small molecules

2026-09-11 | Valve diseases in cardiac amyloidosis: What we have to know.

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of amyloid fibrils, most commonly derived from immunoglobulin light chains (AL) or transthyretin (ATTR). While myocardial involvement has been extensively characterized, valvular disease in CA has received comparatively less attention, despite its frequent occurrence and significant clinical impact. Aortic stenosis (AS) represents the most prevalent valvular manifestation, particularly in wild-type ATTR amyloidosis, where shared demographic and pathophysiological factors contribute to a frequent overlap. Concomitant CA and AS create a synergistic interaction, leading to disproportionate ventricular dysfunction, a high prevalence of the low-flow low-gradient phenotype and increased perioperative risk. Echocardiographic strain analysis, dedicated scoring systems and advanced imaging such as cardiac magnetic resonance and computed tomography allow earlier recognition of this association and aid in patient stratification. Mitral and tricuspid regurgitation, usually functional and related to atrial enlargement, annular dilatation and restrictive physiology, are also common in CA and carry important prognostic implications. Severe regurgitation is associated with heart failure progression, systemic congestion and increased mortality. Although surgical approaches are rarely feasible, transcatheter interventions (TAVR, TEER and emerging tricuspid devices) offer promising therapeutic alternatives in selected patients. Management of valvular disease in CA must therefore integrate interventional options with disease-modifying therapies targeting amyloid deposition, such as TTR stabilizers and silencers, to optimize outcomes. Thus, considering the valves involvement in patients with CA, the aim of this review was to illustrate the main valvular alterations in CA, their prognostic role and their treatment.

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2026-09-01 | Quercetin inhibits wild-type transthyretin fibril formation and attenuates associated cytotoxicity in vitro.

The misfolding and subsequent aggregation of transthyretin (TTR) into amyloid fibrils, which deposit in tissues such as the heart and peripheral nerves, underlies a series of progressive and fatal diseases. Consequently, molecules that inhibit protein misfolding represent a promising therapeutic strategy. Structural analysis of the TTR-quercetin complex indicates that quercetin stabilizes the TTR tetramer. In this study, Thioflavin T fluorescence assays, transmission electron microscopy, circular dichroism spectroscopy, and Fourier transform infrared spectroscopy demonstrated that quercetin significantly delays the aggregation rate of TTR. This leads to a decrease in β-sheet content and fibril formation. Furthermore, the inhibition of fibrillogenesis by quercetin significantly attenuated the cytotoxicity induced by TTR fibrils. These findings suggest that quercetin holds promise as a natural product for treating transthyretin amyloidosis. However, further in vivo studies and clinical trials are required to validate these findings and explore its translational potential.

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2026-08-11 | Vitronectin-driven amyloid deposition disrupts mitochondrial homeostasis via integrin-mediated pathway in a humanized mouse model of transthyretin cardiac amyloidosis.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined. Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide. Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress. Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.

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2026-06-17 | Differential Transthyretin Stabilization in Patients With Wild Type and Variant Transthyretin Amyloidosis.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).

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2026-06-01 | Spectrum of cardiac amyloidosis in clinical practice: insights from a single centre

Abstract Background Cardiac amyloidosis (CA) is a frequently underdiagnosed cause of heart failure. Early identification of affected patients and close interdisciplinary collaboration are essential for accurate diagnosis, appropriate subtyping, and timely initiation of disease-specific therapy. Methods From January 2023 to December 2025, 78 consecutive patients with suspected cardiac amyloidosis were referred to a specialized outpatient clinic. Referrals originated predominantly from cardiology (53.8%) and neurology departments (29.4%), followed by internal medicine (3.8%), hematology (5.1%), and radiology (1.3%). All patients underwent a comprehensive diagnostic evaluation including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, laboratory assessment, genetic testing, and endomyocardial biopsy when clinically indicated. Results Cardiac amyloidosis was confirmed in 44 of 78 patients (56.4%). Wild-type transthyretin amyloidosis (ATTRwt) was the most prevalent subtype (n=26), followed by light-chain amyloidosis (AL, n=12) and hereditary transthyretin amyloidosis (ATTRh, n=6). The median age was 73 years (IQR 66,2–80,5), and 70% of patients were male. All ATTRh patients presented with concomitant polyneuropathy. Compared with ATTRwt, AL patients were younger (median 67.5 vs. 77 years; p=0.007) and more frequently exhibited renal impairment (60% vs. 71%; p=0.01). Biomarker analysis revealed significantly higher NT-proBNP and troponin T levels in AL amyloidosis (p=0.05 and p=0.02, respectively). Echocardiography demonstrated preserved left ventricular ejection fraction across subtypes (median EF: AL 50%, ATTRwt 55%, ATTRh 60%) and increased interventricular septal thickness (median IVSd: 18 mm in AL and ATTRwt, 16 mm in ATTRh). Cardiac magnetic resonance imaging was most frequently utilized in AL patients (80%), whereas bone scintigraphy confirmed the diagnosis in all ATTRwt and ATTRh cases. Endomyocardial biopsy established the diagnosis in 8 patients (5 AL, 3 ATTRwt). Standard heart failure therapy included diuretics (84%), mineralocorticoid receptor antagonists (up to 70%), and SGLT2 inhibitors, particularly in ATTRwt patients (62%). Disease-specific treatment comprised tafamidis in 88% of ATTRwt patients and patisiran in 33% of ATTRh patients. Overall mortality during the study period was 10%. Conclusion This single-centre experience demonstrates the growing recognition of cardiac amyloidosis and emphasizes the necessity of a multidisciplinary diagnostic strategy. ATTRwt amyloidosis was the predominant subtype, characterized by distinct clinical, echocardiographic, and therapeutic features. Accurate and timely subtyping is crucial for guiding tailored therapy and improving patient outcomes.

