Disease-Modifying Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Status and Future Perspectives

Abstract

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is an autosomal dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene resulting in progressive sensorimotor neuropathy, autonomic dysfunction, and effects on other organs, particularly the heart. Historically, treatment options have been limited to liver transplantation and symptomatic management, and the disease was associated with poor prognosis and progressive disability. However, over the past decade, the therapeutic landscape has been transformed by the development of disease-modifying therapies that target the underlying pathophysiology of TTR amyloid formation. These therapies include TTR stabilizers, such as tafamidis, diflunisal, and acoramidis, as well as RNA-silencing agents, such as patisiran, vutrisiran, inotersen, and eplontersen, which reduce hepatic production of TTR and slow disease progression. Clinical trials of RNA interference therapies have demonstrated significant improvements in neuropathy impairment scores, quality of life, and functional outcomes, with acceptable safety profiles and sustained long-term benefits. Emerging gene-editing approaches, including CRISPR-based therapies like NTLA-2001, may provide a one-time treatment and long-term disease control, representing a promising future direction for managing ATTRv-PN. Despite these advances, important challenges remain. These include high treatment costs, limited global accessibility, uncertainty regarding optimal treatment selection and sequencing, and the need for long-term real-world, patient-centered outcome data. This review summarizes current disease-modifying therapies for ATTRv-PN, compares their mechanisms and clinical evidence, and discusses unmet needs and future research directions, with the aim of providing a practical and comprehensive overview for clinicians treating patients with ATTRv-PN.

Key Summary Points

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive multisystem disorder caused by pathogenic variants in the transthyretin (TTR) gene. ATTRv-PN is associated with progressive sensorimotor neuropathy, autonomic dysfunction, and cardiomyopathy.

Over the last decade, the treatment landscape has shifted from liver transplantation and symptomatic care to targeted disease-modifying therapies that stabilize TTR or suppress its production.

TTR stabilizers and RNA-silencing therapies significantly slow disease progression; RNA-silencing agents can improve neurological function and quality of life.

Emerging gene-editing therapies may enable durable long-term disease control and potentially curative treatment, while amyloid clearance strategies may facilitate removal of existing tissue deposits and improve organ function.

However, use of these approaches is restricted by high treatment costs, limited accessibility, delayed diagnosis, and uncertainty in treatment selection and long-term outcomes.

Future studies should focus on precision medicine, early diagnosis, biomarker development, and real-world comparative effectiveness to optimize individualized treatment strategies for ATTRv-PN.

Introduction

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is an autosomal dominant multisystem disorder caused by pathogenic variants in the transthyretin (TTR) gene [1]. ATTRv-PN is characterized by systemic amyloid deposition that predominantly affects the peripheral nervous system [2]. TTR is a transport protein primarily synthesized in the liver that functions as a carrier of thyroxine and retinol-binding protein in circulation [3, 4]. Mutations in TTR destabilize the tetrameric structure of this protein, leading to dissociation into misfolded monomers that aggregate into amyloid fibrils and are deposited in the extracellular space, resulting in progressive organ dysfunction [5, 6].

Clinically, ATTRv-PN presents with a length-dependent sensorimotor polyneuropathy, which is often accompanied by autonomic dysfunction such as orthostatic hypotension, gastrointestinal dysmotility, dysuria, and erectile dysfunction [2, 7, 8]. However, there is substantial variation in the phenotype even for the same mutation. For example, patients with the Val30Met mutation (p. Val50Met, according to the Human Genome Variation Society recommendation) from the conventional endemic foci of Portugal and Japan typically show dissociated sensory loss, defined as predominant impairment of thermal and pain sensation, along with marked autonomic dysfunction [9], whereas patients from non-endemic areas typically exhibit loss of all sensory modalities and relatively mild autonomic dysfunction [9, 10]. Despite these differences, most patients gradually experience severe disability, weight loss, and cardiac involvement, which are significant contributors to morbidity and will ultimately lead to death within several years if untreated [11, 12].

Treatment options for ATTRv-PN have been historically limited. Liver transplantation, which was introduced in the 1990s, aimed to eliminate the primary source of variant TTR production and has demonstrated survival benefits in selected patients, particularly young patients with Val30Met at an early disease stage [13, 14]. However, transplantation is invasive and has significant limitations, including perioperative risk, limited availability, and continued progression of amyloid deposition due to wild-type TTR [15]. Symptomatic management, including pain control and treatment of autonomic dysfunction, has thus remained the mainstay of care for many patients.

Over the past decade, the development of disease-modifying therapies targeting different stages of TTR amyloidogenesis has changed the treatment landscape of ATTRv-PN (Table 1). These therapies include TTR stabilizers that prevent tetramer dissociation as well as RNA-silencing agents that reduce hepatic TTR production [16–21]. These agents have significantly improved the neurological and survival outcomes of ATTRv-PN, fundamentally transforming prognosis and management [22]. More recently, the emergence of gene-editing approaches offers the possibility of long-term—potentially curative—treatment [23].

