Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy.
The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
Suzan M
0000-0002-5640-7569
SM
Hammond
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
Gareth
G
Hazell
Laboratory of Molecular Biology, Medical Research Council, Cambridge CB2 0QH, United Kingdom;
Fazel
F
Shabanpoor
Laboratory of Molecular Biology, Medical Research Council, Cambridge CB2 0QH, United Kingdom;
Amer F
AF
Saleh
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
Melissa
M
Bowerman
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, United Kingdom;
James N
0000-0002-3782-9045
JN
Sleigh
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
Katharina E
KE
Meijboom
Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
Haiyan
H
Zhou
Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
Francesco
F
Muntoni
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, United Kingdom;
Kevin
K
Talbot
Laboratory of Molecular Biology, Medical Research Council, Cambridge CB2 0QH, United Kingdom;
Michael J
MJ
Gait
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom; matthew.wood@dpag.ox.ac.uk.
Matthew J A
MJ
Wood
D000375:Aging; D000483:Alleles; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D006801:Humans; D009068:Movement; D009134:Muscular Atrophy, Spinal / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry*; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics; D016019:Survival Analysis; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
D015415:Biomarkers; D009841:Oligonucleotides; D010455:Peptides; D055540:Survival of Motor Neuron 2 Protein
antisense oligonucleotide; cell-penetrating peptide; spinal muscular atrophy; splice switching oligonucleotide; survival motor neuron