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

2021-03Journal article Open access
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dc.contributor.authorDohrn, Maike F.
dc.contributor.authorIhne, Sandra
dc.contributor.authorHegenbart, Ute
dc.contributor.authorMedina, Jessica
dc.contributor.authorZüchner, Stephan L.
dc.contributor.authorCoelho, Teresa
dc.contributor.authorHahn, Katrin
dc.date.accessioned2024-01-30T13:24:10Z
dc.date.available2024-01-30T13:24:10Z
dc.date.issued2021-03
dc.description.abstractThe 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationDohrn MF, Ihne S, Hegenbart U, et al. Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis. J Neurochem. 2021;156(6):802-818. doi:10.1111/jnc.15233pt_PT
dc.identifier.doi10.1111/jnc.15233pt_PT
dc.identifier.issn0022-3042
dc.identifier.issn1471-4159
dc.identifier.urihttp://hdl.handle.net/10400.16/2910
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/10.1111/jnc.15233pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectATTRv amyloidosispt_PT
dc.subjectTTR knockdownpt_PT
dc.subjectTTR stabilizationpt_PT
dc.subjectamyloid-directed antibodiespt_PT
dc.subjectfamilial amyloid polyneuropathy (FAP)pt_PT
dc.subjecttransthyretinpt_PT
dc.titleTargeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceEnglandpt_PT
oaire.citation.endPage818pt_PT
oaire.citation.issue6pt_PT
oaire.citation.startPage802pt_PT
oaire.citation.titleJournal of Neurochemistrypt_PT
oaire.citation.volume156pt_PT
person.familyNameCoelho
person.givenNameTeresa
person.identifier.ciencia-idC71E-3343-F445
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationca69c0a3-d48a-4b92-bbf7-c17288d609b7
relation.isAuthorOfPublication.latestForDiscoveryca69c0a3-d48a-4b92-bbf7-c17288d609b7

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