Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin-related (hATTR) amyloidosis is a rare disorder that is fatal if left untreated. The disease is caused by mutations in the transthyretin (TTR) gene and is inherited in an autosomal-dominant pattern. The tetrameric TTR molecule misfolds as a result of every known mutation, and misfolding results in the deposition of amyloid protein in numerous organs. Untreated hATTR has an irreversible, progressive course, and patients generally die within 7 to 11 years after the onset of symptoms.1

Because hATTR amyloidosis is a multisystemic disease, a multidisciplinary approach to management is required that focuses on decreasing the deposition of TTR protein.2,3 The 3 principal approaches currently used to treat hATTR amyloidosis are inhibition of TTR synthesis (with gene silencing and liver transplant), stabilization of the TTR native structure, and removal of misfolded TTR.2 Other therapies are available for symptomatic management.4 In addition, various therapies are in an experimental stage. These are summarized below. 

TTR Tetramer Stabilizers


Diflunisal (Dolobid®) is an age-old generic nonsteroidal anti-inflammatory drug, a salicylic acid derivative, that has recently been discovered to complex with the 2 thyroxine-binding sites on the TTR protein.5 Diflunisal was initially studied for the treatment of hATTR amyloid polyneuropathy (hATTR-PN). Single-center open-label and retrospective trials of diflunisal to treat hTTR amyloid cardiomyopathy (hATTR-CM) were conducted later.6,7 The dosage of diflunisal used was 250 mg taken orally 2 times daily. The survival benefits were found to be comparable with outcomes in patients treated with tafamidis (Vyndamax®). The drug was overall well tolerated, with relatively few adverse effects of thrombocytopenia, renal dysfunction, and fluid retention. Diflunisal continues to be a crucial off-label pharmacologic treatment for hATTR-CM because of its favorable safety profile and affordable price, despite the absence of convincing clinical data to support its use. The US Food and Drug Administration (FDA) has not approved this medication for the treatment of hATTR amyloidosis.5,7 


An experimental drug called AG10 (acoramidis) has the potential to stabilize TTR tetramers and prevent them from disintegrating into amyloidogenic monomer fibrils.5,8 A recent phase 2 trial of AG-10 included 49 patients who had hATTR-CM with New York Heart Association (NYHA) functional class II or III symptoms and high circulating levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) at baseline. AG10 caused circulating TTR levels to rise on average by 36% at a dose of 400 mg, and by 50% at a dose of 800 mg. The response was much stronger in the patients who had hATTR-CM than in those who had wild-type ATTR-CM. Serious adverse effects of AG-10 included atrial fibrillation, congestive heart failure, cellulitis, and dyspnea requiring hospitalization.9 Presently, phase 3 trials of AG10 are ongoing: ATTRibute-CM (NCT03860935) for ATTR-CM and ATTRibute-PN (NCT04882735) for ATTR-PN. 3 


Tolcapone (Tasmar®), a potent catechol-O-methyltransferase (COMT) inhibitor, binds with high affinity to the TTR thyroxine-binding pocket, stabilizing the tetramer in vivo in mice and humans and preventing amyloidogenesis.5 The drug has FDA approval for the treatment of Parkinson disease and an Orphan Drug Designation for the treatment of ATTR.10 Tolcapone is a TTR stabilizer that efficiently penetrates the blood-brain barrier and thus is being tested as a potential treatment for leptomeningeal ATTR in a clinical trial (NCT03591757).3 Tolcapone slowed the degradation of highly unstable TTR variant tetramers by 40% to 50% and that of wild-type TTR tetramers by approximately 80% in vitro because of its affinity for the binding pocket, which is stronger than that of tafamidis. Tolcapone was previously taken off the market because of safety concerns and carries an FDA Black Box Warning for hepatotoxicity, GI distress, dyskinesia, and sleep disturbance.5 

