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Transthyretin-associated Familial Amyloid Polyneuropathy—Current and Emerging Therapies

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Published Online: Jun 20th 2008 US Neurology, 2012;8(1):24–32 DOI:
Authors: Mario Nuvolone, Laura Obici, Giampaolo Merlini
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Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP), the most common form of systemic hereditary amyloidosis worldwide, is a late-adult-onset autosomal dominant disease caused by mutations in the TTR gene, with peaks in prevalence in endemic areas. The clinical picture is dominated by a progressive length-dependent polyneuropathy with onset in the feet with loss of temperature and pain sensations, accompanied by life-threatening autonomic dysfunction and infiltrative cardiomyopathy, as well as ocular disturbances. Variable expressivity, in terms of age of onset and involvement of extra-neurological sites, can be due to different mutations, but is also observed among individuals with the same mutation in different countries. Therefore diagnosis of TTR-FAP is often a challenge and must rely on careful clinical assessment combined with a multidisciplinary approach. Elimination of the synthesis of mutated TTR, through liver transplantation, may arrest the progressive neuropathy but not the cardiac and ocular involvement. Novel drugs have recently been developed based on a better understanding of the molecular mechanisms of the disease. Drugs that prevent the misfolding and deposition of mutated TTR have entered clinical trials, and one of these, tafamidis meglumine, has been approved in Europe and is now clinically available. Other medicines are now in the pipeline aimed at suppressing the expression of the mutated TTR gene or at promoting amyloid fibril destructuration, favouring resorption of amyloid deposits. These recent advancements provide grounded hope of an imminent significant improvement in the care of this life-threatening multi-system disease.

Acknowledgements : This work was supported by the Ricerca Finalizzata Malattie Rare, Italian Ministry of Health, Istituto Superiore di Sanità (526D/63), Ministry of Research and University (2007AESFX2-003), and Italian Association for Cancer Research Special Program Molecular Clinical Oncology (grant 9965). Mario Nuvolone is partially supported by an investigator fellowship of Collegio Ghislieri, Pavia. We are indebted to Dr Merrill Benson for generously sharing the table of the transthyretin mutations.


Amyloidosis, familial amyloid polyneuropathy, transthyretin amyloidosis, hereditary neuropathy, peripheral neuropathy


Amyloidoses encompass a heterogeneous group of disorders characterised by the accumulation and extracellular deposition of insoluble aggregates of misfolded fibrillar proteins termed amyloid, which can lead to tissue damage and organ dysfunction.1 They can be exceptionally rare or rather frequent, acquired or hereditary, localised or systemic, quite indolent or life-threatening. Amyloidoses are classified based on the main protein forming the deposits and include, as of today, 28 different forms.2,3

