Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice

Karah Nazor Friberg; Gene Hung; Ed Wancewicz; Kurt Giles; Chris Black; Sue Freier; Frank Bennett; Stephen J DeArmond; Yevgeniy Freyman; Pierre Lessard; Sina Ghaemmaghami; Stanley B Prusiner

doi:10.1038/mtna.2011.6

Molecular Therapy: Nucleic Acids (Jan 2012)

Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice

Karah Nazor Friberg,
Gene Hung,
Ed Wancewicz,
Kurt Giles,
Chris Black,
Sue Freier,
Frank Bennett,
Stephen J DeArmond,
Yevgeniy Freyman,
Pierre Lessard,
Sina Ghaemmaghami,
Stanley B Prusiner

Affiliations

Karah Nazor Friberg: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Gene Hung: Isis Pharmaceuticals, Inc., San Francisco, California, USA
Ed Wancewicz: Isis Pharmaceuticals, Inc., San Francisco, California, USA
Kurt Giles: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Chris Black: Isis Pharmaceuticals, Inc., San Francisco, California, USA
Sue Freier: Isis Pharmaceuticals, Inc., San Francisco, California, USA
Frank Bennett: Isis Pharmaceuticals, Inc., San Francisco, California, USA
Stephen J DeArmond: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Yevgeniy Freyman: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Pierre Lessard: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Sina Ghaemmaghami: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
Stanley B Prusiner: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA

DOI: https://doi.org/10.1038/mtna.2011.6
Journal volume & issue: Vol. 1, no. C

Abstract

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Mice deficient for the cellular prion protein (PrPC) do not develop prion disease; accordingly, gene-based strategies to diminish PrPC expression are of interest. We synthesized a series of chemically modified antisense oligonucleotides (ASOs) targeted against mouse Prnp messenger RNA (mRNA) and identified those that were most effective in decreasing PrPC expression. Those ASOs were also evaluated in scrapie-infected cultured cells (ScN2a) for their efficacy in diminishing the levels of the disease-causing prion protein (PrPSc). When the optimal ASO was infused intracerebrally into FVB mice over a 14-day period beginning 1 day after infection with the Rocky Mountain Laboratory (RML) strain of mouse prions, a prolongation of the incubation period of almost 2 months was observed. Whether ASOs can be used to develop an effective therapy for patients dying of Creutzfeldt–Jakob disease remains to be established.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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