Introduction
Transthyretin (TTR) is a highly conserved protein that is the most prevalent subtype of hereditary amyloidosis. TTR is involved in transportation of thyroxine and retinol-binding protein. It is mainly synthesized in liver, is rich in beta strands, and aggregates into insoluble amyloid fibres¹ that deposit in tissue causing TTR-related amyloidosis (ATTR). ATTR can deposit in either variant or wild-type forms. Mutations in the TTR gene result in peripheral and/or autonomic neuropathy and other systemic manifestations, mainly cardiomyopathy. The V122I variant is the most common mutation associated to cardiomyopathy in the United States and is found in 3.4% of African Americans.² The diagnosis of ATTR is based on cardiac abnormalities including intracardiac conduction disorders, symptoms of dysautonomia, ruptured distal biceps tendon, and carpal tunnel syndrome. Compared with light chain amyloidosis, cardiac ATTR has a favorable survival rate, with a median survival of 75 months versus 11 months.³ ATTR is a progressive disease, and very limited therapeutic options exist. Recently, new significant treatments for ATTR have emerged, including tafamidis (positive phase 3 clinical trial), patisiran,⁴ and inotersen.⁵ This review describes the treatments available for ATTR and recent developments associated with them.

Clinical Manifestation
The clinical presentation of wild-type cardiac ATTR is left ventricular (LV) hypertrophy with symptoms of breathlessness, reduced exercise tolerance, fatigue, lower extremities/abdominal swelling, and early satiety. Wild-type cardiac ATTR was identified in 13% of elderly patients (>60 years old), and bilateral carpal tunnel syndrome frequently presents many years before the development of cardiac symptoms.⁶ The clinical symptoms of variant cardiac ATTR vary extensively from neurological‐predominant phenotype to cardiac‐predominant phenotype. The clinical features depend on the specific TTR mutation site, geographical distribution, inheritance pattern, timing of onset, and epidemic/non‐epidemic aggregation. Some mutation induces progressive peripheral sensory‐motor polyneuropathy; other mutations cause exclusively infiltrative cardiomyopathy.⁷

Diagnosis
The diagnosis of amyloid heart disease begins with a visualization of the two-dimensional echocardiogram in conjunction with the electrocardiogram.⁸ A combination of low voltage on electrocardiogram and increased LV wall thickness on echocardiogram is indicative of amyloid heart disease.⁹ Regional strain imaging, cardiac magnetic resonance imaging (CMRI), and nuclear imaging such as 99mTc-DPD and 99mTc-PYP scintigraphy are useful techniques for early detection of ATTR in patients.¹⁰ Endomyocardial biopsy is considered the definitive diagnostic method for cardiac amyloidosis.

Specific Treatments Available for ATTR

Liver Transplantation
Liver transplantation alone or in combination with heart transplantation has been used to eradicate the main source of precursor TTR. Survival rates of over than 50% in 20 years have been reported in patients with Val30Met mutation after liver transplantation.¹¹ The main documented limitations of the technique are lack of donors, the need for chronic immunosuppression, and advanced age. These limitations initiated the development of many drugs.

Inhibition of TTR Synthesis
The use of small interfering RNA and antisense oligonucleotide drugs showed suppression of TTR synthesis in liver.

• Small interfering RNA. Patisiran (ALN-TTR02) is an investigational RNA interference drug that targets a sequence of messenger RNA conserved across wild-type and all TTR variants and thus decreases serum levels of both wild-type and pathogenic (mutated) protein. The drug reduces TTR production by 80%.¹² Phase 2 of the drug trial showed stable echocardiographic, functional, and analytical parameters at 12 months and 24 months. Patisiran was also approved by the European Commission for the treatment of hereditary ATTR in adults with stage 1 or stage 2 polyneuropathy on the basis of significant improvements in the phase 3 clinical trial APOLLO (The Study of an Investigational Drug, Patisiran [ALN-TTR02], for the Treatment of Transthyretin [TTR]-Mediated Amyloidosis).¹³
• Antisense oligonucleotide drugs. Antisense oligonucleotide drugsare short strands of oligonucleotides that bind to RNA and prevent translation. There are preliminary data from an open-label phase 2 trial of ISIS-TTRRX (subcutaneous antisense oligonucleotide). The study revealed that 22 heart disease patients with wild-type and mutated ATTR who received weekly ISIS-TTRRX injections showed a favourable safety profile.¹⁴

Stabilization of TTR
Dissociation of the TTR tetramer into subunits is important step that leads to ATTR fibril formation. Therapies such as tafamidis and diflunisal for mutated ATTR aim to stabilise the TTR tetramer.

