Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates.
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.
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.
Frank
F
Rigo
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.).
Seung J
SJ
Chun
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.).
Daniel A
DA
Norris
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.).
Gene
G
Hung
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.).
Sam
S
Lee
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.).
John
J
Matson
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.).
Robert A
RA
Fey
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.).
Hans
H
Gaus
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.).
Yimin
Y
Hua
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.).
John S
JS
Grundy
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.).
Adrian R
AR
Krainer
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.).
Scott P
SP
Henry
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.).
C Frank
CF
Bennett
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D057967:Infusions, Intraventricular; D007276:Injections, Intraventricular; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012326:RNA Splicing / Q000187:drug effects*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; D055540:Survival of Motor Neuron 2 Protein; C000590926:nusinersen