Emerging treatments for amyloidosis
2014; Elsevier BV; Volume: 87; Issue: 3 Linguagem: Inglês
10.1038/ki.2014.368
ISSN1523-1755
AutoresRabya Sayed, Philip N. Hawkins, Helen J. Lachmann,
Tópico(s)Parathyroid Disorders and Treatments
ResumoAmyloidosis results from protein misfolding, and ongoing amyloid deposition can ultimately lead to organ failure and death. Historically, this is a group of diseases with limited treatment options and frequently poor prognosis. However, there are now 'targeted' therapeutics emerging in the form of stabilizers of the precursor protein, inhibitors of fibrillogenesis, fibril disruptors, and blockers of protein translation, transcription, and immunotherapy. We review many of these approaches that are currently being assessed in clinical trials. Amyloidosis results from protein misfolding, and ongoing amyloid deposition can ultimately lead to organ failure and death. Historically, this is a group of diseases with limited treatment options and frequently poor prognosis. However, there are now 'targeted' therapeutics emerging in the form of stabilizers of the precursor protein, inhibitors of fibrillogenesis, fibril disruptors, and blockers of protein translation, transcription, and immunotherapy. We review many of these approaches that are currently being assessed in clinical trials. The term amyloidosis encompasses a group of diseases caused by the pathogenic misfolding of specific proteins that differ substantially with respect to organ involvement, management, and prognosis. Recent diagnostic developments have improved disease recognition, and the incidence of systemic amyloidosis is estimated to be at least c. 8 per million per year, although likely to be higher.1.Pinney J.H. Smith C.J. Taube J.B. et al.Systemic amyloidosis in England: an epidemiological study.Br J Haematol. 2013; 161: 525-532Crossref PubMed Scopus (189) Google Scholar Immunoglobulin light-chain associated (AL) and secondary (amyloid A (AA)) amyloidoses are by far the most prevalent subtypes with renal involvement present in two-thirds and >90% of patients, respectively.2.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis: response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Google Scholar,3.Joss N. McLaughlin K. Simpson K. et al.Presentation, survival and prognostic markers in AA amyloidosis.Q J Med. 2000; 93: 535-542Crossref Scopus (95) Google Scholar Renal presentation mainly reflects glomerular deposits with proteinuria, often overt nephrotic syndrome, and varying renal insufficiency.4.Kyle R.A. Gertz M.A. Primary systemic amyloidosis: clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google Scholar,5.Dember L.M. Amyloidosis-associated kidney disease.J Am Soc Nephrol. 2006; 17: 3458-3471Crossref PubMed Scopus (277) Google Scholar However, where tubulointerstitial involvement predominates, particularly in some types of hereditary apolipoprotein A-1 amyloidosis, a gradual decline in renal excretory function, without significant proteinuria, occurs.6.Obici L. Franceschini G. Calabresi L. et al.Structure, function and amyloidogenic propensity of apolipoprotein A-I.Amyloid. 2006; 13: 191-205Crossref PubMed Scopus (114) Google Scholar Untreated, median survival with AL amyloidosis is only 12 months; however, survival after treatment now exceeds 3 years,7.Wechalekar A.D. Hawkins P.N. Gillmore J.D. Perspectives in treatment of AL amyloidosis.Br J Haematol. 2008; 140: 365-377Crossref PubMed Scopus (87) Google Scholar and it remains critically important that we strive to further ameliorate both the morbidity and mortality burden associated with systemic amyloidosis. This review specifically focuses on the novel therapies that have lately entered the clinical testing arena or that loom on the horizon. The amyloidoses are the consequence of protein misfolding and aggregation, subsequent insoluble fibril formation, and accumulation in the extracellular space, ultimately causing organ dysfunction and death.8.Merlini G. Bellotti V. Molecular mechanisms of amyloidosis.N Engl J Med. 2003; 349: 583-596Crossref PubMed Scopus (1446) Google Scholar More than 30 different amyloid fibril precursor proteins are known in humans, but all fibril types essentially share a similar ultrastructure.9.Westermark P. Benson M.D. Buxbaum J.N. et al.A primer of amyloid nomenclature.Amyloid. 