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Preclinical development of siRNA therapeutics for AL amyloidosis

Gene Therapy volume 18, pages 1150–1156 (2011)Cite this article

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Abstract

Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.

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Acknowledgements

Support for this study was provided by Hematology Training Grant T32 HL007501, P01 HL68705, the David S Levine Amyloid Research Fund and gifts from the Gruss and Wildflower Foundations. Special thanks to Kip Bodi and Anna Badiee for their help with bioinformatics, Tucker Berk for his help with immunoblots and IVEP and Dr Tatiana Prokaeva for her help with light chain sequence information.

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Authors and Affiliations

  1. Amyloid Treatment and Research Program, Alan and Sandra Gerry Amyloid Research Laboratory, Boston University School of Medicine, Boston, MA, USA

    B M Hovey, J E Ward, P Soo Hoo, C J O'Hara, L H Connors & D C Seldin

  2. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    B M Hovey, J E Ward & D C Seldin

  3. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA

    P Soo Hoo & C J O'Hara

  4. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    L H Connors

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  1. B M Hovey
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  4. C J O'Hara
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  5. L H Connors
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  6. D C Seldin
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Correspondence to D C Seldin.

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Hovey, B., Ward, J., Soo Hoo, P. et al. Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Ther 18, 1150–1156 (2011). https://doi.org/10.1038/gt.2011.69

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