Gene-Silencing Therapies

Gene-silencing therapies, implemented with the use of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have proved to be effective and safe treatments for ATTR. Eplontersen (previously called AKCEA-TTR-LRX and ION-682884) is a next-generation ASO that targets the same sequence as inotersen (Amvuttra™), but in addition, it is conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand.The ligand conjugation increases delivery to the liver and reduces the total dose required, thus improving upon the safety and dosing profile of inotersen.5 The greater potency and safety of eplontersen have been noted in a phase 1 study (NCT03728634), with no significant adverse events reported. Phase 3 studies are presently underway in both ATTRv-PN (NCT04136184) and ATTR-CM (NCT04136171).3

TTR Gene Editing

In TTR gene editing, clustered, regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) genome editing are used to decrease the amount of amyloid protein produced by hepapocytes in patients with hATTR amyloidosis. NTLA-2001, a novel CRISPR-Cas9-based gene-editing treatment, is composed of a single-guide RNA (sgRNA) targeting human TTR with a human codon-optimized mRNA sequence of Streptococcus pyogenes (Spy)-Cas9 protein. Proprietary lipid nanoparticles facilitate the targeted delivery of NTLA-2001 to liver cells by endocytosis through low-density lipoprotein receptors. The Spy-Cas9 mRNA is translated into a Spy-Cas9 endonuclease once inside the cell, causing the formation of a Cas9-sgRNA ribonucleoprotein complex that enters the nucleus and eliminates the mutant TTR gene. In animal trials, the intravenous infusion of NTLA-2001 was demonstrated to lower TTR protein levels by 95% following a single infusion. After a single infusion of NTLA-2001, a first-in-human study showed that blood levels of TTR protein in patients with hATTR-PN decreased in a dose-dependent manner. No serious side effects were noted. Further trials will be needed to assess the clinical safety and effectiveness of therapeutic methods based on CRISPR-Cas9.3,11

TTR Fibril Removal/TTR Resorption 

Antibody-Mediated Removal

Mixed outcomes have been reported with monoclonal antibodies produced against serum amyloid P (SAP) and TTR (including PRX004).3 

Mutant TTR amyloid fibrils are attached to SAP, a normal plasma protein that is not fibrillar. Fibrillin-bound SAP is left behind after the targeted elimination of plasma SAP with the ligand miridesap (GSK2315698). Dezamizumab (GSK2398852), a therapeutic immunoglobulin G1 anti-SAP antibody, can then target and bind to fibrillin-bound SAP, activating a complement-based cascade that may identify TTR amyloid fibrils targeted for destruction by macrophage-derived multinucleated giant cells.5 This antibody-mediated strategy for TTR breakdown and resorption first appeared promising in a phase 1 clinical trial; however, further research was subsequently halted because of futility and toxicity. Repeat doses of dezamizumab may be clinically beneficial according to some studies, but more research is necessary.12,13

Another monoclonal antibody, called MisTTR (PRX004), binds to residues 89 through 97 of the TTR tetramer, inhibiting the fibrillogenesis of misfolded TTR monomers.5,14 A recently completed phase 1 clinical study revealed improvement in left ventricular systolic function and slowing of neuropathy progression. It can lead to potential reduction in cardiac hospitalizations and deaths. The findings have not yet been published.5 

Doxycycline and Tauroursodeoxycholic Acid

Combination treatment with doxycycline, which interferes with TTR amyloid fibril formation, and tauroursodeoxycholic acid (TUDCA), a biliary acid that decreases the aggregation of nonfibrillary TTR, has been found to have synergistic effects in a TTR mouse model (Val30Met).15,16 TTR tetramer disruption results in the formation of amyloid fibrils, which can be scavenged by macrophages and giant cells in the innate immune system when this combination is used.5 In a preliminary phase 2 clinical research study, doxycycline at 200 mg daily and TUDCA at 250 mg 3 times daily demonstrated the potential to slow disease progression. The results of a later investigation, however, were contradictory and raised questions about the high incidence of major side effects like rash, GI distress etc..5,17 