Table 1.

Disease-modifying therapies for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN)

Therapy	Drug class/mechanism	Administration	Target/effect	Clinical efficacy	Safety/monitoring	Notes
Tafamidis	TTR stabilizer	Oral, daily	Stabilizes the TTR tetramer and prevents dissociation	Delays neurological progression; preserves QOL in early-stage Val30Met	Well tolerated; minimal monitoring required	Most effective in early-stage; less effective in advanced-stage or non-Val30Met
Diflunisal	TTR stabilizer repurposed NSAID	Oral, daily	Stabilizes the TTR tetramer and prevents dissociation	Slows neurological progression; preserves QOL over 2 years	Gastrointestinal bleeding, renal dysfunction, and cardiovascular risks; monitoring is required	Lower-cost option; declining use with newer therapies
Acoramidis	Next-generation TTR stabilizer	Oral, daily	Potently stabilizes the TTR tetramer and prevents dissociation	Promising in ATTR-CM; limited data in ATTRv-PN	Well tolerated	Clinical role in neuropathy is still under investigation
Patisiran	siRNA	IV infusion, every 3 weeks	Reduces hepatic TTR production; lowers serum TTR by ~80%	Improves mNIS+7 and QOL; may improve autonomic and cardiac parameters	Infusion reactions, mild edema, and liver enzyme elevation; premedication and monitoring are required	Lipid nanoparticle delivery; first approved RNAi therapy
Vutrisiran	GalNAc-conjugated siRNA	SC injection, every 3 months	Reduces hepatic TTR production; lowers serum TTR by 80–90%	Comparable efficacy to patisiran; improved convenience and adherence	Favorable; no premedication needed	Subcutaneous, less frequent dosing; preferred RNAi therapy in many settings
Inotersen	ASO	SC injection, weekly	Reduces hepatic TTR production	Slows neurological progression; improves QOL	Thrombocytopenia and glomerulonephritis; requires regular platelet and renal monitoring	No lipid nanoparticle delivery; intensive safety monitoring is required
Eplontersen	GalNAc-conjugated ASO	SC injection, monthly	Reduces hepatic TTR production	Improves mNIS+7 and QOL	Lower risk of thrombocytopenia and renal complications; improved safety profile	Monthly dosing; convenient administration; hepatocyte-specific delivery
NTLA-2001	CRISPR-Cas9 gene-editing therapy	Single IV infusion	Permanent disruption of the TTR gene in hepatocytes; sustained TTR suppression	Phase I: up to 87% TTR reduction; early clinical proof of concept	Off-target effects possible; long-term safety unknown; vitamin A supplementation may be needed	Potential one-time therapy; still under investigation; cost and accessibility challenges

Abbreviations: ASO, antisense oligonucleotide; ATTR-CM, transthyretin amyloidosis with cardiomyopathy; ATTRv-PN, hereditary transthyretin amyloidosis with polyneuropathy; CRISPR, clustered regularly interspaced short palindromic repeats; GalNAc, N-acetylgalactosamine; IV, intravenous; mNIS+7, modified Neuropathy Impairment Score + 7; NSAID, nonsteroidal anti-inflammatory drug; QOL, quality of life; siRNA, small interfering ribonucleic acid; RNAi, ribonucleic acid interference; SC, subcutaneous; TTR, transthyretin

A narrative review was conducted to summarize current disease-modifying therapies for ATTRv-PN. Relevant articles were identified through searches of PubMed up to May 2026. This review provides a comprehensive overview of the current disease-modifying therapies for ATTRv-PN, focusing on their mechanisms of action, clinical efficacy, and practical considerations. We also discuss unmet clinical needs and future research directions, aiming to support clinicians in optimizing treatment strategies for patients with this complex and evolving disease.

TTR Stabilizers

Mechanism and Clinical Overview

TTR stabilizers were among the first pharmacological disease-modifying therapies developed for ATTRv-PN. These agents stabilize the TTR tetramer and prevent its dissociation into amyloidogenic monomers, thereby reducing amyloid fibril formation and slowing disease progression [24, 25]. TTR stabilizers are orally administered and generally well tolerated, which contributes to good treatment adherence and ease of long-term use. However, because they do not suppress circulating TTR production, their clinical efficacy tends to be more modest than that of gene-silencing therapies. As a result, their role has gradually shifted toward a secondary or alternative option [1]. In current practice, TTR stabilizers are mainly used in patients with early-stage ATTRv-PN, particularly in those who prefer oral therapy or cases where gene-silencing agents are not available or contraindicated [26, 27]. Accordingly, gene-silencing agents are generally favored for the treatment of polyneuropathy in ATTRv-PN, whereas TTR stabilizers are considered complementary or alternative options depending on disease stage, availability, cost, and patient preference.

