Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl-Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates

被引：212

作者：

Rigo, Frank ^{[1
]}

Chun, Seung J. ^{[1
]}

Norris, Daniel A. ^{[1
]}

Hung, Gene ^{[1
]}

Lee, Sam ^{[1
]}

Matson, John ^{[1
]}

Fey, Robert A. ^{[1
]}

Gaus, Hans ^{[1
]}

Hua, Yimin ^{[2
]}

Grundy, John S. ^{[1
]}

Krainer, Adrian R. ^{[2
]}

Henry, Scott P. ^{[1
]}

Bennett, C. Frank ^{[1
]}

机构：

[1] ISIS Pharmaceut, Carlsbad, CA 92008 USA

[2] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2014年 / 350卷 / 01期

基金：

美国国家卫生研究院;

关键词：

SPINAL MUSCULAR-ATROPHY; LOCKED NUCLEIC-ACID; SEVERE MOUSE MODEL; ANTISENSE OLIGONUCLEOTIDES; SINGLE NUCLEOTIDE; TRANSGENIC MICE; GENE SMN2; IN-VIVO; RNA; EXON;

D O I：

10.1124/jpet.113.212407

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and non-human primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.

引用

页码：46 / 55

页数：10

共 54 条

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