Liver Transplantation for Hereditary Transthyretin Amyloidosis

Ericzon, Bo Göran; Wilczek, H; Larsson, Markus; Wijayatunga, Priyantha; Stangou, Arie J.; Peña, J; Furtado, Emanuel; Barroso, Eduardo; Daniel, J.; Samuel, Didier; Adam, René; Karam, Vincent; Poterucha, John J.; Lewis, David M.; Ferraz-Neto, Ben Hur; Cruz, Márcia Waddington; Munar-Qués, Miguel; Fabregat, J.; Ikeda, Shu Ichi; Ando, Yumiko; Heaton, Nigel; Otto, Gerd; Suhr, Ole B.

doi:10.1097/tp.0000000000000574

Cited by 268 publications

(129 citation statements)

References 28 publications

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“…Elimination of mutant TTR is the fundamental driver behind liver transplantation for ATTR amyloidosis with polyneuropathy, and the clinical benefits associated with this procedure highlight the potential effect of therapies that can lower hepatic TTR. 20,21 Indeed, the high level of TTR knockdown achieved with revusiran ($90%) is comparable with the reduction in mutant TTR following liver transplantation, with the added advantage of affecting both mutant and WT TTR production. The high potency of revusiran is also particularly promising because a reduction in levels of amyloidogenic protein of only 50% has been associated with clinical benefits in light-chain amyloidosis.…”

Section: Discussionmentioning

confidence: 70%

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

et al. 2017

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Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25-10 mg/kg in the single and 2.5-10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5-10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p < 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

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Section: Discussionmentioning

confidence: 70%

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

et al. 2017

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“…Additionally, the benefits of transplantation may be counterbalanced by the requirement of lifelong immunosuppression, surgical risk in already hemodynamically-compromised patients, and high expense. The literature suggested that liver transplantation in isolation in older adult patients with cardiomyopathy was not effective and combined heart and liver transplantation is usually reserved for younger individuals (41). Additionally, amyloid progression might potentially progress after organ transplant; normal wild-type TTR can build up on previously deposited transthyretin in the heart and nerves, leading to recurrent amyloid cardiomyopathy or progression of polyneuropathy.…”

Section: Discussionmentioning

confidence: 99%

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis

Maurer

Hanna

Grogan

et al. 2016

Journal of the American College of Cardiology

402

247

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BACKGROUND Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES We described ATTR in the United States in the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared to other regions of the world (ROW) (n = 2,140) with a focus on the phenotypic expression and survival in the majority of U.S. subjects with Val122Ile (n = 91) and wild-type ATTR (n = 189). RESULTS U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%) and more often of African descent (25.4% vs. 0.5%) than ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 of 107 patients with Val122Ile (85%) were from the United States, where Val122Ile subjects were younger and more often women and black than wild-type patients, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a TTR mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult males with a cardiac-predominant phenotype. Val122Ile is the most common TTR mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. CLINICAL TRIAL NCT00628745

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“…The median survival after liver transplantation indeed increased to more than 20 years, and the 10-year survival is about 85% [40]. However, this approach is not always successful, because ATTR amyloid sometimes progresses in the heart after liver transplantation.…”

Section: Treatmentmentioning

confidence: 99%

“…It looks as if wild-type ATTR amyloidosis takes over and further progresses in these transplanted patients. Because of this, patients with late disease onset (often males with cardiomyopathy) and patients with non-TTR-Met30 mutations are deemed less eligible for liver transplantation [40,41]. …”

Section: Treatmentmentioning

confidence: 99%

The Prevalence and Management of Systemic Amyloidosis in Western Countries

Nienhuis

Bijzet

Hazenberg³

2016

Kidney Dis

109

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Background: Amyloidosis has been a mystery for centuries, but research of the last decennia has clarified many of the secrets of this group of diseases. A protein-based classification of amyloidosis helps to understand problems that were part of the obsolete clinical classification in primary, secondary, and familial amyloidosis. All types of amyloid are secondary to some underlying precursor-producing process: each type is caused by a misfolded soluble precursor protein that becomes deposited as insoluble amyloid fibrils. Summary: The incidence of amyloidosis is not well documented, but probably falls between 5 and 13 per million per year. Prevalence data are scarce, but one UK study indicates about 20 per million inhabitants. Amyloidosis can be localized (amyloid deposited in the organ or tissue of precursor production) or systemic (amyloid at one or more sites distant from the site of precursor production). The major systemic types of amyloidosis are AL (associated with a light chain-producing plasma cell dyscrasia), AA (associated with longstanding inflammation), wild-type ATTR (associated with normal transthyretin and old age), and hereditary ATTR (associated with a transthyretin mutation) amyloidosis. Imaging techniques, such as cardiac ultrasound, magnetic resonance imaging, bone scintigraphy, and serum amyloid P component scintigraphy, are useful both for diagnosing amyloidosis and for assessing disease severity. Serologic markers are useful for detecting organ disease and disease monitoring during follow-up. Current treatment modalities are directed against the ongoing supply of precursor proteins and thereby aim to stop further accumulation of amyloid. Novel treatment modalities, such as interference with amyloid formation and even removal of amyloid, are being studied. A well-thought and planned monitoring during follow-up helps to assess the effect of treatment and to early detect possible progression of amyloidosis. Key Messages: Clinical management comprises histologic proof of amyloid, evidence of systemic deposition, reliable typing, precursor assessment, severity of organ disease, risk assessment and prognosis, choice of treatment, and planned monitoring during follow-up. Facts from East and West: (1) AL amyloidosis is the most prevalent type of amyloidosis accounting for 65% of the amyloidosis-diagnosed patients in the UK and for 93% of the amyloidosis-diagnosed patients in China. The predisposition of men over women to develop AL amyloidosis might be higher in China than in Western countries (2:1 vs. 1.3:1). Both in the East and West, incidence increases with age. At the time of diagnosis, edema is twice as frequent and the proportion of renal involvement is higher in Chinese compared to Western patients. (2) Melphalan followed by autologous stem cell transplantation (ASCT) is the current standard therapy but is restricted to eligible patients. The efficacy and safety of bortezomib combined with dexamethasone were proven in Western patients and recently confirmed in a Chinese cohort. Recent stu...

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Liver Transplantation for Hereditary Transthyretin Amyloidosis

Abstract: Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

Cited by 268 publications

References 28 publications

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis

The Prevalence and Management of Systemic Amyloidosis in Western Countries

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