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Drug Insight: emerging therapies for amyloidosis

Nature Clinical Practice Nephrology volume 2, pages 263–270 (2006)Cite this article

Abstract

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble, abnormal fibrils that impair organ function. More than 20 unrelated proteins can form amyloid fibrils in vivo. All fibrils share cross-β core structure and pathognomonic red–green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloidosis can be acquired or hereditary, localized or systemic, and is classified according to the fibril precursor protein. Local amyloid deposition occurs in the brain in Alzheimer's disease and in the pancreas in maturity-onset diabetes, but a direct role in the pathogenesis of these diseases remains unproven. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls and connective tissues, is usually fatal and is the cause of about one death per thousand in developed countries. Recent elucidation of fundamental aspects of the pathogenesis of amyloidosis, and developments in diagnosis and monitoring of this disorder have greatly improved outcome for patients. Several exciting novel therapeutic strategies, reviewed in this article, are in development. These include interference with different stages of fibrillogenesis and enhancement of clearance of amyloid deposits.

Key Points

  • Amyloidosis—extracellular deposition of insoluble fibrils composed of misfolded proteins—can be localized or systemic

  • Current treatments (e.g. anti-inflammatory drugs, chemotherapy and transplantation) aim to reduce the supply of amyloid fibril precursor proteins

  • Recent advances in our understanding of the pathogenesis of amyloidosis have spurred attempts to develop novel treatments

  • New therapeutic strategies aim to perturb fibrillogenesis by stabilizing precursor proteins (e.g. Fibrillex®) or promote clearance of amyloid (e.g. immunotherapy, CPHPC)

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Figure 1: Potential therapeutic strategies to inhibit the production, propagation and stability of amyloid.
Figure 2: Serum amyloid P component scintigraphy.
Figure 3: CPHPC targets the serum amyloid P component.

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Acknowledgements

The work of the Centre for Amyloidosis and Acute Phase Proteins is supported by grants from the Medical Research Council (UK), The Wellcome Trust, the Wolfson Foundation, and NHS Research and Development Funds.

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Authors and Affiliations

  1. Senior Lecturer,

    Julian D Gillmore & Philip N Hawkins

  2. Professor of Medicine and Clinical Director, at the National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Royal Free and University College Medical School, London, UK

    Julian D Gillmore & Philip N Hawkins

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  1. Julian D Gillmore
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Corresponding author

Correspondence to Julian D Gillmore.

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Competing interests

Work conducted within Roche was funded entirely by F Hoffmann-La Roche Ltd, which also provided equipment and support to the Centre for Amyloidosis and Acute Phase Proteins.

The patent on CPHPC is held by Roche. Roche retains all rights to commercial exploitation of CPHPC for treatment of Alzheimer's disease and diabetes, but has granted an exclusive licence to UCL Biomedica, the commercial arm of the University College Medical School, for development of CPHPC for other indications.

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Gillmore, J., Hawkins, P. Drug Insight: emerging therapies for amyloidosis. Nat Rev Nephrol 2, 263–270 (2006). https://doi.org/10.1038/ncpneph0169

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