• Tafamidis. Recent data show that at least 60% of participants achieved neurologic stability after more than 4 years of follow-up. Another phase 3 study demonstrated that administration of tafamidis in two different doses (20 mg and 80 mg daily) in wild-type or mutated cardiac ATTR resulted in lower rates of cardiovascular-related hospitalisations, all-cause mortality, and drop in functional capacity compared to a placebo group.¹⁵
• Diflunisal. Diflunisal is nonsteroidal anti-inflammatory drug that binds to the thyroxine-binding sites of tetrameric TTR, leading to decreases in dissociation, misfolding, and subsequent formation of amyloid fibril. A double-blind, randomized controlled trial conducted using 500 mg of diflunisal reduced the rate of progression of neurological impairment and preserved quality of life compared to placebo.¹⁶ However, evidence of diflunisal in patients with ATTR is scant.
• Tolcapone. Tolcapone is a catechol-O-methyltransferase inhibitor that binds to the thyroxine-binding pocket at the TTR dimer-dimer interface and is a stronger aggregation inhibitor than tafamidis.¹⁷ It has the capacity to bind in vitro to the TTR tetramer in patients with wild-type ATTR and V122I mutation with higher affinity than other stabilizers.
• AG10. AG10 has a similar motif to the thyroxine-binding site of the Thr119Met variant and binds to TTR tetramer to inhibit TTR dissociation. A randomized, double-blind, phase 2 study confirmed the safety and efficacy of AG10 in patients with cardiac ATTR (wild type or variant).¹⁸ It protects cardiomyocytes from the proteotoxic effects of amyloidogenic V122I TTR in vitro.

Elimination of Amyloid Deposits

• Doxycycline and tauroursodeoxycholic acid. The combination of doxycycline and tauroursodeoxycholic acid decreased TTR tissue deposition and serum amyloid P in ATTRV30M amyloidosis mouse models.¹⁰ Doxycycline causes disaggregation of amyloid deposits, and tauroursodeoxycholic acid decreases accumulation of toxic TTR aggregates.
• Epigallocatechin-3 gallate. Epigallocatechin-3 gallate is the most abundant catechin in green tea, and an in vitro study showed that it can inhibit amyloid formation and disaggregate and eliminate amyloid deposit.¹⁸ Studies showed that 12 months of green tea consumption significantly decreased LV mass by 6-13%, as evaluated by CMRI in patients with wild-type cardiac ATTR.^3,19
• Serum amyloid P component. All types of amyloid deposits contain serum amyloid P as plasma protein. Anti-serum amyloid P monoclonal antibodies have been shown to elicit immunotherapeutic removal of amyloid deposits from main organs, including liver, in animal studies and in patients with systemic amyloidosis in early-phase clinical trials (NCT01777243).^20,21

Conclusion
Recent advances in the diagnosis of cardiac ATTR have contributed to progressively changing the disease from incurable to treatable. Regional strain imaging, CMRI, and nuclear scans such as 99mTc-DPD and 99mTc-PYP scintigraphy are techniques used in the early diagnosis of cardiac ATTR. Patisiran, a new drug therapy, has been proven to reduce TTR production in a clinical trial. New efficient agents such as tafamidis and tolcapone have proven to be strong aggregation inhibitors and have improved the quality of life of patients with cardiac ATTR. Early-phase clinical trials demonstrated that anti-SAP antibodies aid in removing amyloid deposit. Many new ATTR-specific drugs are in the final phases of clinical trials. All of these promising advancements may soon lead to safe and efficacious therapeutics for patients with ATTR.

References

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17. Sant'Anna R, Gallego P, Robinson LZ, et al. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Nat Commun 2016;7:10787.
18. Judge DP, Heitner SB, Falk RH, et al. Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol 2019;74:285-95.
19. Aus dem Siepen F, Bauer R, Aurich M, et al. Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an observational study. Drug Des Devel Ther 2015;9:6319-25.
20. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010;468:93-7.
21. Richards DB, Cookson LM, Barton SV, et al. Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Sci Transl Med 2018;10:eaan3128.

Clinical Topics: Cardio-Oncology

Keywords: Diflunisal, Catechin, Plaque, Amyloid, Doxycycline, Thyroxine, Myocytes, Cardiac, Prealbumin, RNA, Small Interfering, Survival Rate, Drugs, Investigational, RNA Interference, RNA, Messenger, Liver Transplantation, Exercise Tolerance, African Americans, Cardio-oncology, Cardiotoxicity

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