Naturally Derived Compounds

Epigallocatechin-3-gallate (EGCG), a catechin found in green tea extract, inhibits the production of amyloid fibrils and prevents their aggregation.18 In patients with hATTR amyloidosis, EGCG taken orally stabilized cardiac function.19 However, the role of EGCG in hATTR neuropathy is still unclear, despite the fact that its high CNS bioavailability makes it a promising component of prospective multidrug treatments.3 EGCG was found to be a safe therapeutic option but had no effect on survival in a real-world cohort analysis of patients with ATTR-CM and isolated cardiac involvement.20 


  1. Schilling M. Gentherapieoptionen der hereditären Transthyretinamyloidose [Gene therapy options for hereditary transthyretin-related amyloidosis]. Nervenarzt. 2022;93(6):557-565. Article in German. doi:10.1007/s00115-022-01288-0
  2. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022:1-13. doi:10.1080/13506129.2022.2052838
  3. ​​Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909
  4. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4
  5. Shah RJ, Pan S, Lanier GM, Mellela L, Aronow WS, Jain D. Recent advances in the pharmacotherapy of TTR amyloidosis of the heart. Vessel Plus. 2021;5:53. doi:10.20517/2574-1209.2021.76
  6. Ikram A, Donnelly JP, Sperry BW, Samaras C, Valent J, Hanna M. Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center’s experience. Amyloid. 2018;25:197-202. doi:10.1080/13506129.2018.1519507
  7. Rosenblum H, Castano A, Alvarez J, Goldsmith J, Helmke S, Maurer MS. TTR (transthyretin) stabilizers are associated with improved survival in patients with TTR cardiac amyloidosis. Circ Heart Fail. 2018;11:e004769. doi:10.1161/CIRCHEARTFAILURE.117.004769
  8. Fox JC, Hellawell JL, Rao S, et al. First-in-human study of AG10, a novel, oral, specific, selective, and potent transthyretin stabilizer for the treatment of transthyretin amyloidosis: a phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy adult volunteers. Clin Pharmacol Drug Dev. 2020;9(1):115-129. doi:10.1002/cpdd.700
  9. Judge DP, Heitner SB, Falk RH, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019;74(3):285-295. doi:10.1016/j.jacc.2019.03.012
  10. Roberts JR. Transthyretin-related amyloidosis treatment & management. Medscape. Updated July 19, 2022. Accessed July 31, 2022. 
  11. Trial underway for hATTR therapy. Genomics Education Programme. August 13, 2021. Accessed July 31, 2022. 
  12. Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med. 2015;373:1106-1114. doi:10.1056/NEJMoa1504942
  13. 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. doi:10.1126/scitranslmed.aan3128
  14. Galant NJ, Bugyei-Twum A, Rakhit R, et al. Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses [published correction appears in Sci Rep. 2016;6:27679]. Sci Rep. 2016;6:25080. doi:10.1038/srep25080
  15. Cardoso I, Merlini G, Saraiva MJ. 4′-Iodo-4′-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 2003;17:803-809.  doi:10.1096/fj.02-0764com
  16. Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010;8:74. doi:10.1186/1479-5876-8-74
  17. Obici L, Cortese A, Lozza A, et al.. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012;19 Suppl 1:34-36. doi:10.3109/13506129.2012.678508
  18. Bieschke J, Russ J, Friedrich RP, et al. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A. 2010;107(17):7710-7715. doi:10.1073/pnas.0910723107
  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;9:6319-6325. doi:10.2147/DDDT.S96893
  20. Cappelli F, Martone R, Taborchi G, et al. Epigallocatechin-3-gallate tolerability and impact on survival in a cohort of patients with transthyretin-related cardiac amyloidosis. A single-center retrospective study. Intern Emerg Med. 2018;13(6):873-880.  doi:10.1007/s11739-018-1887-x

Reviewed by Debjyoti Talukdar, MD, on 7/31/2022.