Tafamidis

Tafamidis was the first TTR stabilizer approved for ATTRv-PN and marked a major milestone in disease-modifying therapy. By selectively binding to the thyroxine-binding sites of TTR, tafamidis stabilizes the tetramer and inhibits amyloid formation [25]. A pivotal randomized controlled trial demonstrated that tafamidis significantly delayed neurological progression and preserved quality of life in patients with early-stage Val30Met ATTRv-PN over 18 months [16]. Long-term extension studies showed sustained benefit and good tolerability, supporting its role as a long-term therapy [28, 29]. Tafamidis has now become widely used, particularly in early stages of ATTRv-PN.

However, the clinical impact of tafamidis is limited in more advanced neuropathy, and disease progression may still occur, particularly in late-onset or non-Val30Met cases, as suggested by real-world and open-label extension studies emphasizing the importance of early treatment [29, 30]. Moreover, tafamidis does not reduce circulating TTR levels, limiting its overall efficacy. While tafamidis has demonstrated substantial benefits in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) [31], its role in ATTRv-PN has been partially supplanted by the availability of more potent therapies.

Diflunisal

Diflunisal is a nonsteroidal anti-inflammatory drug that was repurposed as a TTR stabilizer following the discovery of its ability to bind and stabilize the TTR tetramer [24]. A randomized controlled trial showed that diflunisal significantly slowed neurological deterioration and preserved quality of life compared with placebo over 2 years [17]. As diflunisal is orally administered and relatively inexpensive, it is a particularly attractive option in resource-limited settings where access to newer therapies is restricted [1, 32]. However, its use is constrained by its safety profile, including risk of gastrointestinal bleeding, renal dysfunction, and cardiovascular events, particularly in older patients or those with comorbidities [17]. Careful patient selection and monitoring are thus required, and the use of diflunisal has declined with the availability of safer and more effective alternatives.

Acoramidis

Acoramidis is a next-generation TTR stabilizer designed to achieve near-complete stabilization of the TTR tetramer by mimicking the protective Thr119Met variant [33]. Preclinical and clinical studies have demonstrated potent stabilization and favorable pharmacodynamic effects of acoramidis [34]. Recent clinical trials in ATTR-CM have shown promising results, including improved functional outcomes and reduced disease progression [35]. However, there are limited data in the context of ATTRv-PN, and the role of acoramidis in neuropathy-dominant cases has yet to be established. Future studies are thus needed to clarify whether acoramidis can provide meaningful benefits for this specific population.

RNA-Silencing Therapies

Mechanism and Clinical Overview

By directly targeting the production of TTR from the liver, RNA-silencing therapies have revolutionized the treatment of ATTRv-PN. Unlike TTR stabilizers, which prevent tetramer dissociation, RNA-based therapies reduce the synthesis of both variant and wild-type TTR, thereby lowering circulating TTR levels and limiting the formation of amyloid fibrils [1, 2]. These therapies utilize either small interfering RNA (siRNA) or antisense oligonucleotide (ASO) technology to inhibit TTR messenger RNA (mRNA) in hepatocytes, and have been shown to significantly reduce serum TTR concentrations [36, 37]. Clinical trials have demonstrated that RNA-silencing therapies significantly improve neurological function, quality of life, and functional outcomes, making them a cornerstone of modern ATTRv-PN management [18, 19]. Currently available RNA-silencing therapies include patisiran and vutrisiran (siRNA-based agents) and inotersen and eplontersen (ASOs).

Because TTR plays a critical role in the transport of retinol-binding protein, which carries vitamin A in the circulation [4], RNA-silencing therapies that reduce circulating TTR levels may lead to decreases in serum vitamin A. Consequently, patients require routine vitamin A supplementation to prevent deficiency-related complications, such as night blindness and ocular symptoms [18–21]. Notably, this safety consideration is common to all TTR gene-silencing therapies and is an essential component of long-term clinical management.

Patisiran

Patisiran was the first RNA interference therapeutic agent approved to treat ATTRv-PN. Patisiran is a double-stranded siRNA encapsulated in a lipid nanoparticle that selectively targets TTR mRNA in hepatocytes, resulting in degradation of mRNA and reduced TTR protein synthesis [37]. When administered intravenously every 3 weeks, patisiran substantially reduces circulating TTR levels, typically by more than 80% [37].

The efficacy and safety of patisiran were established in the phase III APOLLO trial, a randomized, double-blind, placebo-controlled study involving patients with ATTRv-PN [18]. The trial showed that patisiran significantly improved the modified Neuropathy Impairment Score + 7 (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score compared to placebo over an 18-month period. Importantly, many patients experienced disease stabilization and improved neurological function, which was rarely observed with earlier therapies using TTR stabilizers. Improvements in autonomic symptoms and cardiac parameters were also observed, suggesting systemic benefits of TTR reduction. Long-term extension studies have demonstrated sustained efficacy and an acceptable safety profile of patisiran, with patients showing continued improvement or stabilization of neurological impairment over several years [38].

