New era in transthyretin amyloidosis: From stabilizers to gene editing

(Press-News.org) Transthyretin amyloidosis (ATTR) is caused by the misfolding and aggregation of the transthyretin (TTR) protein, leading to multi-organ damage. Two main forms exist: hereditary ATTR (ATTRv), linked to TTR gene mutations, and wild-type ATTR (ATTRwt), associated with aging. Historically underdiagnosed, ATTR carried poor prognoses, particularly in advanced cardiac or neuropathic disease. However, the past decade has seen unprecedented therapeutic advances.

Diagnostic Advances Enable Earlier Intervention

Improved detection is a cornerstone of modern ATTR management. Bone scintigraphy, cardiac MRI, echocardiography with strain imaging, and specific biomarkers (NT-proBNP, troponin, neurofilament light chain) facilitate early diagnosis. Genetic testing distinguishes hereditary from wild-type disease, guiding treatment and enabling family screening. Earlier identification allows interventions before irreversible organ damage.

From Liver Transplant to Targeted Pharmacotherapy

Liver transplantation, once the only disease-modifying option for ATTRv, has largely been replaced by pharmacologic agents targeting TTR stability, expression, or amyloid clearance. The three main categories are:

(1) TTR Stabilisers – Drugs such as tafamidis and diflunisal bind to TTR tetramers, preventing dissociation and aggregation. Tafamidis has shown mortality and hospitalisation reduction in ATTR cardiomyopathy (ATTR-ACT trial) and is approved for both ATTRv and ATTRwt cardiomyopathy.

(2) Gene Silencers – RNA interference (siRNA) agents like patisiran and vutrisiran, and antisense oligonucleotides like inotersen and eplontersen, reduce hepatic TTR production. Patisiran's APOLLO trial and vutrisiran's HELIOS trials demonstrated significant improvements in neuropathy scores, quality of life, and cardiac parameters.

(3) Amyloid Clearance Agents – Monoclonal antibodies (e.g., PRX004/NNC6019, NI006) target misfolded TTR and deposits, potentially reversing amyloid burden. Early-phase studies report promising cardiac and neuropathic stabilisation.

Emerging Frontiers: CRISPR-Cas9 Gene Editing

One of the most revolutionary developments is NTLA-2001, a CRISPR-Cas9 therapy designed to permanently inactivate the TTR gene in hepatocytes after a single infusion. Early-phase trials show deep, sustained TTR suppression without major safety concerns over more than two years of follow-up. If successful in larger studies, gene editing could eliminate the need for lifelong therapy.

Therapeutic Pipeline and Regulatory Milestones

Several agents have received FDA and EMA approvals for ATTRv polyneuropathy and cardiomyopathy, including tafamidis, patisiran, vutrisiran, inotersen, eplontersen, and acoramidis. Recent approvals, such as vutrisiran for ATTR cardiomyopathy (2025), reflect growing recognition of ATTR as a treatable cause of heart failure.

Remaining Challenges

Despite these breakthroughs, significant hurdles remain: (1) Access and Cost – Many therapies are expensive and not universally reimbursed, limiting availability. (2) Treatment Sequencing – No head-to-head trials guide whether stabilisers, silencers, or combination therapy is optimal. (3) Late-Stage Disease – Patients with advanced cardiac or neurological damage still face poor outcomes, highlighting the need for regenerative or amyloid-clearing therapies. (4) Long-Term Safety – Gene-based treatments require ongoing monitoring for off-target effects. (5) Presymptomatic Carriers – Guidelines are needed for when to start therapy in mutation carriers before symptoms develop.

Future Outlook

Personalised medicine, integrating genomic data, biomarkers, and multimodality imaging, is likely to define the next era of ATTR care. Multidisciplinary management—uniting neurology, cardiology, genetics, and pharmacology—will be critical. Ongoing clinical trials of CRISPR, monoclonal antibodies, and next-generation silencers aim not only to halt but potentially reverse disease progression.

Conclusion

ATTR has transitioned from a fatal, underdiagnosed disease to one with multiple effective treatment avenues. With continued innovation, early detection, and equitable access, the prognosis for patients with ATTR is set to improve dramatically.

 

See the article:

Anan I. Advances in the treatment of transthyretin amyloidosis. eGastroenterology 2025;3:e100198. doi:10.1136/egastro-2025-100198

 

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