Format

Send to

Choose Destination
J Pharmacol Exp Ther. 2014 Jul;350(1):46-55. doi: 10.1124/jpet.113.212407. Epub 2014 Apr 30.

Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates.

Author information

1
Isis Pharmaceuticals, Carlsbad, California (F.R., S.J.C., D.A.N., G.H., S.L., J.M., R.A.F., H.G., J.S.G., S.P.H., C.F.B.); and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (Y.H., A.R.K.) frigo@isisph.com.
2
Isis Pharmaceuticals, Carlsbad, California (F.R., S.J.C., D.A.N., G.H., S.L., J.M., R.A.F., H.G., J.S.G., S.P.H., C.F.B.); and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (Y.H., A.R.K.).

Abstract

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 nonhuman 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.

PMID:
24784568
PMCID:
PMC4056267
DOI:
10.1124/jpet.113.212407
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center