2007; 14: 179-183Crossref PubMed Scopus (271) Google Scholar The acquired highly characteristic β-pleated conformation of amyloid fibrils is associated with specific biophysical properties, including the ability to bind Congo red dye in a spatially ordered manner that produces diagnostic green birefringence when viewed under cross-polarized light10.Puchtler H. Sweat F. Amidoblack as a stain for hemoglobin.Arch Pathol. 1962; 73: 245-249PubMed Google Scholar,11.Westermark G.T. Johnson K.H. Westermark P. Staining methods for identification of amyloid in tissue.Methods Enzymol. 1999; 309: 3-25Crossref PubMed Scopus (238) Google Scholar(Figure 1). Under electron microscopy, amyloid deposits appear as randomly arranged, rigid nonbranching fibrils of ∼10nm in diameter and of indeterminate length.12.Picken M.M. New insights into systemic amyloidosis: the importance of diagnosis of specific type.Curr Opin Nephrol Hypertens. 2007; 16: 196-203Crossref PubMed Scopus (96) Google Scholar The mechanisms by which amyloid deposits cause tissue damage have not yet been fully elucidated. The presence of large amounts of amyloid material can disrupt tissue architecture and mechanically interfere with the physiologic function of affected organs.13.Pepys M.B. Amyloidosis.Annu Rev Med. 2006; 57: 223-241Crossref PubMed Scopus (521) Google Scholar Prefibrillar oligomeric species may also be toxic and contribute to organ dysfunction; cytotoxicity, in these cases, seems to be related to structural flexibility and exposure of hydrophobic residues.14.Campioni S. Mannini B. Zampagni M. et al.A causative link between the structure of aberrant protein oligomers and their toxicity.Nat Chem Biol. 2010; 6: 140-147Crossref PubMed Scopus (447) Google Scholar The major types of systemic amyloidosis are described in Table 1. Ideally, immunofluorescence on fresh tissue or, failing that, immunohistochemistry on fixed sections should be used to distinguish between the different types.12.Picken M.M. New insights into systemic amyloidosis: the importance of diagnosis of specific type.Curr Opin Nephrol Hypertens. 2007; 16: 196-203Crossref PubMed Scopus (96) Google Scholar Sometimes a characteristic distribution of deposits on light microscopy alone can provide diagnostic pointers––for example, isolated heavy glomerular involvement in fibrinogen Aα amyloidosis.15.Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (539) Google Scholar Genetic testing is invaluable in diagnosing and excluding the known hereditary forms of amyloidosis, and fibril typing by mass spectrometry is increasingly used when immunostaining fails to provide definitive results.16.Sethi S. Vrana J.A. Theis J.D. et al.Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis.Kidney Int. 2012; 82: 226-234Abstract Full Text Full Text PDF PubMed Scopus (146) Google ScholarTable 1The major amyloid subtypesAmyloid subtypeFibril precursorTreatmentClinical involvementALMonoclonal-free immunoglobulin light chainsChemotherapy directed at the underlying plasma cell dyscrasiaPotentially novel agentsRenal (50–80%), cardiac, liver, spleen, bones, GI, autonomic and peripheral neuropathy, soft tissueAASerum amyloid A proteinTreatment aimed at the specific underlying inflammatory conditionPotentially eprodisateRenal (>95%), liver, spleen, adrenals, autonomic neuropathyATTR: wild-typeWild-type transthyretinMainly supportive with optimization of fluid statusCardiac, soft tissueATTR: hereditaryVariant transthyretinCardiac transplantationPotentially novel agentsLiver±cardiac±renal transplantationTafamadisPotentially novel agentsDominant neurological±cardiac involvement (dependent upon specific TTR variant)β2Mβ2-Microglobulin (associated with chronic dialysis)Mainly supportive, for example, splints, braces, collars.High-flux dialyzer membranes, frequent hemodialysis, β2M adsorption columns to reduce formationRenal transplantationOsteoarticular, bone cysts, soft tissue. Late visceral deposition including cardiac, GI, and spleenAFib (hereditary)Variant fibrinogen AαRenal±liver transplantationPotentially novel agentsRenalApolipoprotein AI (hereditary)Variant apolipoprotein AIRenal +/- liver transplantationPotentially novel agentsRenal (mainly medullary), liver, heart, skin, larynxApolipoprotein AII (hereditary)Variant apolipoprotein AIIRenal transplantationPotentially novel agentsRenalLysozyme (hereditary)Variant lysozymeRenal transplantationPotentially novel agentsRenal, liver, GI, spleen, lymph nodes, lung, thyroid, salivary glandsAbbreviations: AA, amyloid A; AFib, fibrinogen Aα-chain; AL, immunoglobulin light chain amyloidosis; ATTR, amyoidogenic transthyretin; β2M, β2-microglobulin; GI, gastrointestinal; TTR, transthyretin. Open table in a new tab Abbreviations: AA, amyloid A; AFib, fibrinogen Aα-chain; AL, immunoglobulin light chain amyloidosis; ATTR, amyoidogenic transthyretin; β2M, β2-microglobulin; GI, gastrointestinal; TTR, transthyretin. Transthyretin (TTR) is a 55-kDa homotetrameric plasma protein that transports thyroxine and Vitamin A and is associated in its wild-type (wt) form with acquired amyloidosis, termed wild-type TTR (wtTTR) amyloidosis and formerly known as senile systemic amyloidosis.17.Dubrey S.W. Hawkins P.N. Falk R.H. Amyloid diseases of the heart: assessment, diagnosis, and referral.Heart. 