The transport protein transthyretin is one of the few proteins in the body capable of misfolding or otherwise becoming altered in ways that allow formation of solid deposits of aggregated proteins. These aggregates and their surrounding biochemistry are toxic, a contributing cause of age-related dysfunction and disease. Transthyretin amyloidosis may be near universal in older people, but only a tiny fraction develop this form of amyloidosis to the exaggerated level required for it to be identified and diagnosed. The more likely outcome for any given individual is that amyloidosis goes undiagnosed while nonetheless contributing to, for example, cardiovascular mortality.
Thus while therapies to treat transthyretin amyloidosis now exist, regulators and industry treat it as a rare disease, focused only on very severe instances of the condition, whether or not caused by mutation. This ensures that therapies are sold at the very high prices that characterize the rare disease industry, and in turn makes it hard to take the important next step, which is to greatly expand the detection of lesser degrees of amyloidosis and more widely deploy the best of the existing treatments for the condition, those lacking severe side-effects, into the broader aged population.
Advances in the treatment of transthyretin amyloidosis
Transthyretin (TTR) is a tetrameric plasma protein primarily synthesised by hepatocytes in the liver. It plays a key role in the transport of thyroxine (T4) and retinol-binding protein bound to vitamin A. More than 220 mutations in the TTR gene have been identified, many of which are associated with hereditary forms of amyloidosis. TTR amyloidosis occurs when the TTR tetramer dissociates into monomers, which then misfold and aggregate into insoluble amyloid fibrils. These oligomers eventually aggregate into amyloid fibrils that deposit extracellularly in tissues such as the peripheral nerves, myocardium, gastrointestinal tract, kidneys and eyes. These deposits disrupt tissue architecture and function, leading to organ dysfunction and clinical symptoms. Mutations in the TTR gene destabilise the tetramer structure, accelerating the aggregation process. However, even wild type TTR can form amyloid fibrils with ageing, leading to the non-hereditary form of the disease.
Once considered rare, transthyretin amyloidosis (ATTR) is now recognised as more prevalent, largely due to improved diagnostic methods. Wild type transthyretin amyloidosis (ATTRwt) occurs sporadically and primarily affects older men. Autopsy studies reveal that over 25% of men above age 80 years have cardiac ATTR deposits, most of which go unrecognised during life. Prospective imaging studies suggest that up to 13% of patients with heart failure with preserved ejection fraction (HFpEF) and 12% of those undergoing transcatheter aortic valve replacement have cardiac ATTR. These findings highlight the extent of underdiagnosis in elderly populations with cardiac symptoms.
In recent years, substantial progress has been achieved in the treatment of ATTR, fundamentally transforming the clinical outlook for affected individuals. The introduction of TTR stabilisers, gene-silencing therapies, and emerging disease-modifying approaches – including monoclonal antibodies and CRISPR-based genome editing – has enabled a more comprehensive and multifaceted approach to disease management. These therapeutic advancements, in combination with innovations in non-invasive diagnostic techniques such as scintigraphy and advanced cardiac imaging, have significantly improved the potential for early detection, which is crucial for optimising treatment outcomes.
Despite these remarkable developments, several important challenges and unanswered questions persist. One major gap is the absence of head-to-head clinical trials comparing the efficacy and safety of different therapeutic classes. Additionally, while multiple treatment modalities are now available or in late-stage development, the optimal sequencing of therapies – or whether combination treatments may confer additive or synergistic benefits – remains unclear. Another concern is the high cost and variable accessibility of novel therapies, particularly gene-based treatments and biologics. There is a pressing need for real-world data on cost-effectiveness and long-term clinical benefit, as well as strategies to ensure equitable access across diverse healthcare settings.
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