technologies like gene editing, RNA interference, and antibody engineering, researchers are bringing hope to patients and families affected by this devastating disease. These innovative approaches offer the promise of transformative treatments that could significantly improve the lives of individuals living with ATTR-Cardiomyopathy.