2011; 97: 75-84Crossref PubMed Scopus (144) Google Scholar,18.Cornwell III, G.G. Murdoch W.L. Kyle R.A. et al.Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation.Am J Med. 1983; 75: 618-623Abstract Full Text PDF PubMed Scopus (333) Google Scholar More than 100 genetic variants of TTR are associated with autosomal dominant hereditary amyloidosis, and these usually involve the peripheral and autonomic nervous system and/or the heart.19.Connors L.H. Lim A. Prokaeva T. et al.Tabulation of human transthyretin (TTR) variants.Amyloid. 2003; 10: 160-184Crossref PubMed Scopus (414) Google Scholar,20.Schmidt H.H. Tafamidis for the treatment of transthyretin-associated familial amyloid polyneuropathy. Expert Opinion in Orphan Drugs.. 2013; 1: 837-845Google Scholar Notable variants include TTR Val30Met, which is the most common cause of familial amyloid polyneuropathy (FAP), and Val122Ile, which occurs in ∼4% of African Americans and is associated with late-onset familial amyloid cardiomyopathy, although with quite low penetrance.21.Berk J.L. Suhr O.B. Sekijima Y. et al.Familial Amyloidosis ConsortiumThe Diflunisal Trial: study accrual and drug tolerance.Amyloid. 2012; 19: 37-38Crossref PubMed Scopus (38) Google Scholar, 22.Benson M.D. Kincaid J.C. The molecular biology and clinical features of amyloid neuropathy.Muscle Nerve. 2007; 36 (Review): 411-423Crossref PubMed Scopus (341) Google Scholar, 23.Connors L.H. Richardson A.M. 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Guimarães S.M. et al.Familiar amyloidotic polyneuropathy type I (Portuguese): distribution and characterization of renal amyloid deposits.Am J Kidney Dis. 1998; 31: 940-946Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The conversion of circulating TTR protein into amyloid requires dissociation of the normal tetrameric protein into monomers, conformational change, and assembly to form the fibrils.19.Connors L.H. Lim A. Prokaeva T. et al.Tabulation of human transthyretin (TTR) variants.Amyloid. 2003; 10: 160-184Crossref PubMed Scopus (414) Google Scholar,21.Berk J.L. Suhr O.B. Sekijima Y. et al.Familial Amyloidosis ConsortiumThe Diflunisal Trial: study accrual and drug tolerance.Amyloid. 2012; 19: 37-38Crossref PubMed Scopus (38) Google Scholar The propensity to form amyloid is influenced by specific amino-acid substitutions and environmental factors such as pH and oxidative stress.28.Tajiri T. Ando Y. Hata K. et al.Amyloid formation in rat transthyretin: effect of oxidative stress.Clin Chim Acta. 2002; 323: 129-137Crossref PubMed Scopus (13) Google Scholar WtTTR amyloidosis is very likely to be an underdiagnosed condition that commonly presents in the older population with symptoms predominantly of right-sided heart failure and often a history of the carpal tunnel syndrome.29.Tanskanen M. Peuralinna T. Polvikoski T. et al.Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study.Ann Med. 2008; 40: 232-239Crossref PubMed Scopus (326) Google Scholar Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where supraventricular arrhythmias are present, and an avoidance of digoxin and calcium channel blockers. Antihypertensives are usually poorly tolerated as these patients can be profoundly hypotensive.30.Falk R.H. Diagnosis and management of the cardiac amyloidoses.Circulation. 2005; 112: 2047-2060Crossref PubMed Scopus (588) Google Scholar,31.Dubrey S.W. Falk R.H. Amyloid heart disease.Br J Hosp Med (Lond). 2010; 71: 76-82Crossref PubMed Scopus (9) Google Scholar Circulating TTR protein is almost exclusively liver derived,32.Ong D.E. Davis J.T. O'Day W.T. et al.Synthesis and secretion of retinol-binding protein and transthyretin by cultured retinal pigment epithelium.Biochemistry. 1994; 33: 1835-1842Crossref PubMed Scopus (85) Google Scholar and the 'surgical gene therapy' with liver transplantation has been undertaken in more than 2000 FAP patients since 1990.33.Holmgren G. Steen L. Ekstedt J. et al.Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAPmet30).Clin Genet. 1991; 40: 242-246Crossref PubMed Scopus (354) Google Scholar,34.Wilczek H. Larsson M. Ericzon B. Long-term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR).Amyloid. 2011; 18: 188-190Google Scholar Liver transplantation, when performed early, prolongs life, particularly in patients with the TTR Met30 variant, but neurological impairment and a poor quality of life remain problematic.35.Benson M.D. Liver transplantation and transthyretin amyloidosis.Muscle Nerve. 2013; 47: 157-162Crossref PubMed Scopus (74) Google Scholar In other mutations, and in older patients, outcomes are less favorable, and may reflect postoperative amyloid cardiomyopathy.36.Lipeniks J.J. Benson M.D. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation.Amyloid. 2007; 14: 277-282Crossref PubMed Scopus (91) Google Scholar This is thought to be due to the deposition of wt TTR on a template of preexisting cardiac amyloid derived from variant proteins.37.Yazaki M. Tokuda T. Nakamura A. et al.Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wildtype transthyretin.Biochem Biophys Res Commun. 2000; 274: 702-706Crossref PubMed Scopus (148) Google Scholar The need for better therapies has resulted in the development of a number of novel strategies, and some of these have been assessed in clinical trials. Diflunisal is a nonsteroidal anti-inflammatory drug that stabilizes tetrameric TTR in vitro by binding via the thyroid hormone receptor sites.38.Miller S.R. Sekijima Y. Kelly J.W. Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants.Lab Invest. 2004; 84: 545-552Crossref PubMed Scopus (173) Google Scholar,39.Sekijima Y. Dendle M.A. Kelly J.W. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis.Amyloid. 2006; 13: 236-249Crossref PubMed Scopus (191) Google Scholar Berk et al.40.Berk J.L. Suhr O.B. Obici L. et al.Diflunisal Trial ConsortiumRepurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.JAMA. 2013; 310: 2658-2667Crossref PubMed Scopus (467) Google Scholar recently completed an international, multicenter, placebo-controlled study of 130 FAP patients, with neurological outcome as the primary end point. The exclusion criteria included patients >75 years of age, a history of gastrointestinal bleeding, estimated glomerular filtration rate <30ml/min, and NYHA (New York Heart Association) Class IV heart failure. Sixty-three patients with a median age of 59.7 years, of whom 54.6% had TTR Met30, completed the study, having taken either 250mg diflunisal or placebo daily over a 2-year period. The authors reported a significant reduction in the rate of progression of neurological impairment and an improved quality of life in the diflunisal-treated group, with 29.7% of the diflunisal and 9.4% of the placebo group displaying a stable neurological score by Neuropathy Impairment Score plus 7 nerve tests (NIS+7) at 2 years. Drug-related adverse events, including gastrointestinal bleeding and renal dysfunction, did not differ between the two groups.40.Berk J.L. Suhr O.B. Obici L. et al.Diflunisal Trial ConsortiumRepurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.JAMA. 2013; 310: 2658-2667Crossref PubMed Scopus (467) Google Scholar Tafamadis (2-(3,5–dichloro–phenyl)-benzox-azole-6-carboxylic acid) is an orally administered drug that acts to stabilize the TTR tetramer through its affinity for the T4-binding site, and it does not carry the risks associated with nonsteroidal anti-inflammatory drug use.41.Bulawa C.E. Connelly S. Devit M. et al.Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.Proc Natl Acad Sci USA. 2012; 109: 9629-9634Crossref PubMed Scopus (491) Google Scholar It is protein bound, metabolically stable, and ≥94% is excreted unchanged from the digestive tract. Coelho et al.42.Coelho T. Maia L.F. Martins da S.A. et al.Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial.Neurology. 