Amyloidoses encompass a heterogeneous group of disorders characterised by the accumulation and extracellular deposition of insoluble aggregates of misfolded fibrillar proteins termed amyloid, which can lead to tissue damage and organ dysfunction.1 They can be exceptionally rare or rather frequent, acquired or hereditary, localised or systemic, quite indolent or life-threatening. Amyloidoses are classified based on the main protein forming the deposits and include, as of today, 28 different forms.2,3
Transthyretin (TTR) amyloidoses (ATTR) retain much of the complexity of this family of maladies. Age-related deposition of wild-type TTR causes senile cardiac or systemic amyloidosis (SCA or SSA),4 affecting up to 25 % of ultra-octogenarian people,5 whereas mutations in the TTR gene can result in hereditary forms of the disease,6 characterised either by a predominant neurological phenotype, also known as familial amyloid polyneuropathy (FAP), by a unique cardiac disease or by a mixture of the two. Several mutations are exceedingly rare and have been described only in single individuals or in single kindreds,7 whereas others are highly prevalent in certain geographical regions or among certain ethnic groups (such as the Val122Ile mutation, which can lead to isolated heart involvement and is carried by up to 4 % of African-Americans).8 In addition, TTR-derived amyloid deposits can be focal (in the ligaments and tendons of aged individuals)9,10 or can be widespread in systemic forms of ATTR.
Here we will review the pathophysiological and clinical characteristics of TTR-associated familial amyloid polyneuropathy (TTR-FAP), with a focus on current and prospective treatments.
Transthyretin – Intrinsic Instability and Pathogenic Mutations
Transthyretin, formerly termed prealbumin for its electrophoretic migration pattern, is a secreted polypeptide chain consisting of 127 amino acid residues11 with an approximate mass of 14 kDa and a prominent β-sheet secondary structure.12 Four monomers associate non-covalently to form a tetramer which can bind thyroxine and holo-retinol-binding protein and circulates in the blood and in cerebrospinal fluid. However, the majority of circulating TTR is not bound. Virtually all TTR in plasma is of hepatic origin, but extrahepatic sites of TTR secretion include the choroid plexus and retinal pigment epithelium. Under physiological conditions, TTR reaches a plasma concentration of 0.2–0.4 g/l and has a half-life of approximately 1–2 days.7,13
Mutations in the TTR gene can be associated with hereditary forms of ATTR that are transmitted as an autosomal-dominant trait (see Table 1). Based on in vitro studies, disease-associated mutations have been shown to reduce the thermodynamic stability of TTR tetramers, favouring their dissociation into monomers, which can undergo unfolding, self-aggregation and amyloid formation.6,7,14,15 This concept has been corroborated by observations made on a non-pathogenic variant of TTR, Thr119Met, which confers a stabilising effect on TTR tetramers in association with both the wild-type and the amyloidogenic Val30Met variant of TTR.16,17 Remarkably, compound heterozygotes for Thr119Met and Val30Met variants of TTR display a more benign evolution of the TTR-FAP associated with the Val30Met mutation.16
A certain degree of instability is an intrinsic feature of TTR, since even wild-type TTR can form amyloid deposits during ageing.4 Such inherent amyloidogenic propensity of TTR is further enhanced in the presence of a disease-related variant of the protein. In affected individuals heterozygous for one of the pathogenic mutations, both normal and variant TTR are found within the deposits18–21 and this could explain why amyloid deposits can progress in patients for whom liver transplantation has almost eradicated the mutant TTR circulating in the blood.18–20
C-terminal fragments of TTR are found in the deposits in addition to full-length TTR molecules in some cases.22–24 The enzyme responsible for this remains to be identified and it is currently unknown whether proteolysis of TTR precedes or follows amyloid formation.1 Also, TTR fibrillogenesis and deposition are believed to be influenced by the interaction with glycosaminoglycans and the serum amyloid P component (SAP), which are common constituents of all types of amyloid deposits.1
Transthyretin-related Familial Amyloid Polyneuropathy
Epidemiology and Genetics
FAP associated with mutations of TTR is the most common form of hereditary ATTR and of hereditary amyloidoses in general.25 First reported in 1952 by Andrade in Portugal,26 it was subsequently described in Japan27 and Sweden28 and it is now believed to occur worldwide. At present, 113 different mutations in the TTR gene have been associated with amyloid formation (see Table 1). Among these, the most common pathogenic mutation by far is Val30Met, which is responsible for the presence of endemic foci of TTR-FAP in northern Portugal,29 northern Sweden,28 Japan30 and the Balearic Islands,31 but has also been reported elsewhere. For some mutations there is a strong genotype–phenotype correlation, whereas other variants show higher degrees of phenotypic variation.7,32,33 For example, the Val30Met mutation has a later clinical onset (at 55–60 years of age on average) and a lower penetrance (69 % at 90 years) in northern Sweden34 and an earlier clinical manifestation (at 30–35 years of age) and a much higher penetrance (89 % at 60 years and 91 % at 80 years) in Portugal.35 The gender of the transmitting parent was shown to impact the penetrance of the disease.34,36 Genetic anticipation has been described in several kindreds in endemic areas.37–39 The genetic factors underlying these phenomena are currently unknown but are under intense scrutiny.40–44 Moreover, anecdotal reports of discordant cases of TTR-FAP in monozygotic twins45–49 suggest the involvement of presently unidentified environmental factors.