The most common adverse effects of patisiran are infusion-related reactions, mild peripheral edema, and transient elevations in liver enzyme, which are generally manageable. Premedication is required to reduce infusion reactions [18, 38]. Although patisiran has become a widely used disease-modifying therapy, including patients with progressive ATTRv-PN [1], the need for intravenous infusion every 3 weeks and the associated healthcare burden remain important limitations, prompting the development of next-generation RNA interference (RNAi) therapies.

Vutrisiran

Vutrisiran is a next-generation RNA interference therapy designed to improve the convenience and tolerability of TTR RNA silencing. It utilizes a GalNAc-conjugated siRNA platform that enables targeted delivery to hepatocytes through subcutaneous administration, eliminating the need for lipid nanoparticles and intravenous infusion [39]. Vutrisiran is administered once every 3 months, resulting in a more convenient dosing schedule than patisiran [20].

The phase III HELIOS-A trial, which evaluated the efficacy and safety of vutrisiran in patients with ATTRv-PN, demonstrated significant improvements in neurological impairment assessed by mNIS+7, quality of life measured by Norfolk QoL-DN, and physical function compared with an external placebo group [20, 40]. Serum TTR levels were reduced by approximately 80–90%, and improvements in mNIS+7 and Norfolk QoL-DN scores were comparable to those observed with patisiran [20]. The safety profile was also favorable, with few serious adverse events and no requirement for premedication. Subcutaneous administration and the quarterly dosing schedule reduce treatment burden and improve patient adherence. In addition, the absence of lipid nanoparticles reduces the risk of infusion-related reactions and simplifies clinical management. Given these advantages, vutrisiran has increasingly become a preferred RNAi therapy in many clinical settings [41].

From a clinical perspective, vutrisiran offers similar efficacy to patisiran with improved convenience and tolerability, making it an attractive option for long-term treatment. The phase 3 HELIOS-B trial also demonstrated a role for vutrisiran in ATTR-CM, further extending its therapeutic potential [42].

Inotersen

Inotersen is an ASO that reduces hepatic production of TTR by binding to TTR mRNA and promoting RNase H1–mediated degradation [19, 43]. Unlike siRNA therapies, inotersen is administered as a weekly subcutaneous injection and does not require lipid nanoparticle delivery systems.

The efficacy of inotersen was demonstrated in the phase III NEURO-TTR trial, which showed significant slowing of neuropathy progression assessed by mNIS+7 and improved quality of life assessed by Norfolk QoL-DN scores over 15 months [19]. A subsequent open-label extension study confirmed sustained efficacy [44], while an open-label study in patients with ATTR-CM demonstrated its efficacy even for cases with cardiac involvement [45].

However, inotersen is associated with important safety concerns, particularly thrombocytopenia and glomerulonephritis. Cases of severe thrombocytopenia and renal complications have been reported in clinical trials and resulted in the need for regular platelet and renal function monitoring during treatment [1, 19]. As a result, strict monitoring programs were implemented, with at least weekly platelet counts and periodic renal function assessments [44]. These concerns have limited the widespread use of inotersen in certain regions, particularly when safer alternatives are available.

Eplontersen

Eplontersen is a next-generation ASO designed to improve the safety and efficacy of TTR RNA silencing. It incorporates GalNAc conjugation to enhance hepatocyte-specific delivery and reduce systemic exposure, enabling monthly subcutaneous administration and improved tolerability [46]. The phase III NEURO-TTRansform trial demonstrated that eplontersen significantly reduced serum TTR levels and improved neuropathy impairment assessed by mNIS+7 and quality of life assessed by Norfolk QoL-DN in patients with ATTRv-PN compared with an external placebo group derived from the NEURO-TTR trial [21]. It also has a favorable safety profile, with a lower incidence of thrombocytopenia and renal complications than inotersen, reflecting improved drug design and targeted delivery.

Eplontersen thus represents a significant advancement in ASO therapy, offering effective TTR reduction with a more convenient dosing schedule and improved safety. Monthly subcutaneous administration reduces treatment burden and may enhance patient adherence and long-term outcomes. As clinical experience with eplontersen increases in regions where it has been approved, it may play a growing role in the management of ATTRv-PN.