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proteins

2026-02-26 | Lysozyme as an amyloid fibril protein together with transthyretin in the ligamentum flavum in association with lumbar spinal stenosis

Transthyretin amyloid (ATTR) is frequently found in aging ligaments and may represent an early sign of systemic ATTR amyloidosis, particularly of wild-type origin. Amyloid deposits of other compositions are commonly observed alongside ATTR deposits. Ligamentum flavum samples obtained during surgery for lumbar spinal stenosis, containing distinct ATTR amyloid deposits as well as amyloid of unknown composition, were analyzed using high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS), electron microscopy, immunohistochemistry, and immunofluorescence confocal microscopy. In vitro fibril formation and potential cross-seeding by the two major proteins, transthyretin and lysozyme, were assessed with the thioflavin-T assay. A close topographic association between ATTR deposits and elastic material was evident. Distinct ATTR amyloid was intermingled with non-ATTR amyloid. HPLC-MS/MS identified three major amyloid fibril proteins with high score: transthyretin (TTR), apolipoprotein AI, and lysozyme. Congo red positivity combined with immunoreactivity for TTR and lysozyme demonstrated that ATTR predominated, though distinct lysozyme amyloid deposits were also present. Only minimal apolipoprotein AI-positive amyloid was detected. In vitro, cross-seeding between TTR and lysozyme was not observed; however, lysozyme inhibited TTR fibrillation. In lumbar spinal stenosis, ATTR amyloid deposits are predominant but are often intermixed with other amyloid deposits, notably those of lysozyme origin.

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2025-09-03 | Medin and transthyretin: a new amyloid double act in the aortic wall and valves.

Cross-seeding and co-assembly of multiple amyloid species are increasingly recognised in various organs and amyloidoses. Medin and wild-type transthyretin (TTR) both form age-related amyloid deposits and have been identified within the aortic wall. Given the emerging role of amyloid in aortic disease, this study investigates the potential colocalisation of TTR and medin in the aorta. Medin and TTR levels were measured in thoracic aortic wall samples from 30 patients undergoing surgical replacement for aortic aneurysm. Immunohistochemistry was performed on five aortic wall samples and two excised aortic valves to assess colocalisation patterns. In vitro assays, including Thioflavin T fluorescence and immunogold labelling electron microscopy, evaluated protein co-aggregation and fibril formation. Cellular toxicity assays examined the impact of TTR on medin aggregates. A positive correlation was observed between medin and TTR levels in the aortic wall. In vitro assays revealed enhanced fibril formation and co-aggregation, with TTR reducing the cellular toxicity of medin aggregates, suggesting altered fibril properties. Immunohistochemistry confirmed colocalisation of medin and TTR in both aortic wall and valve samples. This study identifies a novel association between medin and TTR, highlighting a potential role for co-aggregation in vascular amyloid deposition.

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2024-07-28 | Identification of the interfacial regions in misfolded transthyretin oligomers.

Misfolding and aggregation of transthyretin (TTR) is associated with numerous ATTR amyloidosis. TTR aggregates extracted from ATTR patients consist of not only full-length TTR, but also N-terminally truncated TTR fragments that can be produced by proteolytic cleavage, suggesting the presence of multiple misfolding pathways. Here, we report mechanistic studies of an early stage of TTR aggregation to probe the oligomerization process for the full-length as well as N-terminally truncated TTR. Our kinetic analyses using size exclusion chromatography revealed that amyloidogenic monomers dissociated from wild-type (WT) as well as pathogenic variants (V30M and L55P) form misfolded dimers, which self-assemble into oligomers, precursors of fibril formation. Dimeric interfaces in the full-length misfolded oligomers were investigated by examining the effect of single-point mutations on the two β-strands (F and H). The single-point mutations on the two β-strands (E92P on strand F and T119W on strand H) inhibited the dimerization of misfolded monomers, while the TTR variants can still form native dimers through the same F and H strands. These results suggest that the two strands are involved in intermolecular associations for both native and misfolded dimers, but detailed intermolecular interactions are different in the two forms of dimers. In the presence of a proteolytic enzyme, TTR aggregation is greatly accelerated. The two mutations on the two β-strands, however, inhibited TTR aggregation even in the presence of a proteolytic enzyme, trypsin. These results suggest that the two β-strands (F and H) play a critical role in aggregation of the N-terminally truncated TTR as well.