Clinical Features
The clinical picture of TTR-FAP is dominated by the association of a sensorimotor and autonomic polyneuropathy with a family history of neuropathy.7,50,51 The clinical onset is characterised by numbness and spontaneous pains in the feet, impaired thermal sensitivity over the feet and reduced pinprick sensation with preserved light touch sensation and proprioception. The hallmark is the relentless proximal progression of the sensory deficits, which, during the following months and years, extend to the thighs and to the upper limbs. As larger sensory and motor nerve fibres become involved, impairment of light touch and deep sensations, with motor deficits, ensues. These manifestations are often accompanied or preceded by carpal tunnel syndrome. Unassisted walking becomes progressively difficult and autonomic dysfunction emerges with cardiocirculatory, gastrointestinal and genitourinary dysfunctions including orthostatic hypotension, severe constipation/episodic postprandial diarrhoea or alternation thereof, dysuria, urinary retention and erectile dysfunction in men.7,50,51 The latter can often be the first manifestation of the disease.
Differences have been reported in presentation between early-onset cases in endemic areas and late-onset cases in non-endemic areas (reviewed by Plante-Bordeneuve and Said).51 In the latter cases there is a preponderance of males, milder autonomic dysfunction and more frequent heart involvement.
Involvement of the ciliary nerve may lead to the so-called ‘scalloped pupils’, which are almost pathognomonic for FAP26,52 and involvement of the recurrent laryngeal nerve can cause vocal hoarseness.
Central nervous system (CNS) manifestations – including recurrent cerebral haemorrhage, seizures, psychosis, deafness and visual impairment – are present in association with some TTR mutations and, when they dominate the clinical picture, they are indicated as TTR-associated leptomeningeal or oculoleptomeningeal amyloidosis or cerebral amyloid angiopathy.53–56
Non-neurological manifestations can arise as a result of TTR amyloid deposition in the heart, eyes and kidneys. Progressive amyloid deposition within the heart induces electrical disturbances and restrictive cardiomyopathy with distinctive features with respect to other types of amyloid cardiomyopathy and which is often the cause of death in TTR-FAP patients.57–59 When, in association with specific mutations, the cardiac involvement dominates the clinical picture, the disease is rather referred to as familial amyloid cardiomyopathy (FAC).8,60 Ocular manifestations comprise abnormal conjunctival vessels, keratoconjunctivitis sicca, vitreous opacity and glaucoma.61
Renal involvement can lead to proteinuria and end-stage renal disease requiring replacement therapy62 and TTR-FAP patients have been shown to display inappropriately low serum levels of erythropoietin and anaemia.63
Over the years, progression of amyloid neuropathy and visceral organ involvement is paralleled by significant body weight loss, eventually leading to cachexia. Death occurs on average within 10 years of clinical onset.7,50,51,64
Pathology and Pathophysiology
Amyloid deposits, which can be unambiguously detected based on their pathognomonic green birefringence when stained with Congo red and analysed under polarised light, start around endoneurial capillaries and slowly progress. The process is accompanied by degeneration of Schwann cells, destruction of unmyelinated fibres and in late stages, distortion of nerve fibres, demyelination and distal axonal degeneration.51 The mechanisms underlying the toxic effect of TTR amyloid formation are poorly understood. Mechanical effects, as well as a direct toxic insult from intermediates of the amyloidogenic process, could coincide to drive the neurodegeneration observed in TTR-FAP patients.65–69 Among Val30Met TTR-FAP patients, the composition of amyloid deposits seems to have some phenotypic and prognostic implications. Presence of TTR fragments in addition to full-length TTR within amyloid deposits is associated with later clinical onset and cardiac involvement.70 Moreover, patients having both fragmented and intact TTR molecules within the amyloid deposits are more likely to deteriorate pre-existing cardiomyopathy and heart failure after liver transplantation.71


Physical examination and electrophysiological tests should point towards a form of length-dependent small-fibre sensorimotor polyneuropathy.51
In patients with no family history of neuropathy – not an uncommon occurrence in TTR-FAP due to the late onset and the low penetrance of TTR mutations in some areas51 – a nerve biopsy may be required to differentiate amyloid polyneuropathy from other conditions, such as chronic inflammatory demyelinating polyneuropathy (CIDP).51,72,73 In these cases, demonstration of amyloid deposits within the nerve allows diagnosis of an amyloid polyneuropathy. However, to possibly spare such an invasive procedure, abdominal fat aspiration, even if associated with a lower sensitivity compared with amyloid light-chain (AL) amyloidosis, should be performed early in the diagnostic work-up when amyloidosis is suspected, together with a search for mutations in TTR by means of direct sequencing. The demonstration of an amyloidogenic variant in the gene is mandatory for the ultimate diagnosis of this disease. Due to its significant allelic heterogeneity, sequencing of the entire coding regions of the TTR gene is always recommended.
A differential diagnosis among the various forms of amyloidosis associated with peripheral nerve involvement – that is, immunoglobulin AL amyloidosis and FAP with mutation in apolipoprotein A-I or gelsolin – may be required in some cases.74

