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Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA..
Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 25080Article in journal (Refereed) Published
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Abstract [en]

Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis (R) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

Place, publisher, year, edition, pages
2016. Vol. 6, 25080
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Immunology in the medical area
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URN: urn:nbn:se:uu:diva-297346DOI: 10.1038/srep25080ISI: 000374935700002PubMedID: 27122057OAI: oai:DiVA.org:uu-297346DiVA: diva2:942014
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2017-11-28Bibliographically approved

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Westermark, Per

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