2012; 79: 785-792Crossref PubMed Scopus (574) Google Scholar undertook a randomized phase II/III double-blinded trial that assigned either 20mg oral tafamadis or placebo to 128 FAP patients (mean age 39 years) with the V30M TTR mutation and early neuropathy for a period of 18 months. Plasma TTR stabilization was seen in 98% of tafamadis-treated patients and none of the placebo arm. The study did not show a significant change in the predefined primary end point but suggested a slowed deterioration in small fiber neuropathy in the tafamadis arm at 18 months, with 45.3% of the evaluable diflunisal and 29.5% of the placebo group displaying a stable neurological score by NIS of the lower limb at 18 months. The most common side effects included urinary tract infections and diarrhea. There has been no evidence that Tafamadis affects thyroid function tests; however, routine monitoring is advised. Notably, Coelho's study excluded patients with an estimated glomerular filtration rate of <30ml/min, and there currently remains no evidence of efficacy in cardiac TTR amyloidosis. This study has split the drug regulatory authorities with the European Medicine Agency granting approval for Tafamadis use in FAP for TTR Met30 patients with early disease who can still walk independently. It has not yet been approved by the US Food and Drug Administration. These two studies highlight some of the difficulties in conducting drug trials in amyloidosis and amyloid neuropathy in particular. These include problems with patient selection (the study populations were very different) and quantifying the amyloid deposits; there are no imaging techniques that can accurately identify let alone quantify neural amyloid deposits, and biopsies are subject to sampling error. In addition, nerve biopsies can only be used very sparingly, and it is not clear that assessment of amyloid by serial fat aspirates (a safe and easily obtained source of tissue) provides a reliable insight into changes in amyloid load. The assessment of neurological function is currently onerous and dependent on clinical experience and subjective interpretation. The widely used measures reported in these two studies are taken from the diabetic literature and may not be entirely appropriate; the rate of deterioration of neurological function in FAP is much more rapid than that seen in diabetes, and there have been no prospective observational studies to validate these methodologies in amyloid neuropathy. The numerical scores that are generated give the impression that any particular change in score has similar clinical weight regardless of baseline function, and this seems inherently unlikely. Ongoing questions relating to whether either of these agents will be beneficial in cardiac amyloidosis are being addressed at present. Recent in vitro experiments show that 50μmol/l epigallocatechin-3-gallate, the most abundant catechin in green tea (GT), efficiently inhibits fibril formation from amyloid β-protein, α-synucleine, and TTR and converts existing fibrils into nonfibril conformers.43.Ferreira N. Cardoso I. Domingues M.R. et al.Binding of epigallocatechin-3-gallate to transthyretin modulates its amyloidogenicity.FEBS Lett. 2009; 583: 3569-3576Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,44.Bieschke J. Russ J. Friedrich R.P. et al.EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity.Proc Natl Acad Sci USA. 2010; 107: 7710-7715Crossref PubMed Scopus (765) Google Scholar TTR tetramer stabilization is observed when epigallocathechin-3-gallate binds to recombinant wt and variant TTR tetramers at three sites different from the thyroxine-binding site.45.Miyata M. Sato T. Kugimiya M. et al.The crystal structure of the green tea polyphenol (-)-epigallocatechin gallate-transthyretin complex reveals a novel binding site distinct from the thyroxine binding site.Biochemistry. 2010; 49: 6104-6114Crossref PubMed Scopus (82) Google Scholar Kristen et al.46.Kristen A.V. Lehrke S. Buss S. et al.Green tea halts progression of cardiac transthyretin amyloidosis: an observational report.Clin Res Cardiol. 2012; 101: 805-813Crossref PubMed Scopus (97) Google Scholar undertook a prospective study of 19 patients with cardiac TTR amyloidosis consuming either standardized GT extract in the form of capsules or 1.2–2l of GT/day over a year. Ten patients had hereditary ATTR amyloidosis and 9 patients had wtTTR amyloidosis. Five patients did not complete the study (2 died, 2 discontinued GT/GT extract, and one underwent heart transplantation). In the subgroup of patients evaluated by cardiac magnetic resonance imaging, a mean decrease in 12.5% left ventricular mass was detected. There were no serious adverse effects reported by any of the participants.46.Kristen A.V. Lehrke S. Buss S. et al.Green tea halts progression of cardiac transthyretin amyloidosis: an observational report.Clin Res Cardiol. 2012; 101: 805-813Crossref PubMed Scopus (97) Google Scholar The discovery of RNA interference by Fire and Mello,47.Fire A. Xu S. Montgomery M.K. et al.Potent and specific genetic interference by doublestranded RNA in Caenorhabditis elegans.Nature. 