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2023-03-23 | The Regulatory Mechanism of Transthyretin Irreversible Aggregation through Liquid-to-Solid Phase Transition.

Transthyretin (TTR) aggregation and amyloid formation are associated with several ATTR diseases, such as senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). However, the mechanism that triggers the initial pathologic aggregation process of TTR remains largely elusive. Lately, increasing evidence has suggested that many proteins associated with neurodegenerative diseases undergo liquid-liquid phase separation (LLPS) and subsequent liquid-to-solid phase transition before the formation of amyloid fibrils. Here, we demonstrate that electrostatic interactions mediate LLPS of TTR, followed by a liquid-solid phase transition, and eventually the formation of amyloid fibrils under a mildly acidic pH in vitro. Furthermore, pathogenic mutations (V30M, R34T, and K35T) of TTR and heparin promote the process of phase transition and facilitate the formation of fibrillar aggregates. In addition, S-cysteinylation, which is a kind of post-translational modification of TTR, reduces the kinetic stability of TTR and increases the propensity for aggregation, while another modification, S-sulfonation, stabilizes the TTR tetramer and reduces the aggregation rate. Once TTR was S-cysteinylated or S-sulfonated, they dramatically underwent the process of phase transition, providing a foundation for post-translational modifications that could modulate TTR LLPS in the context of pathological interactions. These novel findings reveal molecular insights into the mechanism of TTR from initial LLPS and subsequent liquid-to-solid phase transition to amyloid fibrils, providing a new dimension for ATTR therapy.

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2022-04-06 | Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. "Amyloid seeds" are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.

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oligonucleotides

2026-08-30 | Gene Silencer Therapy in Transthyretin Amyloid Cardiomyopathy: A Meta-Analysis of Outcomes Trials.

Gene-silencing therapies reduce hepatic transthyretin (TTR) production and have been evaluated in phase 3 trials in TTR amyloid cardiomyopathy (ATTR-CM). However, differences in trial design and background therapies have limited assessment of the overall treatment effect and its consistency according to baseline TTR stabilizer use. To assess the effect of TTR gene-silencing therapies in patients with ATTR-CM. PubMed was searched through June 15, 2026, for randomized, placebo-controlled, phase 3 outcome trials of gene-silencing therapies in ATTR-CM. Two reviewers independently extracted data, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Fixed-effects meta-analysis estimated rate ratios (RRs) or hazard ratios (HRs) with 95% CIs. The prespecified primary outcome was the composite of all-cause mortality and recurrent cardiovascular events. Secondary outcomes included all-cause mortality, cardiovascular death, time to first primary outcome, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary Score). A total of 2 studies (HELIOS-B and CARDIO-TTRansform) met the inclusion criteria and included 2086 patients with ATTR-CM. The studies included 1902 men with a median age of 77 years (range for HELIOS-B, 45-85 years; for CARDIO-TTRansform, 41-91 years). Gene-silencing therapy reduced the primary end point by 20% (RR, 0.80; 95% CI, 0.69-0.94; P = .006), with no heterogeneity between trials (P for heterogeneity = .28). Gene-silencing therapy also reduced the risk of all-cause death (HR, 0.74; 95% CI, 0.61-0.91) and time to first all-cause death or cardiovascular events (HR, 0.77; 95% CI, 0.67-0.89) compared with placebo. Gene silencers preserved 6-minute walk distance (placebo-corrected difference, +22.2 m; 95% CI, 14.3-30.0) and Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (+4.5; 95% CI, 2.7-6.2), with no evidence of between-trial heterogeneity. Treatment effects on primary end points differed according to baseline stabilizer use, with significant benefits observed among patients not receiving background stabilizer therapy (RR, 0.69; 95% CI, 0.57-0.85) and no significant incremental benefit observed for those receiving concomitant stabilizer at baseline (RR, 0.97; 95% CI, 0.77-1.23; P for heterogeneity = .03). Similar heterogeneity was observed for functional capacity and health status. The findings from this meta-analysis support TTR gene silencing for ATTR-CM. The attenuated benefit observed for patients receiving concomitant TTR stabilizer therapy may reflect residual differences in case mix, disease duration, or magnitude of TTR suppression or a true ceiling on additional benefit of gene silencing in the setting of background TTR stabilization. PROSPERO registration: CRD420261421656. ClinicalTrials.gov Identifier: HELIOS-B, NCT04153149; and CARDIO-TTRansform, NCT04136171.