The demonstration of a monoclonal component in a patient with amyloid neuropathy is compatible with a diagnosis of AL amyloidosis requiring aggressive chemotherapy against the causal plasma cell clone.75 However, the possibility of an incidental association of a non-AL systemic amyloidosis and an unrelated monoclonal gammopathy (more often a monoclonal gammopathy of undetermined significance [MGUS])76 should be taken into account. 77,78 In these cases, unambiguous typing of the amyloid deposits with immuno-electron microscopy79 or mass spectrometry-based techniques80–82 and DNA testing is decisive.
FAP associated with mutations of apolipoprotein A-I (Gly26Arg, also termed Iowa type) is rare and is generally accompanied by extra-neurological involvement including renal, hepatic and gastrointestinal involvement.83 If ATTR and AL amyloidosis have been excluded as causes of a biopsy-proven amyloid polyneuropathy, apolipoprotein A-I Gly26Arg is the most likely candidate to be considered. On the other hand, the epidemiological and clinical peculiarities of the remaining type of FAP render it unlikely to be considered in the differential diagnosis of an amyloid-associated sensorimotor polyneuropathy. Indeed, the form associated with mutations of gelsolin (also called FAP of Finnish type) is extremely rare, is present almost exclusively in Finland and typically presents with corneal lattice dystrophy followed by cranial neuropathy and cutis laxa.84
Alternatively, in the presence of a family history of TTR-FAP and a clear clinical picture, DNA testing is often sufficient to achieve a diagnosis.51 However, the possibility of alternative aetiologies (CIDP, AL amyloidosis) should be formally considered.
Finally, once a diagnosis of TTR-FAP has been achieved, careful extra-neurological investigations, including ophthalmological, cardiological and nephrological assessment, should be performed to determine the level of systemic involvement. Patients and family members are also to be offered adequate genetic counselling.

Treatment – Current and Prospective Therapies

An intensive and multidisciplinary approach – including neurological, cardiological, ophthalmological, nutritional, nephrological and rehabilitative interventions – is required to alleviate the symptoms of TTR-FAP patients and to prevent complications associated with disease.51,85
However, aetiological treatments are needed to interfere with the cascade of events leading from TTR production to amyloidogenesis and organ dysfunction (see Figure 1).
Reduction of the Amyloidogenic Precursor – Liver Transplantation Akin to other types of systemic amyloidosis, the most effective way to achieve this goal is to eradicate or minimise the synthesis of the amyloidogenic precursor. This was attempted for the first time in 1990 through liver transplantation.86 Since then, more than 1,900 liver transplantation procedures have been performed, both from cadaveric and living donors (FAP World Transplant Registry, as of 31 December 2010, see Liver transplantation in TTR-FAP patients results in a sustained and significant reduction in plasma levels of mutated TTR87–89 and leads to increased survival.64,90 Non-Val30Met genotypes, a clinical onset after 50 years of age and an advanced clinical stage at the time of surgery adversely influence the outcome of liver transplantation.64,91 Therefore liver transplantation should ideally be performed in TTR-FAP patients at an early stage of the disease. On the other hand, pre-emptive liver transplantation in individuals at genetic risk of the disease is not feasible due to the incomplete penetrance of pathogenic TTR mutations.51
Following liver transplantation, visceral amyloid deposits can slowly regress, as documented by whole-body scintigraphy using radiolabelled SAP.92 More often, amyloid neuropathy does not significantly improve, but its progression can be halted.93 Liver transplantation does not generally impact the progression or de novo appearance of amyloid deposition in the eye or in the CNS, probably due to the unaffected local production of mutated TTR in the retina and in the choroid plexus.94–96 In the former case, pan-retinal laser photocoagulation aimed at destroying the TTR-producing retinal pigment epithelium could represent a valid therapeutic option,97 but further investigations are needed.
Remarkably, cardiac amyloidosis also progresses despite almost complete removal of variant TTR from the circulation with liver transplantation, most probably due to the continuous deposition of wild-type TTR in the myocardium.18,19 The same mechanism could explain the progression of amyloid neuropathy occasionally seen in TTR-FAP patients who underwent liver transplantation,20 but in these cases the participation of mutated TTR synthesised by the choroid plexus and released in the endoneurial space via the subarachnoid space98 should be considered. In highly selected patients with severe involvement of the heart or kidney, a combined heart and liver or kidney and liver transplantation is a valid therapeutic option.99,100
Explanted livers of TTR-FAP patients, which are typically amyloid-free and do not show any abnormality other than producing a mutated TTR, can be used for so-called ‘domino’ liver transplantations, which, however, entail the risk of transmitting ATTR to the final recipient.101,102 Due to the shortage of liver donors, the requirement for life-long immunosuppressive regimens in recipients, the slight effect on ocular and cerebral deposits and the unfeasibility of liver transplantation for asymptomatic mutation carriers, other therapeutic approaches are urgently needed to halt the production of mutant TTR.103

