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Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice.

ABSTRACT: Mice deficient for the cellular prion protein (PrP(C)) do not develop prion disease; accordingly, gene-based strategies to diminish PrP(C) 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 PrP(C) 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 (PrP(Sc)). 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.

SUBMITTER: Nazor Friberg K

PROVIDER: S-EPMC3381600 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice.

Nazor Friberg Karah K Hung Gene G Wancewicz Ed E Giles Kurt K Black Chris C Freier Sue S Bennett Frank F Dearmond Stephen J SJ Freyman Yevgeniy Y Lessard Pierre P Ghaemmaghami Sina S Prusiner Stanley B SB

Molecular therapy. Nucleic acids 20120207

Mice deficient for the cellular prion protein (PrP(C)) do not develop prion disease; accordingly, gene-based strategies to diminish PrP(C) 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 PrP(C) expression. Those ASOs were also evaluated in scrapie-infected cultured cells (ScN2a) for their efficacy in diminishing the levels of th ...[more]

PMID: 23344724

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Project description:Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.

Dataset Information

Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice.

Publications

Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice.

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