Emerging Therapies

Gene-Editing Agents

Gene-editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, represent a major advancement in the treatment of ATTRv-PN and offer the potential to provide long-term or even curative therapy. These methods enable targeted modification of specific DNA sequences, resulting in direct disruption of the TTR gene in hepatocytes and permanent reduction of TTR production [47]. At present, NTLA-2001 is the most clinically advanced candidate under investigation for ATTRv-PN [23]. NTLA-2001 is an in vivo CRISPR-Cas9 gene-editing therapy delivered via lipid nanoparticles to hepatocytes where it induces targeted cleavage of the TTR gene, thereby reducing TTR synthesis [48]. Early clinical studies have demonstrated substantial and sustained reductions in serum TTR levels. In a first-in-human phase 1 study, NTLA-2001 achieved dose-dependent reductions in circulating TTR levels up to 87% [23]. Subsequent clinical evaluation in patients with ATTR-CM has demonstrated sustained reductions of approximately 90% after a single administration, further supporting the feasibility of in vivo CRISPR-based gene editing in humans [49].

Gene-editing therapies offer several advantages over existing disease-modifying treatments, including the potential for long-term TTR suppression after a single administration, improved patient convenience, and reduced need for lifelong therapy [48, 50].

Nevertheless, important safety considerations remain. Off-target genetic modifications and long-term adverse effects require careful monitoring, and the irreversible nature of gene editing necessitates rigorous patient selection and informed consent. As genome editing results in permanent modification of the target gene, any unintended off-target effects may also be irreversible. Patients should therefore be informed about the potential long-term risks, uncertainties regarding long-term safety and durability, and the inability to reverse the intervention once administered. Because TTR plays a key role in vitamin A transport, sustained TTR suppression may lead to reduced serum vitamin A levels. As in RNA-silencing therapies, vitamin A supplementation may be necessary. Cost and accessibility are also major challenges, as gene-editing therapies are likely to be expensive and initially limited to specialized centers.

Antibody-Based Amyloid Clearance Therapies

Amyloid clearance therapies represent an emerging strategy for ATTRv-PN that directly target and remove deposited amyloid fibrils from affected tissues [51]. Pathological studies have demonstrated that amyloid fibril deposition is associated with Schwann cell damage in peripheral nerves of patients with ATTRv-PN [6], suggesting that persistent amyloid deposits may contribute to ongoing tissue injury and limit functional recovery, particularly in advanced disease stages.

Monoclonal antibodies targeting misfolded TTR are the most advanced amyloid-clearing strategies currently under clinical investigation. These antibodies selectively bind to amyloid conformations of TTR without interacting with native tetrameric TTR, promoting immune-mediated phagocytosis of amyloid fibrils [52, 53]. In a phase 1 clinical trial of patients with ATTR-CM, NI006, a human monoclonal antibody that selectively targets misfolded TTR, demonstrated acceptable safety and findings suggestive of cardiac amyloid reduction [52]. A phase 2 trial of PRX004 (coramitug), a humanized monoclonal antibody directed against misfolded TTR, showed favorable tolerability and efficacy in patients with ATTR-CM [54]. Besides TTR-specific monoclonal antibodies, pan-amyloid targeting agents such as AT-02, an antibody–peptide fusion protein with pan-amyloid reactivity, have been investigated as potential amyloid-clearing strategies [55, 56]. Although existing clinical trials have primarily focused on ATTR-CM, these agents may also be beneficial in patients with ATTRv-PN. Further clinical studies are thus warranted to evaluate their therapeutic potential.

Amyloid-clearing therapies are expected to complement TTR-suppressing treatments by addressing existing tissue deposits and potentially improving organ function. In the future, combination therapy integrating TTR production suppression with amyloid clearance may provide a more comprehensive treatment approach, particularly for patients with advanced neuropathy or significant organ involvement.

Small Molecules Promoting Amyloid Degradation

Small molecules that promote amyloid degradation offer an alternative to antibody-based clearance in ATTRv-PN. These compounds destabilize TTR fibrils or enhance lysosomal and proteasomal degradation. In preclinical and early clinical studies, doxycycline plus tauroursodeoxycholic acid (TUDCA) has been shown to reduce amyloid deposition and stabilize disease progression [57–59].

At present, clinical evidence is limited, and no small-molecule amyloid degraders have reached advanced clinical trials in ATTRv-PN. However, preclinical and exploratory studies continue to identify candidate compounds capable of destabilizing amyloid fibrils or directly degrading TTR aggregates [60, 61]. These compounds could complement TTR-suppressing treatments or gene-editing approaches by combining prevention of new amyloid formation with removal of existing deposits, which may be particularly beneficial for patients with advanced disease.

Advantages and Disadvantages of Disease-Modifying Therapies

TTR Stabilizers

TTR stabilizers, including tafamidis and acoramidis, offer significant advantages including oral administration, a favorable safety profile, and ease of long-term clinical use [62, 63]. Notably, patients with mild neuropathy treated with tafamidis showed long-term benefits in neuropathy scores [29]. Because of these properties, TTR stabilizers are often considered a suitable first-line option for patients with early-stage disease and mild neuropathy [29, 64, 65]. Diflunisal is a lower-cost alternative that may be particularly valuable in resource-limited settings or regions where access to newer disease-modifying therapies is restricted [66].