Targeted Gene Repair
The possibility of correcting a pathogenic mutation in the mammalian genome by RNA/DNA oligonucleotides104 has encouraged researchers to apply this approach in order to repair a mutated TTR allele. As a proof of principle, a human hepatic cell line (HepG2) has been used to convert the endogenous wild-type TTR gene into the gene encoding the Val30Met mutant of TTR.105 Single-stranded oligonucleotides (SSOs) proved more efficient than chimeraplasts in achieving the desired gene conversion in vitro.106 The same approach was then applied to transgenic mice expressing murine TTR Val30Met. Intrahepatic, but not intraperitoneal, injection of SSOs led to a gene conversion of 8–9 % at both messenger RNA (mRNA) and protein level.107
This strategy requires further methodological development103 and the capacity to target extrahepatic sites of TTR production needs to be assessed. Moreover, as observed with liver transplantation, this approach will not halt the progression of amyloid brought about by wild-type TTR if started after disease onset.
However, targeted gene repair could find invaluable applications in the treatment of asymptomatic carriers, especially in areas with high penetrance of pathogenic mutations, provided that safe and efficient protocols for gene conversion can be developed.
Suppression of Mutant Transthyretin Messenger Ribonucleic Acid
Earlier attempts at gene knockdown therapy in ATTR have aimed at achieving specific downregulation of mutant TTR mRNA, without altering the expression of wild-type TTR mRNA. Catalytically active RNAs termed hammerhead ribozymes allowed a significant reduction in wild-type or Val30Met TTR at mRNA and protein levels, in a cell-free system or in cell lines, to be achieved, using different constructs for the normal and mutated TTR.106,107 Also, hammerhead and hairpin ribozymes designed against another pathogenic TTR mutation, Glu61Lys, resulted in a significant reduction in mutant – but not wild-type – TTR (both mRNA and protein) in cell lines.108 Likewise, small interfering RNA (siRNA) was shown to downregulate Val30Met, but not wild-type, TTR mRNA and protein expression, even in cell lines expressing both alleles.109
Compared with targeted gene repair, which aims at correcting the genetic defect at the genomic level and can, therefore, be permanent, the above-mentioned gene knockdown technologies are transient and rely on continuous administration of the knockdown agent. A Phase I study for evaluating the toxicity profile, best schedule and effect on plasma TTR concentration of siRNA targeting TTR mRNA has been performed. The results were reported at the recent Eighth International Symposium on Familial Amyloidotic Polyneuropathy held 20–22 November 2011 at Kumamoto, Japan. Data presented at that time were from 31 patients (eight received placebo and 23 received drug) and showed that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels in ATTR patients. Lowering of serum TTR protein was found to be dose-dependent, rapid and durable after just a single dose.110
Alternative knockdown strategies based on the use of antisense oligonucleotides (ASOs) have been developed which aim at silencing both variant and normal TTR. The basis for this strategy relies on the fact that both variant and normal TTR are found in the deposits of TTR-FAP patients and, on the other hand, that TTR expression is dispensable, since TTR-null mice are viable, fertile and do not show any obvious phenotype apart from depressed levels of plasma retinol and thyroid hormone.111
Subcutaneous injection of anti-TTR ASOs in transgenic mice homozygous for human Ile84Ser TTR and expressing high levels of the variant TTR resulted in a significant reduction in hepatic TTR mRNA and in circulating levels of TTR.112 This reduction in TTR levels could be protracted for up to six weeks by repeated applications of ASOs and was not accompanied by significant hepatotoxicity.112 No reduction in TTR levels could be observed in the choroid plexus, unless anti-TTR ASOs were administered locally via intracerebral ventricular injection.113 Studies are currently on-going to assess the safety of anti-TTR ASOs in non-human primates.114
Based on the enthusiasm accompanying the development of amyloid-β (Aβ) immunotherapy against Alzheimer’s disease,115 an active immunisation approach has been tested as a potential treatment of ATTR in a preclinical model. Previous work had identified a TTR variant – TTR Tyr78Phe – which exposes a cryptic epitope present only on highly amyloidogenic TTR variants or on amyloid fibrils.116 Immunisation of transgenic mice expressing human Val30Met TTR117 with TTR Tyr78Phe reduced or inhibited the formation of non-fibrillary and amyloid TTR as opposed to vehicle-treated or TTR Val30Met-immunised mice.118 In TTR Tyr78Phe-treated animals, common sites of TTR deposition were characterised by the presence of an inflammatory infiltrate composed mainly of B lymphocytes and macrophages, whereas no histological modifications were observed at TTR-synthesising sites.118 These results are encouraging, but further investigations are needed to extend these observations and develop a safe and effective immunotherapy against ATTR.
Anti-serum Amyloid P Component Therapy
Another strategy to interfere with the formation and persistence of amyloid deposits is directed against SAP. This is based on the observation that SAP prevents proteolysis of amyloid fibrils119 and accelerates their formation in vitro.120 A palindromic compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) has been developed which inhibits SAP binding to amyloid fibrils, dramatically depletes circulating SAP and eventually removes SAP from amyloid deposits.121 The safety and biochemical and clinical effects of CPHPC in systemic amyloidoses have been investigated in a recent open-label proof-of-principle study.122 Overall, the drug appeared to be safe, but amyloid deposits persisted in most patients. The observation that residual SAP was still present in amyloid-laden tissues despite long-term treatment with CPHPC, and might therefore account for the persistence of amyloid deposits in the study subjects, formed the rationale for an integrative approach. Using an experimental mouse model of amyloidosis, the same group has investigated the effect of a combination of CPHPC treatment with the administration of a specific anti-SAP antibody.123 Mice treated with CPHPC and receiving a single injection of anti-SAP antibody showed a rapid complement-dependent, macrophage-derived giant-cell reaction, which resulted in a striking reduction in amyloid load when compared with untreated animals or animals receiving CPHPC alone.123 A fully humanised version of an anti-SAP monoclonal antibody is currently under investigation.