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2026-05-22 | Clinical And Genetic Profile Of Hereditary Transthyretin (ATTRv) Amyloidosis In The Middle East: A Single-Center Report

Background and Purpose: Transthyretin (ATTR) amyloidosis, including wild-type (ATTRwt) and hereditary (ATTRv) forms, is a rare but increasingly recognized disease. This first report from the Middle East presents our experience diagnosing ATTRv amyloidosis at the Abdali National Amyloidosis Center Methods: All referred patients underwent comprehensive evaluation. ATTR amyloidosis was established by a Perugini grade 2 or 3 positive pyrophosphate (PYP) scan, with exclusion of light chain monoclonality by serum and urine immunofixation and free light chain assay. Confirmed cases subsequently underwent genetic testing for TTR mutations Results: Between July 2021 and October 2025, 21 patients with ATTRv amyloidosis were identified (19 men, 2 women), mean age 59 years (range 40-75). Fifteen were from Iraq, two from Libya, two from Jordan, and one each from Sudan and Syria. Twenty patients had a Perugini grade 3 positive PYP scan and in one patient with the Thr60Ala mutation, the grade was 0. Mutations included Thr60Ala (n=16, Northern Iraq, Jordan, Syria), Lys55Asn (n=2, Libya), Val142Ile (n=1, Sudan), Ser43Asn (n=1, Iraq), and Val50Met (n=1, Jordan). Clinical features were heart failure in 16, neuropathy (peripheral/autonomic) in 14, diarrhea in 9, and weight loss (6-35 kg) in 14. Symptom duration ranged from 4 months to 6 years. Electrocardiographic findings included low voltage (n=7), atrial fibrillation (n=3), QRS prolongation (n=10), and permanent pacemaker implantation (n=4). All had elevated BNP/NT-proBNP and hs-troponin. Echocardiography showed left ventricular hypertrophy in 20 and pericardial effusion in 14; left ventricular ejection fraction ranged from 28-69%. Genetic screening of 16 relatives (7 men, 9 women) identified 12 carriers, with further workup confirming ATTRv in one Conclusions: This first report from the Middle East highlights the clinical profile and genetics of ATTRv amyloidosis in the region, underscoring the need for greater awareness and continued research.

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2026-05-11 | Association Between Severe Aortic Stenosis and Amyloid Deposition in the Myocardium of Patients With Wild-Type Transthyretin Cardiac Amyloidosis.

Although wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is frequently observed in older patients with aortic stenosis (AS), its relationship with AS is unclear. Therefore, this exploratory study aimed to investigate the relationship between myocardial amyloid deposition and AS in patients with ATTRwt-CA. This study included 39 patients (mean age 76 years) with biopsy-confirmed ATTRwt-CA. Myocardial amyloid deposition was quantitatively analyzed using histological evaluation of the biopsied myocardium and the heart-to-contralateral (H/CL) ratio was evaluated using bone scintigraphy. These parameters were then compared between 5 patients with severe AS and 34 patients without severe AS, and predictors of severe AS were evaluated. Myocardial amyloid deposition was greater in ATTRwt-CA patients with severe AS than in those without severe AS (mean [±SD] 32.6±12.7% vs. 19.9±11.7%; P=0.0311) but there was no difference in the H/CL ratio between the 2 groups. Multivariate analysis identified only greater myocardial amyloid deposition (per 10%) as an independent determinant of severe AS in patients with ATTRwt-CA (odds ratio 2.91; 95% confidence interval 1.23-8.67; P=0.0254). This exploratory study suggests that severe AS may be associated with myocardial amyloid deposition in patients with ATTRwt-CA, although larger prospective research is needed to validate our results.

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2026-02-04 | Precision medicine with pioneering RNAi therapeutics in ATTR amyloidosis: from bench to bedside.