However, the clinical benefits of TTR stabilizers are generally more modest than those of RNA-silencing therapies because they do not directly suppress TTR production. As a result, they may be less effective in patients with rapidly progressive or advanced disease [27]. Diflunisal requires regular monitoring for renal dysfunction, gastrointestinal complications, and cardiovascular risks associated with nonsteroidal anti-inflammatory drugs, which can limit long-term use—particularly in elderly patients or those with comorbidities [1, 17]. Consequently, while TTR stabilizers remain an important therapeutic option, their role is often best suited to early-stage disease or in combination with other emerging treatment strategies [67].

RNA-Silencing Therapies

RNA-silencing therapies, which include patisiran, vutrisiran, inotersen, and eplontersen, directly suppress hepatic TTR production, resulting in substantial reductions in circulating TTR levels and subsequent stabilization or improvement of neuropathy and functional outcomes [18–21]. These therapies represent a major advance in the treatment of ATTRv-PN, with clinical trials demonstrating that they can slow disease progression and, in some cases, even improve neurological function and quality of life [18, 19].

Newer agents, such as vutrisiran and eplontersen, offer convenient subcutaneous administration with extended dosing intervals and reduced monitoring requirements, thereby improving treatment accessibility and patient convenience for long-term management [20, 21]. Despite their robust clinical efficacy, they are limited by their high treatment cost, the need for repeated lifelong administration, and the healthcare system burden associated with chronic therapy [68]. Specific safety monitoring is also required for certain agents, such as for thrombocytopenia and renal dysfunction with inotersen, necessitating regular laboratory surveillance [19].

While RNA-silencing therapies effectively suppress TTR production, they do not remove existing amyloid deposits, and the disease may progress in advanced stages with substantial tissue amyloid accumulation [46]. Combination strategies integrating RNA silencing with amyloid clearance may further enhance long-term outcomes and thus represent a promising direction for future treatment development.

Gene-Editing Therapies

Gene-editing approaches such as CRISPR offer the potential for a one-time curative therapy for ATTRv-PN [47]. Early clinical studies of NTLA-2001 have demonstrated substantial and sustained reductions in serum TTR levels after a single administration, suggesting long-lasting suppression of TTR production and a significant reduction in long-term treatment burden [23, 49].

However, before this potential can be realized, several challenges must be addressed. These include limited long-term safety data, potential off-target genome editing, immune responses to CRISPR–Cas9 components, and the irreversible nature of gene editing [46, 69]. The irreversible nature of gene editing further highlights the need for careful patient selection, informed consent, and long-term safety monitoring. Although gene-editing therapies are currently being evaluated in phase III trials, their efficacy and safety across diverse patient populations remain to be established. As with other TTR-suppressing strategies, gene editing does not directly remove existing amyloid deposits. As a result, combination approaches with amyloid clearance therapies may be required to optimize outcomes in advanced cases [51]. As with other TTR-suppressing strategies, long-term vitamin A supplementation may be required due to the role of transthyretin as a retinol transport protein.

Amyloid Clearance Therapies

Amyloid clearance therapies aim to remove existing amyloid deposits from affected tissues and may complement TTR-suppressing treatments [51]. A major advantage of this approach is the potential to improve organ function by directly reducing amyloid burden, which is especially relevant in advanced disease stages where substantial tissue deposition has already occurred. However, as most studies have focused on ATTR-CM and early-phase trials [52, 54, 55], current clinical evidence remains limited. Moreover, the long-term safety and efficacy of amyloid clearance therapies in ATTRv-PN—particularly in terms of neurological outcomes—have not been established. Further clinical trials are thus needed to determine the therapeutic role of this approach and optimal integration with existing disease-modifying treatments.

Unmet Needs of Patients with ATTRv-PN

Economic Burden and Treatment Accessibility

High treatment costs are a major barrier to optimal management of ATTRv-PN. Disease-modifying therapies are associated with substantial financial burden, which limits access in many healthcare systems and regions [68, 70, 71]. Tafamidis, although widely used as a TTR stabilizer, has significant cost-effectiveness challenges, with economic analyses demonstrating that its price far exceeds commonly accepted cost-effectiveness thresholds, raising concerns about affordability and reimbursement sustainability [68].

RNA-silencing therapies impose an even greater economic burden [72]. Pharmacoeconomic analyses and clinical reviews have indicated that siRNA-based therapies require substantial healthcare resources and pose challenges for widespread implementation, particularly in resource-limited healthcare systems [46, 48, 73]. Recent cost-effectiveness analyses comparing vutrisiran and tafamidis further highlight this challenge, noting the high costs of both therapies and generally greater financial investment of RNA-silencing strategies than stabilizer-based therapy [73].