Fibril Disruptors
In 1995, we serendipitously discovered the anthracycline 4′-iodo-4′-deoxydoxorubicin (IDOX) as the prototype of a class of compounds able to inhibit protein aggregation in vitro, in animal models of systemic amyloidosis124 and in patients.125,126 The first study showed that IDOX presented high affinity for all types of amyloid deposits and would have been a candidate for the treatment of all types of amyloidosis.124 It was demonstrated that IDOX was capable of inducing the destructuration of TTR amyloid fibrils.127 In consideration of the cytotoxicity of IDOX, in the following years the tetracycline antibiotics were investigated on the basis of structural homologies with the aglycone moiety of the anthracyclines. Doxycycline was able to interfere with TTR Leu55Pro amyloid formation and to disrupt TTR fibrils.128 Cardoso and Saraiva assessed the activity of doxycycline in vivo in the transgenic mouse model of ATTR and showed that the administration of doxycycline in drinking water resulted in the complete prevention of amyloid deposit formation.129 More recently, it has been reported that tauroursodeoxycholic acid (TUDCA), a biliary acid, administered to the same transgenic mouse model was effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. Combined cyclic doxycycline and TUDCA administration to mice with amyloid deposition was more effective than either doxycycline or TUDCA individually in significantly lowering TTR deposition and associated tissue markers.130 The observed synergistic effect of doxycycline plus TUDCA, in the range of quantities tolerable in humans, in the TTR transgenic mice models prompted their application in FAP, particularly in the early stages of disease. Based on these data, a Phase II clinical trial assessing the safety, efficacy and pharmacokinetics of doxycycline plus TUDCA in ATTR was designed and implemented at our institution in Pavia (NCT01171859 The preliminary results were reported at the recent Eighth International Symposium on Familial Amyloidotic Polyneuropathy.131 In the 20 patients treated, no serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over one year. These preliminary data indicate that the combination of doxycycline and TUDCA stabilises the disease for at least one year in the majority of patients with an acceptable toxicity profile.131
Stabilisation of Transthyretin Tetramers
The discovery that TTR tetramer dissociation is the required first step in the amyloidogenic cascade has opened the avenue to the discovery of TTR kinetic stabilisers, acting like pharmacological chaperones which halt the amyloid process by preventing tetramer dissociation.15,132 Although numerous structurally distinct TTR kinetic stabilisers have been identified,132 only two drugs, diflunisal (NCT00294671) and tafamidis meglumine (NCT01435655) have entered clinical trials. The results of the double-blind placebo-controlled diflunisal trial are not yet available; preliminary data indicate that the drug is well tolerated.133 The efficacy and safety of tafamidis (20 mg orally administered once daily) were evaluated in an 18-month randomised double-blind placebo-controlled trial involving 128 patients with TTR-FAP with the Val30Met mutation and primarily stage I disease. After 18 months of treatment, neuropathy did not progress in 60 % of patients who received tafamidis meglumine versus 38 % of the placebo group. Neurological deterioration was decreased by 52 %; quality of life and modified body mass index were maintained under tafamidis meglumine and worsened under placebo.134 Of the 91 patients completing the 18-month treatment period, 86 were subsequently enrolled in an open-label extension study, in which they all received once-daily 20 mg tafamidis for a further 12 months. The rate of change in the NIS-LL score during the 12 months of treatment in this study was similar to that observed in those patients who had been randomised and treated with tafamidis in the previous double-blind 18-month period.134
