Background
Transthyretin is a protein produced in the liver, choroid plexus, and retinal pigment epithelium and transports thyroid hormone thyroxine and the retinal-binding protein bound to retinol.1,2 In transthyretin amyloidosis (ATTR) the homotetrameric protein is destabilized, leading to monomers that misfold, aggregate and form amyloid fibrils. These fibrils are deposited in certain organs including the heart, eyes, digestive tract, nervous system, and kidneys.3 There are two types of ATTR: a sporadic, non-genetic form known as wild-type ATTR (wtATTR) and a hereditary form (hATTR, also referred to as the variant form ATTRv) caused by pathogenic variants in the TTR gene inherited in an autosomal dominant (AD) manner. In patients with wtATTR, amyloid fibrils are deposited almost entirely in the myocardium, resulting in ATTR cardiomyopathy (ATTR-CM).4,5 In contrast, hATTR may present as ATTR-CM, polyneuropathy (ATTR-PN), or a mixed phenotype of both through the deposition of the misfolded protein in both the cardiovascular and peripheral nervous systems.3,6 The true prevalence of wtATTR is unknown; however autopsy studies have suggested that it is higher than previously recognized with some studies showing that ~25% of individuals 80 or older have wild-type fibrils, regardless of symptoms.5,7-9 Historically, hATTR was thought to be endemic to certain regions including northern Portugal, northern Sweden and Japan with a prevalence of 1-10 per 10,000 individuals. However, to date the disorder has now been reported in multiple countries with an estimated global prevalence of 5000-40,000 individuals.9-11
Diagnosis
Symptoms of patients with ATTR-CM include those commonly seen in heart failure including fatigue, exercise intolerance, palpitations, conduction abnormalities, and arrhythmias.4,5 Other early indicator disease characteristics include elevated troponin or N-terminal pro-brain natriuretic peptide levels, an intolerance of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, carpel tunnel syndrome (CTS), lumbar spinal stenosis, and biceps tendon rupture.4,12,13 The age of onset of wtATTR-CM is generally above the age of 60, whereas that of hATTR-CM varies from 30-80 years old depending on the TTR variant. The median survival after diagnosis is ~3.5 and ~2.5 years respectively for wtATTR-CM and hATTR-CM.4 The clinical presentation of patients with hATTR-PN is also variable with no specific signs or symptoms uniquely associated with the disease. However, a number of “red flags” have been identified that should raise suspicion.14 Karam et al. reported that the most important features suggestive of hATTR are the rate of neuropathy progression and comorbidities such as gastrointestinal dysmotility, heart failure with preserved ejection fraction, autonomic failure and CTS.15 For example, although common in the general population, CTS in patients with hATTR is more often bilateral, more prone to recurrence and more refractory to treatment. A family or personal history of idiopathic neuropathy that does not respond to treatments for other neuropathies or is rapidly progressing is also suggestive for hATTR.
Due to the variability of clinical presentation and overlap with other disorders, misdiagnoses are common. Studies have suggested that 32-74% of patients with hATTR have received at least one misdiagnosis with 18% receiving multiple misdiagnoses.3 For example, the resulting heart failure in ATTR-CM may be attributed to other more common disorders such as hypertrophic cardiomyopathy, aortic stenosis and hypertensive heart disease.5 The peripheral neuropathy is often mistaken for other neurologic conditions such as chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy or motor neuropathy.3,15 Historically, a diagnosis of hATTR was made through identification of amyloid deposits through biopsy followed by confirmatory gene sequencing. This often requires assessment of multiple tissue sites and interpretation of pathology can be variable with a reported sensitivity of 60-80% depending on the tissue type.16,17 Therefore, a negative biopsy does not definitively exclude a diagnosis and further testing, including additional biopsies, are necessary. Cardiac technetium (99mTc)-based tracer scintigraphy scanning may also be utilized if available. A positive grade 2 or 3 myocardial uptake of radiotracer and the absence of a clonal plasma cell process has shown a positive predictive value of 100% for ATTR-CM.18 However, detection of a pathogenic variant in the TTR gene is definitive for hereditary disease.