Gene-editing therapies, such as NTLA-2001, have the potential to reduce long-term treatment burden through one-time administration; however, their high up-front costs raise concerns regarding affordability and reimbursement frameworks. Global pricing strategies, value-based reimbursement models, and international collaboration will be essential to ensure equitable access to these therapies for patients with ATTRv-PN.

Quality of Life and Treatment Burden

Despite these therapeutic advances, ATTRv-PN continues to significantly impair quality of life. Many patients experience persistent functional limitations and residual disability resulting from neuropathy-related sensorimotor deficits (e.g., pain, weakness), and autonomic dysfunction even after intervention [18, 19, 30, 64]. Clinical and real-world studies have documented profound reductions in health-related quality of life across multiple domains. Patients with ATTRv-PN exhibit poorer physical functioning and overall quality of life compared with the general population and levels of impairment comparable to severe diabetic neuropathy with complications such as ulceration and amputation [74].

In observational cohorts, disease progression and advanced stages are strongly associated with lower utility scores. Untreated patients exhibit a progressive decline in quality of life, and even treated patients may experience a significant burden [70]. Autonomic symptoms, such as orthostatic intolerance, gastrointestinal dysfunction, urinary disturbances, and sexual dysfunction, further disrupt daily activities and independence [75].

Repeated infusions, regular laboratory tests, frequent hospital visits, and side effects can all reduce treatment adherence and long-term satisfaction. Real-world studies show that these burdens make it challenging for patients with ATTRv-PN to maintain treatment over time [72, 76]. The hereditary, progressive nature of ATTRv-PN also imposes psychological stress, caregiver burden, and concerns about familial transmission, highlighting the need for the integration of patient-reported outcomes and longitudinal quality-of-life assessments to better capture the full patient experience [77].

Early Diagnosis and Global Accessibility

Despite recent advances in diagnostic techniques and growing awareness of ATTRv-PN among clinicians, its clinical heterogeneity often results in delayed diagnosis. Neuropathic features in late-onset Val30Met cases from non-endemic regions are often nonspecific, contrasting with the classical dissociated sensory loss and autonomic dysfunction observed in early-onset cases from conventional endemic foci [9, 78]. Although axonal neuropathy is considered the hallmark of this disease, slowing of nerve conduction velocity and prolonged distal latency can mimic demyelination and lead to misdiagnosis as other neuropathies, particularly chronic inflammatory demyelinating polyneuropathy (CIDP) [10, 79, 80]. Individuals with affected family members are often diagnosed pre-symptomatically through cascade genetic screening. However, individuals without a clear family history frequently experience prolonged diagnostic delays, resulting in advanced neuropathy and irreversible nerve damage before treatment initiation [81, 82]. Early recognition requires clinicians to consider ATTRv-PN in differential diagnosis, highlighting the importance of awareness and education.

Screening programs and genetic testing, including systematic monitoring of at-risk relatives and gene mutation carriers, have improved early detection in endemic regions such as Portugal and Japan, whereas diagnostic delays remain common in non-endemic regions [8, 83]. Such at-risk cohorts may also provide an opportunity to evaluate future preemptive therapeutic strategies before irreversible nerve damage occurs. However, the optimal timing and criteria for intervention remain to be established. In addition, access to genetic testing and specialized care varies widely across countries. Data from the international Transthyretin Amyloidosis Outcomes Survey (THAOS) indicate persistent global disparities in diagnosis and management, with substantial diagnostic delays observed across regions, underscoring the need for coordinated international efforts to improve both early detection and healthcare infrastructure [84, 85].

Central Nervous System and Ocular Involvement

Extrahepatic production of TTR represents a critical biological limitation of current therapies. TTR is synthesized in the liver as well as in the choroid plexus and retinal pigment epithelium, resulting in continued amyloid fibril formation in the central nervous system (CNS) and eye even after effective hepatic TTR suppression [1, 86, 87]. CNS and ocular manifestations resulting from oculoleptomeningeal amyloidosis may progress despite liver transplantation or RNA-silencing therapy due to persistent local TTR production behind the blood–brain and blood–retinal barriers [88, 89]. The development of ocular manifestations after liver transplantation—particularly vitreous opacity—provides direct clinical evidence that extrahepatic TTR production from the retinal pigment epithelium contributes to ongoing amyloid deposition [90]. Cerebral amyloid angiopathy and CNS amyloid deposition have been reported in long-term survivors after liver transplantation, further supporting the role of extrahepatic TTR production [88].

TTR stabilizers have limited ability to penetrate barrier-protected organs. For example, tafamidis is detected at low concentrations in cerebrospinal fluid and vitreous humor, resulting in limited stabilization of TTR and continued CNS and ocular disease progression [91, 92]. A pilot study demonstrated a marked reduction in serum TTR, but minimal reduction in aqueous humor TTR, after patisiran treatment [93]. These findings highlight the need to develop TTR stabilizers capable of penetrating the blood–brain and blood–retinal barriers, as well as RNA-silencing agents that can be effectively delivered to the choroid plexus and retinal pigment epithelium.