In November 2011, tafamidis (Vyndaqel®, Pfizer) was granted marketing authorisation by the European Commission for the treatment of ATTR in adult patients with stage I symptomatic polyneuropathy to delay peripheral neurological impairment. The availability of a pharmacological treatment for TTR-FAP is a milestone in the field of FAPs.
Treatment Strategy
A multidisciplinary approach to treatment of symptoms such as neuropathic pain, orthostatic hypotension, gastrointestinal malfunction, cardiac arrhythmias, cardiac failure, renal insufficiency and ocular disturbances remains fundamental. In all patients (carrying the Val30Met mutation or other mutations) diagnosed at stage I of the disease, the choice now is between early liver transplantation and tafamidis. Liver transplantation seems to reduce the rate of progression of the neuropathy but does not protect against cardiac involvement, which occurs in about 80 % of cases of TTR-FAP. Cardiac and ocular amyloid depositions progress in patients who have undergone transplants,135 but whether these manifestations will be controlled by tafamidis remains to be seen. Patients with early disease manifestation should be put on a liver transplant waiting list and tafamidis may be started with mandatory periodic (every six months) evaluation. The patient may stay continuously on tafamidis unless early signs of disease progression should appear. In this case, liver transplantation should be promptly carried out. These indications are subject to modification as more data on the long-term effects of tafamidis treatment are gathered through the on-going post-marketing evaluation. As the data on the efficacy of diflunisal and doxycycline plus TUDCA mature, more treatment options might become available that will certainly affect treatment strategies.
Concluding Remarks
TTR-FAP has experienced revolutionary progress in our understanding of the mechanisms of this disease, which has translated into an unprecedented blooming of novel medicines. In the near future, the exploitation of these remedies is likely to deeply affect patient outcomes, with the grounded hope of making the invasive liver transplantation procedure no longer necessary. The availability of effective therapies will render the need for early diagnosis even more acute, as the amyloidoses are progressive, devastating diseases. We know now that it is very difficult to recover a damaged nervous system or heart; time is life. For this reason, the role of the neurologist remains fundamental: maintaining a high level of alert towards this rare, but potentially treatable, disease, will allow the timely identification of patients and the prompt institution of therapy.

Article Information:

Mario Nuvolone received a travel grant from Pfizer. Laura Obici received consultancy honoraria from Pfizer. Giampaolo Merlini received speaker honoraria from Pfizer.


Giampaolo Merlini, Amyloidosis Research and Treatment Centre, Foundation IRCCS San Matteo Hospital and Department of Molecular Medicine, University of Pavia, Piazzale Golgi 2, 27100 Pavia, Italy. E:




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