Transthyretin (ATTR) amyloidosis is a multisystem disease caused by misfolding and aggregation of the plasma protein transthyretin (TTR) into insoluble amyloid fibrils in various organs. In clinical practice, ATTRwt amyloidosis manifests as a predominant cardiomyopathy (ATTR-CM), while ATTRv amyloidosis is typically associated with polyneuropathy (ATTR-PN) as well as cardiomyopathy. Over the past decade, major advances in the understanding of ATTR pathophysiology have enabled the development of disease-modifying therapies, marking a paradigm shift toward precision medicine in this condition. Among these, RNA-targeted therapies have emerged as a cornerstone of treatment by directly suppressing hepatic production of TTR. This review provides an overview of the biological rationale, molecular mechanisms, and clinical translation of RNA-based therapeutics in ATTR amyloidosis, with a particular focus on RNA interference (RNAi) and antisense oligonucleotide (ASO) strategies. Key mechanistic differences between small interfering RNAs and ASOs are discussed, including intracellular pathways, pharmacokinetic properties, and delivery platforms such as lipid nanoparticles and GalNAc conjugation for hepatocyte-specific targeting. Major clinical trials evaluating first- and second-generation RNA-targeted agents-including patisiran, vutrisiran, inotersen, and eplontersen-are summarized, highlighting efficacy, safety profiles, dosing regimens, and relevance across different ATTR phenotypes. As RNA-based therapies continue to evolve, integration of molecular insights with clinical phenotyping and real-world evidence will be essential to fully realize the potential of precision medicine for patients with ATTR amyloidosis.

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2026-01-01 | Hereditary Transthyretin Cardiac Amyloidosis Associated with Two Pathogenic Variants in the TTR Gene

Introduction Amyloidosis encompasses a group of rare diseases characterized by the accumulation of amyloidosis. Amyloidosis is an abnormal formation of misfolded proteins in tissues and organs. These proteins adopt a highly stable beta-sheet structure, forming insoluble fibrils that are deposited in the extracellular space. Amyloidosis is classified according to the precursor protein and the type of polymer formed, resulting in different subtypes of the disease, each with distinct clinical manifestations. Transthyretin amyloidosis (ATTR) has two primary subtypes: wild-type ATTR (wild-type [...]

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gene therapies

2026-09-25 | Transthyretin Amyloidosis: From Mechanisms to Treatment

Transthyretin amyloidosis (ATTR) is a progressive systemic disorder driven by the misfolding of transthyretin (TTR) proteins and their deposition as amyloid fibrils. It manifests as hereditary ATTR (ATTRv), caused by pathogenic variants, and wild-type ATTR (ATTRwt), linked primarily to aging. These deposits preferentially affect the myocardium and peripheral nerves, producing severe cardiomyopathy and polyneuropathy. The amyloidogenic cascade is initiated by the dissociation of TTR tetramers into misfolded monomers that aggregate into insoluble fibrils. Historically, treatment was limited to supportive care or organ transplantation; however, it has been transformed by TTR stabilizers, RNA interference (RNAi) agents, and antisense oligonucleotides (ASOs). More recently, CRISPR-Cas9 genome editing has emerged as a potential single-dose strategy for durable TTR suppression. In parallel, anti-fibril therapies, including amyloid-depleting monoclonal antibodies designed to clear existing tissue deposits, are being developed as a complementary disease-modifying strategy. This review delineates the molecular mechanisms of amyloidogenesis and evaluates current clinical management strategies. Recent advances in noninvasive diagnostics and targeted molecular therapies, enabled by precision medicine, have markedly improved disease management and clinical outcomes.

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2026-09-14 | Pathophysiology and Comprehensive Pharmacological Management of ATTR Cardiac Amyloidosis: Knowledge Gaps, Ongoing Clinical Trials, and Future Research Directions

The purpose of this review article is to discuss the current treatment modalities and ongoing clinical trials regarding cardiac amyloidosis (CA), specifically transthyretin cardiac amyloidosis (ATTR-CA). Amyloidosis refers to the extracellular deposition of insoluble amyloid fibrillar proteins. When these proteins are deposited in the heart's myocardium, it is referred to as cardiac amyloidosis. CA can be divided into two main groups: light chain cardiac amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA), which can be further subdivided into wild-type transthyretin amyloidosis (ATTRwt) and hereditary transthyretin amyloidosis (ATTRv). ATTR-CA is an increasingly recognized cause of heart failure in the setting of progressive restrictive cardiomyopathy, particularly among older adults, males, and individuals of African descent, with remarkable advances in the therapeutic landscape. TTR stabilizers, including Tafamidis (approved in 2019) and Acoramidis (approved in 2024), have demonstrated significant reductions in mortality and cardiovascular hospitalizations. Gene silencing therapies, including Vutrisiran (approved in 2025), represent a new drug group that targets TTR production at the RNA level. Meanwhile, CRISPR-based gene editing with Nexiguran Ziclumeran (nex-z or NTLA-2001) and amyloid-depleting monoclonal antibodies offer the prospect of one-time curative treatments and active fibril clearance, respectively. However, despite these advances, substantial knowledge gaps persist: no head-to-head trials have compared stabilizers to silencers, optimal combination therapy regimens remain undefined, and the role of conventional guideline-directed medical therapy in ATTR-CA has only been supported by observational data.