Future Research Directions and Therapeutic Perspectives

Future therapeutic development in ATTRv-PN must move beyond TTR stabilization and suppression toward more comprehensive disease control. Strategies that promote amyloid clearance and target extrahepatic TTR production, including improved drug delivery to the eye and CNS, may complement current therapies and enable better control of residual organ involvement and long-term outcomes [51, 89]. Another research priority is the accumulation of real-world and long-term clinical evidence for existing disease-modifying therapies. Although randomized clinical trials have demonstrated significant efficacy, treatment responses vary across genotypes, disease stages, and organ involvement, and long-term safety and durability remain incompletely understood. International registries, such as THAOS, and longitudinal observational studies will be essential for clarifying treatment sequencing, identifying predictors of response, and evaluating outcomes in underrepresented populations, including elderly patients and those with advanced neuropathy or cardiac involvement [84, 94].

Greater emphasis is also needed on patient-centered outcomes and precision medicine approaches. Patient-reported quality of life, functional status, and psychosocial burden are increasingly incorporated into clinical trials alongside neurological endpoints such as NIS+7, reflecting growing recognition that patient-centered outcomes capture the real-world impact of ATTRv-PN beyond traditional clinical measures [18, 19, 74, 76]. In parallel, biomarker- and genotype-based treatment stratification, including the use of neurofilament light chain and genotype–phenotype correlations, may help identify patients at high risk of progression and optimize the timing of therapy initiation [1, 95, 96]. As presymptomatic identification and future preventive therapeutic strategies become increasingly feasible in ATTRv-PN, active patient and family engagement will be essential. Improving genomic literacy may facilitate informed decision-making regarding genetic testing, longitudinal monitoring, and potential future preventive interventions.

Overall, continued integration of next-generation therapies, real-world evidence, and patient-centered precision medicine approaches will be essential for optimizing treatment strategies and improving long-term outcomes in ATTRv-PN, paving the way for more durable disease control and future curative interventions.

Conclusion

As a narrative review, this article has inherent limitations, and the selection and interpretation of the literature may be influenced by the available evidence and the authors’ judgment. In addition, several emerging therapies discussed in this review remain under clinical investigation, and long-term efficacy and safety data are still limited. Despite these limitations, the available evidence indicates that treatment of ATTRv-PN has undergone a remarkable shift, evolving from predominantly supportive care to the availability of multiple disease-modifying therapies that target distinct pathogenic steps. TTR stabilizers, such as tafamidis and diflunisal, represented the first effective disease-modifying approach by inhibiting tetramer dissociation and slowing amyloid formation [16, 17]. However, their inability to reduce circulating TTR levels has limited their overall efficacy, especially in progressive or advanced neuropathy, leading to a gradual shift in treatment paradigms.

In the last decade, RNA-silencing therapies have transformed clinical practice by achieving robust and sustained reductions in serum TTR and providing meaningful clinical benefits in neurological function and quality of life [18, 19]. Next-generation agents, such as vutrisiran and eplontersen, have further improved convenience and reduced treatment burden while maintaining strong efficacy [20, 21]. These advances have established TTR suppression as the current therapeutic backbone of ATTRv-PN management.

Emerging strategies, including CRISPR-based gene editing such as NTLA-2001, offer the possibility of durable, potentially one-time therapy with profound and sustained TTR reduction [23, 49]. In parallel, amyloid clearance therapies aim to address the unmet need of removing existing tissue deposits that drive organ dysfunction [51, 52].

Despite these advances, important challenges remain in the management of ATTRv-PN, including delayed diagnosis, treatment accessibility, high economic burden, and incomplete reversal of multi-organ damage [10, 68, 84]. Future progress will depend on earlier diagnosis, equitable access, and combination strategies that integrate TTR suppression with amyloid clearance, with the aim of ultimately achieving sustained disease control and potentially curative outcomes.

Authors’ Contributions

Haruki Koike developed the concept of the article, conducted the literature review, and wrote the first draft. Toshihiro Ide and Masaaki Yoshikawa critically evaluated the manuscript. All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Funding

This work was supported in part by a Health, Labor, and Welfare Sciences research grant (Research on Rare and Intractable Diseases; grant no. 26FC0201) from the Ministry of Health, Labor, and Welfare of Japan. No funding or sponsorship was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed.

Declarations

Conflicts of Interest

Haruki Koike is a member of the Editorial Board of Neurology and Therapy. Haruki Koike was not involved in the selection of peer reviewers for the manuscript nor any subsequent editorial decisions. Toshihiro Ide and Masaaki Yoshikawa have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals.