Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis

Abstract

The liver‐derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild‐type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate‐limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence‐specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac‐conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood–brain barrier, but its half‐life is short and liver failure a potential side effect. Amyloid‐directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR‐amyloidosis has become a model disease for pathophysiology‐based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood–brain barrier permeability.

Semi-Automatic MRI Muscle Volumetry to Diagnose and Monitor Hereditary and Acquired Polyneuropathies

“…For CMT1A, represented by six patients in this cohort, the novel substance PXT003 containing a fixed combination of baclofen, naltrexone, and sorbitol has already undergone a phase three clinical trial with promising results [5], and the decision on approval is currently pending. With patisiran and inotersen, two new substances for the treatment of ATTRv amyloidosis have been approved in 2018 as another example of recent developments in pathophysiology-based treatment in hereditary neuropathies [6].…”

“…As such, both entities belong to the group of rare diseases and therefore remain challenging to diagnose [4]. With new upcoming treatment approaches for both hereditary [5,6] and inflammatory [7][8][9][10] neuropathies, it becomes more and more important to recognize underlying causes and monitor treatment response [1,11]. Currently, the standard diagnostics comprise a detailed neurological examination and nerve conduction studies (NCS) [12].…”

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

“…Both the phase 3 trial, and the long-term safety and efficacy evaluation have shown that Patisiran is an effective treatment for FAP [ 124 , 125 ]. Another drug, Inotersen is a 2′-o-(2-methoxyethyl) (2′-MOE)-modified antisense oligonucleotide can also silence the TTR gene to treat the hereditary transthyretin amyloidosis [ 126 ]. Recently, a newly designed in vivo CRISPR-Cas9-based gene-editing therapeutic agent, NTLA-2001 was introduced.…”

Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

“…While the genetic cause of ATTRv amyloidosis itself is well understood and even targetable by several treatment options, important aspects like differences in organ tropism and manifestation onset are not well understood to date. As potential modifiers, influencing factors in the extracellular matrix, in the TTR gene itself or in other genes like RBP4 [ 5 ] have been discussed in the literature (for review see [ 6 ]). It further seems to play a role whether a patient or the affected antecedent is male or female, suggesting that X-linked genes like AR affect TTR amyloidogenesis as well [ 7 ].…”