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2026-01-02 | Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility.

Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down the TTR gene by CRISPR-Cas9 represents a promising strategy for treating ATTR amyloidosis, its efficiency and safety remain to be further investigated. Here, we report a systematic investigation of SpCas9-based TTR editing. Besides the target site, wild-type SpCas9 and the reported variants induced extensive off-target edits. To improve the fidelity, we performed structural analysis and designed a series of SpCas9 variants. Studies demonstrated that SpCas9-Mut5 is an ultrahigh-fidelity variant, which induces extremely low levels of off-target edits and translocations without substantial impairment of on-target editing activity. SpCas9-Mut5 is compatible with the adenine base editor (ABE) system, markedly reducing off-target edits and narrowing the editing window. In conclusion, our study suggests that SpCas9-Mut5 is an excellent candidate for TTR gene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases.

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2025-07-13 | Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options.

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents-such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen-have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes.

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2025-05-26 | Transthyretin Amyloid Cardiomyopathy–2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options

Transthyretin‐related (ATTR) amyloidosis is a progressive and life‐threatening disease caused by the systemic accumulation of amyloid fibril deposits composed of misfolded transthyretin (TTR) monomers. Clinical manifestations are highly heterogeneous, including symptoms of cardiomyopathy and/or polyneuropathy, depending on the composition and location of fibril deposits. Although ATTR amyloidosis is considered a rare disease, the clinical relevance of the disease in daily practice becomes more and more apparent. Especially in older patients with unexplained heart failure it is increasingly recognized as an underdiagnosed condition. ATTR amyloidosis can be hereditary (ATTRv), resulting from mutations in the TTR gene, or due to misfolded wild‐type TTR (ATTRwt), affecting mainly male patients over 70 years of age. Advances in understanding the pathogenesis have led to the development of disease‐specific therapies that can significantly slow disease progression and improve survival. This review focuses on diagnostic strategies and therapeutic options for patients with ATTR cardiomyopathy (ATTR‐CM), including mixed phenotypes with additional polyneuropathy (ATTR‐PN). We discuss emerging and newly approved second‐generation therapies such as acoramidis, vutrisiran and eplontersen, as well as promising future treatment options such as gene editing and ATTR‐directed monoclonal antibodies. The growing arsenal of specific therapies underlines the importance of earlier diagnosis and raises crucial questions: What is the best first‐line therapy for each patient? How should we manage non‐ responders, and how can we optimize treatment strategies for patients with mixed phenotypes or advanced disease?

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2026-01-01 | Multimodality imaging and genetic assessment in the diagnosis of amyloid cardiomyopathy

Abstract Background Amyloid cardiomyopathy (CM) is an increasingly diagnosed condition causing heart failure, being light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), the two most common subtypes. Although wild-type transthyretin amyloidosis (ATTRwt) is the most frequent form of ATTR-CM, hereditary transthyretin amyloidosis (ATTRv) can also occur. Multimodality cardiac imaging is essential to diagnose and risk stratify these patients. Purpose To assess the contribution of multimodality cardiac imaging and genetic testing to amyloid CM diagnosis and to investigate the relationship with clinical and imaging characteristics. Methods Twenty patients (mean age: 75±3 years, 15% women) with heart failure and red flags of amyloidosis were included. All had strain echocardiography, 99mTc-pyrophosphate (PYP) scintigraphy and cardiac magnetic resonance (CMR). In all cases the serum free light chains test was negative. A TTR gene sequencing was done in those with diagnosis of ATTR-CM by PYP scintigraphy. Results In three patients (77±6 years, 33% women) cardiac amyloidosis was not the cause of their clinical picture. Among the other 17 cases, ATTRv was detected in 41%: V142I (n=5), V50M (n=1) (in both cases of Afro-caribbean origin) and I88L (n=1) were the mutations found. ATTRwt patients were mainly of non-African origin and slightly older (75 vs. 72 years, pNS). The more frequent atherosclerotic risk factor present in both groups was high blood pressure (50% of cases). Only one ATTRv patient was also diabetic. Five patients (50%) showed a carpal tunnel syndrome in the ATTRwt group vs. 28% of ATTRv. Only two patients with ATTRwt had a NYHA class III, the rest of patients (both ATTRwt and ATTRv) had NYHA class II. Atrial fibrillation was more frequent in ATTRv (57% of cases) vs. 40% in ATTRwt. Regarding echocardiography results, there was no difference in the degree of hypertrophy. Ventricular volumes were slightly higher in ATTRwt, but without statistical significance. All patients showed a reduced longitudinal strain with apical sparing pattern and granular sparkling of the myocardium. The diastolic dysfunction was slightly worse in ATTRv. 99mTc-PYP scintigraphy showed a Perugini degree 3 in 70% of ATTRwt cases, while all ATTRv had a Perugini degree 3. Right ventricular uptake of 99mTc-PYP was significantly more frequent in ATTRv (70% of cases vs. 40% of ATTRwt). LVEF and RVEF by CMR were higher in ATTRwt. No transmural late Gadolinium enhancement (LGE) was detected. Subendocardial and intramyocardial LGE were equally present in ATTRwt, while the intramyocardial LGE was more frequent in ATTRv. Conclusion ATTRv was present in 41% of our cases, mainly in patients of Afro-caribbean origin. The most frequent variant found was V142I. Atrial fibrillation, diastolic dysfunction, Perugini degree 3 and right ventricular uptake in scintigraphy, as well as intramyocardial LGE in CMR were more frequent in ATTRv.

