title: Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.
abstract: Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141-150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.
authors.affiliation: 1 Medical Research Council, Laboratory of Molecular Biology , Cambridge, United Kingdom .
authors.forename: Fazel
authors.initials: F
authors.lastname: Shabanpoor
authors.affiliation: 2 Department of Physiology, Anatomy, and Genetics, University of Oxford , Oxford, United Kingdom .
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Hammond
authors.affiliation: 1 Medical Research Council, Laboratory of Molecular Biology , Cambridge, United Kingdom .
authors.forename: Frank
authors.initials: F
authors.lastname: Abendroth
authors.affiliation: 2 Department of Physiology, Anatomy, and Genetics, University of Oxford , Oxford, United Kingdom .
authors.forename: Gareth
authors.initials: G
authors.lastname: Hazell
authors.affiliation: 2 Department of Physiology, Anatomy, and Genetics, University of Oxford , Oxford, United Kingdom .
authors.forename: Matthew J A
authors.initials: MJA
authors.lastname: Wood
authors.affiliation: 1 Medical Research Council, Laboratory of Molecular Biology , Cambridge, United Kingdom .
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005091:Exons; D005347:Fibroblasts / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000737:chemistry; D051379:Mice; D060172:Morpholinos / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D058726:Nanoconjugates / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D010641:Phenotype; D052097:Quadriceps Muscle / Q000737:chemistry; D055540:Survival of Motor Neuron 2 Protein / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D060172:Morpholinos; D058726:Nanoconjugates; D010455:Peptides; C000597152:SMN2 protein, mouse; D055540:Survival of Motor Neuron 2 Protein
keywords: brain delivery; peptides; spinal muscular atrophy; splice-switching oligonucleotide; survival motor neuron