1998; 391: 806-811Crossref PubMed Scopus (11775) Google Scholar for which they were awarded the Nobel Prize in Physiology in 2006, demonstrated how the transfer of genetic information from DNA to protein can be blocked. Oligonucleotide-based therapies, including small interfering RNAs (siRNAs) and antisense RNAs, have the ability to cause changes at the translational level without becoming integrated into the human genome.48.Goodchild J. Therapeutic oligonucleotides.Methods Mol Biol. 2011; 764: 1-15Crossref PubMed Scopus (57) Google Scholar The siRNAs are noncoding, double-stranded molecules that are components of the endogenous RNA interference pathway that serves to control gene expression. They vary in length from 18 to 30 base pairs and are chemically modified for drug delivery to increase stability and limit immunogenicity.49.Sehgal A. Vaishnaw A. Fitzgerald K. Liver as a target for oligonucleotide therapeutics.J Hepatol. 2013; 59: 1354-1359Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Lipid nanoparticles have been used to deliver siRNAs to hepatocytes parenterally; these have resulted in a robust and durable reduction in genetic expression across a variety of species.50.Akinc A. Querbes W. De S. et al.Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.Mol Ther. 2010; 18: 1357-1364Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar Antisense oligonucleotides (ASOs) are 13–25 nucleotide single-stranded DNA molecules that hybridize to a specific messenger RNA (mRNA) sequence and prevent transcription.51.Loke S.L. Stein C.A. Zhang X.H. et al.Characterization of oligonucleotide transport into living cells.Proc Natl Acad Sci USA. 1989; 86: 3474-3478Crossref PubMed Scopus (734) Google Scholar,52.Elbashir S.M. Lendeckel W. Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs.Genes Dev. 2001; 15: 188-200Crossref PubMed Scopus (2704) Google Scholar The mechanisms through which both types of oligonucleotide work are illustrated in Figure 2. Oligonucleotide therapies for ATTR have shown great promise in preclinical models, and both siRNAs and antisense RNAs are being investigated in clinical studies (ClinicalTrial.gov NCT01960348 and NCT01737398). Coelho et al.53.Coelho T. Maia L.F. da Silva A.M. et al.Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.J Neurol. 2013; 260: 2802-2814Crossref PubMed Scopus (257) Google Scholar undertook a single-dose, randomized, placebo-controlled phase I trial using ALN-TTR01 and ALN-TTR02 (first- and second-generation lipid nanoparticles); these contain an identical siRNA that binds to an mRNA segment common to both wt and mutant TTR. There was a rapid, dose-dependent, and durable reduction in transthyretin levels in the 32 patients with TTR amyloidosis.53.Coelho T. Maia L.F. da Silva A.M. et al.Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.J Neurol. 2013; 260: 2802-2814Crossref PubMed Scopus (257) Google Scholar Alnylam Pharmaceuticals (Massachusetts) have developed an RNA interference therapeutic that has been chemically modified by conjugation to an N-acetylgalactosamine moiety, thereby refining hepatocyte targeting and allowing subcutaneous administration;49.Sehgal A. Vaishnaw A. Fitzgerald K. Liver as a target for oligonucleotide therapeutics.J Hepatol. 2013; 59: 1354-1359Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,54.Akshay V. Sara N. Kevin F. et al.Advances in oligonucleotide clinical development.in: 8th annual meeting of the Oligonucleotide Therapeutics Society. Boston, MA2012Google Scholar,55.Guo S. Booten S. 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Mipomersen sodium: first global approval.Drugs. 2013; 73: 487-493Crossref PubMed Scopus (87) Google Scholar ISIS-TTRRX is a second-generation chimeric antisense inhibitor of TTR. It binds selectively and with high affinity to the nontranslated portion of the human TTR mRNA and results in its degradation, preventing production of both wt and variant TTR protein. ISIS-TTRRX twice-weekly subcutaneous injections have been well tolerated in both TTR transgenic mouse models and monkeys with a reduction in hepatic TTR mRNA and plasma wt TTR protein levels by ∼80%, and it is currently under evaluation in a phase I clinical trial in normal healthy volunteers.26.Adams D. [Review of the recent literature on peripheral neuropathies: therapeutic advances.Rev Neurol (Paris). 2013; 169: 1004-1009Crossref PubMed Scopus (3) Google Scholar,59.Ackermann E.J. Guo S. Booten S. et al.Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy.Amyloid. 2012; 19: 43-44Crossre
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