Reviewing Approaches to Treating Transthyretin Amyloidosis

Transthyretin amyloidosis may be a primary component of the present limit on human longevity. Transthyretin is one of the few proteins in the human body that can misfold in ways that encourage other molecules of the same protein to misfold in the same way, joining together form solid aggregates that disrupt cell and tissue function. This is particularly an issue in the cardiovascular system, and while it is presently thought that transthyretin amyloidosis only contributes to a minority of fatal cardiovascular disease in younger old age, autopsies of supercentenarians suggested that it is the major cause of death in the oldest old.

Transthyretin amyloidosis has both normal and accelerated forms, the later resulting from inherited mutations. Most of the work done in developing therapies has focused on treating the rare mutant form of the condition, given the favorable incentives placed on therapies for rare diseases by regulators. Fortunately many of these treatments are also applicable to the age-related normal form of transthyretin amyloidosis. We might hope to see this condition better diagnosed and periodically reversed in its earlier stages, as this part of the industry progresses. Removal of this and other forms of amyloid should be a part of any comprehensive toolkit of rejuvenation therapies in order to prevent its contribution to degenerative aging.

A Review of Transthyretin Cardiac Amyloidosis

Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from severe cardiomyopathy, prevalence and incident rates are often underreported. As global longevity is increasing and rates of amyloidosis are also increasing, there is a need to improve diagnostic and therapeutic interventions. Previously, symptom management and transplantation were the mainstay of treatment for heart failure symptoms, but studies using RNAi and siRNA technologies have shifted the paradigm of therapeutic strategy in amyloid cardiomyopathy management.

Transthyretin (TTR) stabilizers are a new class of medication which function to selectively bind to TTR tetramers, stabilizer tetramer formation, and preventing dissociation of TTR into monomers, which happens to be the rate-limiting step in the formation of amyloidogenic protein deposits. Tafamidis is currently one of the few FDA-approved medications for cardiac amyloidosis that has shown promising results in clinical trials. Double-blind randomized control trials (n = 87) have shown increased quality of life, decreased or complete resolution of neuropathy, and reduction in all-cause mortality and hospitalization at 30 months. Tafamidis remains a very costly medication, estimated to cost $250,000 per year which may pose limitations for consumers.

Diflunisal, a non-steroidal anti-inflammatory, is another TTR stabilizer that has been FDA-approved for the treatment of musculoskeletal pathologies but is used for off-label purposes to treat cardiac amyloidosis. Like tafamidis, diflunisal also stabilizes the TTR tetramer but does so by binding specifically at the dimer-dimer interface and decreasing dissociation. Fewer studies have been conducted using diflunisal, but it has been shown to reduce progression of neuropathy by around 70% in the span of 24 months from the date of diagnosis.

TTR silencers work by inhibiting translation and reduction production of TTR protein. This can be accomplished either with the use of small-interfering RNA (siRNA) or antisense oligonucleotides (ASO). Patisiran is an siRNA that functions by binding to untranslated regions of TTR mRNA and effectively marking it for degradation to avoid protein production from mutated TTR genes. The Phase III APOLLO-A trial, a randomized placebo-controlled trial of 25 patients, investigated the use of patisiran in the treatment of systemic amyloidosis and showed improvements in polyneuropathy, global longitudinal heart strain, NT-proBNP levels, and numerous echocardiographic parameters. In fact, the study demonstrated a sustained 81% reduction in serum TTR levels after 18 months in patients treated with IV patisiran every 3 weeks.

Vutrisiran is a second-generation siRNA functions like patisiran but has the advantage of enhanced stabilization chemistry enabling longer binding to mRNA sequences and, as a result, infrequent dosing of the medication. Inotersen is also a TTR silencer but acts as an ASO, not an siRNA. This medication is a TTR-directed ASO which binds TTR mRNA, reduces these levels, and hereby reduces tissue deposition. The NEURO-TTR clinical trial, an international, randomized, double-blind, placebo-controlled trial of 172 patients, showed improved course of neurologic disease and quality of life. However, unlike the APOLLO study, it did not demonstrate improvement in echocardiographic parameters.

Kinetic stabilizers are yet another class of medications that have the potential to control cardiac amyloidosis disease progression. Acoramidis, which is currently under development, is an orally deliverable TTR designed to strengthen interactions between amyloid dimers and prevent tetramer dissociation. One Phase II randomized, double-blind, placebo-controlled trial with 49 patients is assessing the use of placebo versus 400 mg of acoramidis versus 800 mg of acoramidis and preliminary results have shown an increase in serum TTR with treatment, which is a marker for TTR stabilization. Tolcapone is another stabilizer which is typically used in the management of Parkinson's disease but has the potential to cross the blood brain barrier and treat systemic amyloidosis patients with leptomeningeal involvement. There is currently a Phase IIA proof-of-concept trial of two phases with 17 subjects showing significant stabilization of TTR with administration of tolcapone.

By targeting loose, floating pathogenic amyloid fibrils, fibril disruptors have the potential to prevent further deposition and tissue damage. Doxycycline, which belongs to the class of tetracycline antibiotics, is interestingly being considered as a fibril disruptor. Research has shown that, when combined with ambiphilic bile acid supplements like tauro-ursodeoxycholic acid (TUDCA), doxycycline can disrupt amyloid components. While studies thus far have shown decreased cardiac involvement, many study participants have voluntarily dropped out of studies due to poor tolerability and adverse effects like sun sensitivity. Currently, there is limited evidence supporting the use of doxycycline for the indication of cardiac amyloidosis, but it has shown some signs of effectiveness.

Numerous other avenues are being explored to treat TTR cardiac amyloidosis. Antibody therapies are being developed to target certain epitopes and have been increasingly studied for their role in removing ATTR amyloid or misfolded fibrils. Studies are now showing that the antibodies did not react with native tetramers in vivo but did appropriately react with TTR deposits in vivo and in vitro. In fact, a Phase I open-label three-phase clinical trial PRX004 involving 36 subjects has shown that antibodies targeting TTR89-97 residues improved neuropathy, reassuring drug tolerability, and favorable side effect profile at various dosages. There is a lot of promise in the science behind antibodies targeting amyloid genes.

The CRISPR-Cas9 system is a well-known gene editing treatment which has been engineered to identify and knock out TTR gene in a single administration. Pilot studies with less than 10 subjects have demonstrated reduced serum TTR by up to 87% in the span of just four weeks. Further studies are needed to assess tolerability and drug safety, but this system serves as an excellent example of translational science and the use of gene editing technologies to treat amyloidosis.

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