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2025-11-01 | Tolerability of continued treatment with ATTR depleter ALXN2220 in the open-label extension of Phase 1 study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational monoclonal antibody for the treatment of ATTR amyloidosis. ALXN2220 selectively targets ATTR deposits in tissues and activates the clearance of ATTR by macrophages. Data from the first-in-human, ascending dose, placebo-controlled study NI006-101 show that ALXN2220 is generally safe and well tolerated. Treatment with doses ≥ 10mg/kg q4w was associated with time-dependent reductions in scintigraphic and cardiac MRI measures of amyloid load accompanied by transient increases in C-reactive protein at treatment initiation. Adverse events observed in NI006-101 that could potentially affect long-term tolerability of ALXN2220 included platelet reduction (1 case) and the occurrence of non-serious musculoskeletal complaints. Purpose To evaluate the long-term tolerability of continued treatment with ALXN2220 in the open-label extension of study NI006-101 up to a total of 24 administrations. Methods Participants completing the placebo-controlled period of study NI006-101 had the option to participate in an open-label study extension, during which monthly infusions of ALXN2220 were continued with a stepwise up-titration to doses of 30 or 60 mg/kg q4w. Results Out of 39 potentially eligible participants who completed the placebo-controlled period, 38 patients chose to participate in the open-label extension (all were male, median age 72 years, 84% ATTRwt, 89% on tafamidis). Compliance to treatment was high with >95% of planned infusions being administered. No treatment-related serious adverse events were observed, and no discontinuations due to musculoskeletal complaints or other treatment-related adverse events occurred. Musculoskeletal complaints were managed with acetaminophen and/or low-dose steroids in the majority of affected subjects, and the frequency and severity of musculoskeletal events decreased with continued treatment of ALXN2220. No events of infusion-related reactions were reported and no treatment-associated increases in CRP or cytokines were observed. No additional platelet reductions were observed. No anti-drug antibodies were found in any patient. Conclusions Continued treatment with ALXN2220 was well-tolerated during the open-label extension of study NI006-101 up to a total of 24 administrations. Compliance to study drug administrations was high and musculoskeletal complaints appeared to decrease in frequency and severity with continued treatment. No episodes of platelet reductions were observed. No discontinuations occurred due to treatment-related adverse events, indicating good long-term tolerability of this targeted immunotherapy in ATTR amyloidosis.

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2025-11-01 | Characteristics and prognosis of wild-type transthyretin cardiac amyloidosis patients diagnosed before 65 years old

Abstract Background Guidelines suggest screening patients for transthyretin amyloid cardiomyopathy (ATTR-CM) after the age of 65 years. However, in clinical practice a few but not insignificant number of patients are diagnosed younger than the 65-year age cut-off. To date, the characteristics and outcomes in these young patients have not been specifically studied. Purpose This study aimed to compare the prevalence, characteristics, and prognosis of wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) diagnosed at or before 65 years old (ATTRwt-Yy) with those diagnosed after 65 (ATTRwt-O). Methods Data were obtained from the Healthcare European Amyloidosis Registry (HEAR), a multicenter, non-interventional, longitudinal registry for amyloidosis patients. Patients with confirmed ATTRwt-CM were included in study. ATTRwt-CM diagnosis could be established either invasively by a biopsy-proven diagnosis, or non-invasively based on the current guidelines. Patients were classified by age at diagnosis: ATTRwt-Yy (≤65 years) and ATTRwt-O (>65 years) and by onset of first cardiac symptom ATTRwt-Oy (≤65 years) and ATTRwt-Oo (>65years). Results Between July 2021 and May 2024, 3,980 ATTR patients were enrolled, with 1,417 diagnosed with ATTRwt-CM and documented first cardiac symptom onset. Among them, 67 (4.7%) were ATTRwt-Yy, 111 (7.8%) were ATTRwt-Oy (≤65 years), and 1,239 (87.4%) were ATTRwt-Oo (>65 years). Median diagnostic delays from first symptoms were 0.65 years for ATTRwt-Yy, 0.77 years for ATTRwt-Oo, and 20.58 years for ATTRwt-Oy (p<0.001). Heart failure signs were present initially in 34.9% of ATTRwt-Yy, 30.2% of ATTRwt-Oo, and 8.1% of ATTRwt-Oy (p<0.001). ATTRwt-Yy patients exhibited more extracardiac manifestations, particularly osteoarticular disease, while rhythm disturbances were more common in ATTRwt-Oy. Morphological and functional echocardiographic data were similar between the groups. The analysis of survival in the study groups showed a significantly reduced life expectancy in ATTRwt-Yy patients. Conclusion Patients diagnosed with ATTRwt-CM before 65 years are not uncommon. They have a distinct phenotype with more severe osteo-tendinous disease and shorter survival, indicating a need for adapted diagnostic and care strategies.