To date, nearly 150 different pathogenic variants in TTR have been associated with hATTR. Penetrance is variable and is highest in endemic regions due to founder mutations.3,9 However, the penetrance increases with age reaching nearly 100% by the ninth decade regardless of the variant.19-21 The p.Val50Met (legacy p.Val30Met) variant was the first discovered and is the most common word wide. It leads to a variable clinical presentation ranging from asymptomatic to systemic disease with both early (age <50 years) and late (age ≥50 years) onset forms.9,11,22 The early onset disease is highly penetrant and presents as ATTR-PN with sensorimotor symptoms beginning in the lower extremities with relatively mild autonomic symptoms whereas late onset typically presents with peripheral rather than autonomic neuropathy, is more likely to occur in males, and penetrance increases with age. In the United States, the most common pathogenic variant associated with hATTR is p.Val142Ile (legacy p.Val122Ile).11,23 In contrast to p.Val50Met, the clinical presentation is almost exclusively cardiac. Population studies suggest it is present in 3.4% of individuals of African descent with a disease penetrance of ~40% and has been reported in 10% of African Americans older than 65 with severe congestive heart failure.23-25 Given the increased availability of effective therapies, gene sequencing performed earlier in the diagnostic strategy confirms an hATTR diagnosis and facilitates optimal treatment choices. This strategy is endorsed by multiple societies, associations, and disease experts.4,26-28
Therapeutic strategies
Historically, liver transplantation was the only available treatment for hATTR. Since transthyretin is primarily produced in the liver, a transplant stops the production of mutant protein, decreasing amyloid formation and inhibits disease progression.29,30 However, studies have suggested that outcomes are less favorable for patients with alterations other than p.Val50Met and those with late onset or more advanced disease.30,31 Also, transplantation eliminates the production of abnormal but not wild-type transthyretin, so further deposition of wild-type transthyretin continues after transplantation. In addition, production of abnormal protein from the ocular and central nervous systems continues and cardiovascular complications post-transplant are more common than in patients undergoing transplant for end stage liver disease.30 Today, available treatments target different aspects of the production of amyloid deposits that when administered early in the course of disease slow it’s progression.
In the early 1990s, it was reported that patients with a p.Thr139Met (legacy p.Thr119Met) variant in a compound heterozygous state with p.Val50Met had no or mild symptoms of disease.32 Functional studies demonstrated that this amino acid change increased the kinetic stability of the tetramer, slowing dissociation and suppressing disease.33,34 Further studies established that the dissociation was the first and slowest step of the aggregation cascade and that small molecules that bind to and stabilize the tetramer would have a similar effect.35-37 These studies led to the identification of tafamidis (trade name: Vyndaqel®) a small molecule that binds selectively to unoccupied thyroxine-binding sites and kinetically stabilizes the tetramer.38,39 Based on clinical trial outcomes, tafamidis was approved for use in stage 1 patients with ATTR-PN in Europe, Japan, and Mexico.40-42 More recently in the US, clinical trial outcomes showed patients that were prescribed tafamidis had a decrease in all-cause mortality, rates of cardiovascular hospitalizations, and reduced functional capacity43 and in 2019 tafamidis became the first FDA-approved medication for use in ATTR-CM as a TTR stabilizer. The non-steroidal anti-inflammatory drug (NSAID) diflunisal is also a strong stabilizer and has shown to be effective.44 However, NSAIDs are relatively contraindicated in patients with heart failure and therefore it is not an optimal choice for patients with cardiac manifestations. Gillmore et al. recently reported results of the ATTRibute-CM trial in which patients that received acoramidis, a novel TTR stabilizer, had significantly better outcomes in mortality, morbidity and function than the placebo group.45
A more recent therapeutic strategy is RNA interference (RNAi), a process by which small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs) mediate the cleavage of target mRNA resulting in a robust decrease in the expression of the gene of interest thereby preventing the production of protein.46,47 There are currently four FDA-approved RNAi therapies targeting hepatic messenger RNA (mRNA) available for patients with hATTR. The Neuro-TTR Trial demonstrated that inotersen (trade name: TegsediTM), an antisense oligonucleotide (ASO) that targets the 3’ untranslated region (UTR) of TTR, was shown to improve the course of neurologic disease and quality of life in patients with hATTR when administered as a weekly subcutaneous injection.48 However, there were some safety concerns around thrombocytopenia and glomerulonephritis requiring additional monitoring after FDA approval. In a similar study published simultaneously, data from the landmark APOLLO trial showed that intravenous administration every three weeks of patisiran (trade name: Onpattro), an siRNA also targeting the 3’ UTR, reduced the mean serum levels of TTR by ~80% and significantly improved neuropathy with all study endpoints better than placebo regardless of age of onset, stage of the disease or TTR variant.49 Vutrisiran (trade name: Amvuttra) is a second-generation form of patisiran with an enhanced stabilizing chemistry administered every three months subcutaneously approved by the FDA in 2022.50 The most recent therapy to receive FDA approval in 2023, eplontersen (trade name: WainuaTM), is a second-generation version of inotersen with an enhanced delivery method that increases the potency of the molecules by 20 to 30-fold allowing for lower effective doses.51 Studies on newly emerging therapies such as gene editing, amyloid disruption, and aggregation inhibition as well as the results of combination therapies are also underway.52,53
