Disease-modifying therapy for proteinopathies: Can the exception become the rule? - PubMed (original) (raw)

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Disease-modifying therapy for proteinopathies: Can the exception become the rule?

Gal Bitan. Prog Mol Biol Transl Sci. 2019.

Abstract

Disease-modifying therapies for proteinopathies are urgently needed yet clinical trials for the major neurodegenerative diseases, Alzheimer's and Parkinson's, have been failing at an alarming rate leaving patients and caregivers scrambling for any sign of hope. At the same time, for one family of proteinopathies, the rare TTR amyloidoses, disease-modifying therapy has existed for almost 3 decades and two new types of disease-modifying therapy have become available more recently. In this chapter, I discuss those therapies, examine to what extent they can be generalized for other diseases, and consider what we may learn from their relative success.

Keywords: Amyloid; Antisense oligonucleotide; Kinetic stabilizers; Proteinopathy; RNAi; Transthyretin.

© 2019 Elsevier Inc. All rights reserved.

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Figures

Fig. 1

Fig. 1

TTR and its ligands. (A) Schematic structures of the thyroid hormone, thyroxine, a natural ligand of TTR, and of the TTR ligands tafamidis, an FDA-approved drug for FAP, diflunisal, available off-label for TTR amyloidoses, and AG10, a compound in clinical trial for FAC. (B) A ribbon diagram of TTR showing the tetramer structure composed of yellow, red, blue, and green monomers.

Fig. 2

Fig. 2

Crystal structures of V122I-TTR ligand complexes. (A) Quaternary structure of AG10 bound to V122I-TTR shown as a ribbon representation with monomers colored individually and positions of each of the V122I mutations shown as black spheres located on the H β-strand, which interacts with the adjacent _AB_-loop on the AC/BD interface. (B) AG10 in complex with V122I-TTR. (C) Tafamidis in complex with V122I-TTR. Close-up views of one of the two identical thyroxine binding sites with different colored ribbons for the two monomers of the tetramer composing the binding site. A Connolly molecular surface was applied to residues within 10 Å of ligand in the thyroxine binding pocket and colored gray for hydrophobic and purple for polar residues. Reproduced from reference Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc. Natl. Acad. Sci. USA 2013;110:9992–9997.

Fig. 3

Fig. 3

Cu/Zn-Superoxide dismutase 1 (SOD1) and its natural substrate. Left—a ribbon diagram of SOD1. Right—an electronic diagram of superoxide radical anion.

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