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2025-11-01 | Early symptoms and medical history of patients with transthyretin amyloidosis cardiomyopathy: Results from the multi-country OverTTuRe study

Abstract Background/Introduction Transthyretin amyloidosis is a progressive and life-threatening condition causing multisystem dysfunction, notably in the heart (ATTR-CM) and peripheral nerves (ATTR-PN), with many patients exhibiting symptoms of both. It can result from hereditary mutations (ATTRv) or an age-related process in wild-type (ATTRwt). The condition is significantly underdiagnosed and an underrecognised cause of heart failure. Real-world data on ATTR-CM, including patient characteristics, from different countries and populations are limited. Purpose The aim of this study was to describe demographics, clinical characteristics and medical history of patients identified as having ATTR-CM across different regions, healthcare systems and populations with different genetic compositions to support earlier recognition and treatment. Methods OverTTuRe is a multi-country study generating real-world evidence on adult symptomatic patients with ATTR amyloidosis. The study population included patients diagnosed with ATTR amyloidosis in several national registries (Sweden, Germany, Canada) or through retrospective chart reviews (Spain and China). Here we present data recorded in the Swedish Transthyretin amyloidosis registry (SveaTTR) from 2000 to October 2024 and patients diagnosed with ATTR amyloidosis from 2009 to 2023 sampled through a chart review at 11 hospitals in Spain. Analyses of data from other countries are ongoing and will also be presented. Patients were assigned to the cardiac phenotype of the disease based on their symptoms and manifestations at baseline (Sweden), or as judged by the investigator (Spain). Results In total, 640 patients were included; 277 from Sweden and 363 from Spain. Besides cardiac manifestations, 61 (22%) patients in Sweden had neuropathic symptoms at the time of disease onset and were classified as having ATTR amyloidosis with mixed phenotype. The corresponding proportion in Spain based on medical records was as high as 41% (n=150). Baseline patient characteristics are presented in the table. Patients with a mixed phenotype were generally younger, more likely female, having a genetic mutation, with peripheral neuropathy being the most common non-cardiac manifestation at diagnosis. The Swedish population of patients with ATTR amyloidosis was in comparison to the Spanish population younger, having fewer chronic conditions, and with ATTR-CM more often being hereditary. The discrepancies between mean and median time from first manifestation to diagnosis of ATTR amyloidosis indicate that some patients suffer from a severe delay, particularly in Spain. Conclusions These findings demonstrate the high degree of neuropathic manifestations across the spectrum of ATTR amyloidosis with cardiomyopathy phenotype, with peripheral neuropathy being the most common. The observed delay in diagnosis of ATTR amyloidosis indicates the need for an increased awareness and earlier clinical suspicion given the poor prognosis if untreated.

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2025-08-16 | Successful Heart and Kidney Transplant in End-Stage Wild-Type TTR Amyloidosis and Renal Failure.

End-stage heart failure secondary to transthyretin cardiac amyloidosis (ATTR-CM) has a poor prognosis, particularly when complicated by multiorgan involvement such as renal failure. Combined heart and kidney transplantation remains a viable therapeutic option in carefully selected patients. A 73-year-old man recently diagnosed with ATTR-CM via technetium-99m pyrophosphate scintigraphy presented in multiorgan shock. The patient required inotropic and temporary mechanical circulatory support. Given the severity of cardiac and renal dysfunction, he underwent combined orthotopic heart and kidney transplantation. Postoperative recovery was uneventful, with continued improvement noted at 6-week follow-up. This case highlights the importance of timely consideration of advanced therapies in patients with advanced ATTR-CM and multiorgan failure, particularly when traditional medical therapy is no longer viable. In selected patients with end-stage ATTR-CM and secondary organ failure, multiorgan transplantation can be a lifesaving therapeutic option.

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