PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-<i>O</i>-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

Geary, Richard S.; Yu, Rosie Z.; Watanabe, Tanya; Henry, Scott P.; Hardee, Gregory E.; Chappell, Alfred E.; Matson, John; Sasmor, Henri; Cummins, L.B.; Levin, Arthur A.

doi:10.1124/dmd.31.11.1419

Cited by 159 publications

(140 citation statements)

References 21 publications

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“…In that study, therapeutic success was aided by the fact that antisense compounds reach high concentrations in the liver, where virtually all of the apoB100 and LDL cholesterol originate. In the case of the progeria, the antisense reagents would probably need to reduce prelamin A levels in bone, muscle, and fat - tissues where the concentrations of oligonucleotide tend to be lower (30). However, even if oligonucleotide concentrations in these tissues were relatively low, it is still conceivable that disease phenotypes could be partially ameliorated.…”

Section: Figurementioning

confidence: 99%

“…We are cautiously optimistic that ISIS 359445 might be effective in vivo. One reason for optimism is that chimeric phosphorothioate oligodeoxynucleotides containing 2′-O-methoxyethyl (2′-MOE) modifications are extremely resistant to nucleases, have long half-lives (up to a week in mice), and support the RNAse H-mediated removal of the target transcript (29,30). Oligonucleotides specific for mouse (or human) apoB (employing the same chemistry) have previously been found to be very effective, lowering the levels of both apoB100 and LDL cholesterol in the plasma (31).…”

Section: Figurementioning

confidence: 99%

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Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Fong

Ng²,

Lammerding³

et al. 2006

Journal of Clinical Investigation

219

200

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Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna LCO/LCO ), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna LCO/LCO mice were entirely healthy, and Lmna LCO/LCO cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna LCO allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24 -/-mice. Moreover, treating Zmpste24 -/-cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Fong

Ng²,

Lammerding³

et al. 2006

Journal of Clinical Investigation

219

200

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“…NAPs may be of therapeutic benefit to treat many viral infections, as NAPs share the well-conserved pharmacokinetic characteristics of PS-ONs in mammalian species: following administration, PS-ONs are rapidly cleared from the blood (typically less than 1 h), with significant and durable accumulations in the kidney, liver, spleen, and lung (levels of accumulation are greatest in the kidney, with decreasing but still significant amounts in liver, spleen, and lung), and up to 40% of the administered dose accumulates in the liver (13)(14)(15)(16). Consistent with this behavior, NAPs have been shown to be active in vivo against virus infections with tropism in these organs: CMV, HCV, LCMV, influenza virus A, and respiratory syncytial virus (RSV) (7, 10, 11; A. Vaillant, unpublished observation).…”

mentioning

confidence: 99%

Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro

Noordeen

Vaillant²,

Jilbert

2013

Antimicrob Agents Chemother

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A pproximately 2 billion individuals are infected with hepatitis B virus (HBV) at some point in their life. Of these, over 400 million develop chronic HBV infection, with persistent HBV DNA and HBV surface antigen (HBsAg) in serum due to continuous production of HBV antigens and HBV DNA in the liver (1). The consequences of chronic HBV infection include cirrhosis, hepatocellular carcinoma (HCC), and liver failure. These end stage disease outcomes cause over a million deaths each year (1, 2). Currently approved drugs for chronic HBV infection work well to suppress HBV replication during treatment, but virus replication generally rebounds when treatment is stopped. In addition, adverse reactions to the commonly used immunomodulators 2-alpha interferon (IFN-2␣) and pegylated IFN-2␣ (pegIFN-2␣) and the development of resistance to nucleotide/nucleoside-based viral polymerase inhibitors justify the need for research into new therapeutic agents for HBV (3, 4).Nucleic acid polymers (NAPs) are water soluble and amphipathic in nature. These NAPs are constructed from oligonucleotides in which phosphorothioation of a nonbridging oxygen atom in the phosphodiester linkage, traditionally used as a modification to stabilize oligonucleotides against nuclease attack, is used to enhance the amphipathic properties of oligonucleotides (5).

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“…By comparing hundreds of ASOs that target various splicing silencers in exon 7 and both flanking introns (Hua et al 2008; data not shown), we identified an optimal 18mer 29-O-(2-methoxyethyl) (MOE) ASO (#10-27) that targets ISS-N1 in intron 7. The lead ASO also promotes efficient SMN2 exon 7 inclusion in the liver and kidneys of transgenic mice after systemic administration, but not in the spinal cord (Hua et al 2008), owing to a lack of distribution across an intact blood-brain barrier (BBB) (Geary et al 2003).…”

mentioning

confidence: 99%

Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model

Hua¹,

Sahashi²,

Hung³

et al. 2010

Genes Dev.

559

518

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Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in motor neurons is a promising approach to treat spinal muscular atrophy (SMA), a genetic neurodegenerative disease. Previously, we identified a potent 29-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes exon 7 inclusion in transgenic mouse peripheral tissues after systemic administration. Here we address its efficacy in the spinal cord-a prerequisite for disease treatment-and its ability to rescue a mild SMA mouse model that develops tail and ear necrosis, resembling the distal tissue necrosis reported in some SMA infants. Using a microosmotic pump, we directly infused the ASO into a lateral cerebral ventricle in adult mice expressing a human SMN2 transgene; the ASO gave a robust and long-lasting increase in SMN2 exon 7 inclusion measured at both the mRNA and protein levels in spinal cord motor neurons. A single embryonic or neonatal intracerebroventricular ASO injection strikingly rescued the tail and ear necrosis in SMA mice. We conclude that this MOE ASO is a promising drug candidate for SMA therapy, and, more generally, that ASOs can be used to efficiently redirect alternative splicing of target genes in the CNS.[Keywords: Spinal muscular atrophy; SMN2; antisense oligonucleotide; splicing correction; spinal cord; mouse models] Supplemental material is available at http://www.genesdev.org.

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PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-O-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES

Cited by 159 publications

References 21 publications

Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro

Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model

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