{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T22:28:39Z","timestamp":1788560919278,"version":"build-2803163510"},"reference-count":131,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Muscular Dystrophy Canada"},{"name":"Friends of Garrett Cumming Research Fund"},{"name":"HM Toupin Neurological Science Research Fund"},{"name":"Canadian Institute of Health Research (CIHR)"},{"name":"Alberta Innovates: Health Solutions (AIHS)"},{"name":"Jesse\u2019s Journey"},{"name":"Women and Children\u2019s Health Research Institute (WCHRI)"},{"name":"Heart and Stroke Foundation Canada, and the US Department of Defense"},{"name":"University of Alberta Faculty of Medicine and Dentistry"},{"name":"CIHR Strategic Master\u2019s Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood\u2013brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.<\/jats:p>","DOI":"10.3390\/molecules29112658","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T11:48:50Z","timestamp":1717501730000},"page":"2658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA"],"prefix":"10.3390","volume":"29","author":[{"given":"Jamie","family":"Leckie","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-6742","authenticated-orcid":false,"given":"Toshifumi","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada"},{"name":"The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Sciences Research, Edmonton, AB T6G 2H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). GeneReviews(\u00ae), University of Washington."},{"key":"ref_2","first-page":"194","article-title":"Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy","volume":"24","author":"Neil","year":"2019","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nbt1016-1002","article-title":"Big win possible for Ionis\/Biogen antisense drug in muscular atrophy","volume":"34","author":"Garber","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wang, F., Liu, L.S., Li, P., Lau, C.H., Leung, H.M., Chin, Y.R., Tin, C., and Lo, P.K. (2022). Cellular uptake, tissue penetration, biodistribution, and biosafety of threose nucleic acids: Assessing in vitro and in vivo delivery. Mater. Today Bio, 15.","DOI":"10.1016\/j.mtbio.2022.100299"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10962","DOI":"10.1073\/pnas.1605731113","article-title":"Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy","volume":"113","author":"Hammond","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1089\/nat.2016.0652","article-title":"Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy","volume":"27","author":"Shabanpoor","year":"2017","journal-title":"Nucleic Acid Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"120398","DOI":"10.1016\/j.ijpharm.2021.120398","article-title":"Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides","volume":"599","author":"Dastpeyman","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.ymthe.2021.11.012","article-title":"Cell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model","volume":"30","author":"Bersani","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e160516","DOI":"10.1172\/jci.insight.160516","article-title":"DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration","volume":"8","author":"Aslesh","year":"2023","journal-title":"JCI Insight"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Haque, U.S., and Yokota, T. (2023). Enhancing Antisense Oligonucleotide-Based Therapeutic Delivery with DG9, a Versatile Cell-Penetrating Peptide. Cells, 12.","DOI":"10.3390\/cells12192395"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1093\/brain\/aws108","article-title":"Autosomal dominant congenital spinal muscular atrophy: A true form of spinal muscular atrophy caused by early loss of anterior horn cells","volume":"135","author":"Oates","year":"2012","journal-title":"Brain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.nmd.2017.11.005","article-title":"Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care","volume":"28","author":"Mercuri","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s00439-002-0828-x","article-title":"Genetic testing and risk assessment for spinal muscular atrophy (SMA)","volume":"111","author":"Ogino","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ejhg.2011.134","article-title":"Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72,400 specimens","volume":"20","author":"Sugarman","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/00125817-200201000-00004","article-title":"Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2","volume":"4","author":"Mailman","year":"2002","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9472","DOI":"10.1038\/s41598-019-45822-8","article-title":"Functional characterization of SMN evolution in mouse models of SMA","volume":"9","author":"Osman","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.4155\/fmc.14.63","article-title":"Advances in therapeutic development for spinal muscular atrophy","volume":"6","author":"Howell","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbagrm.2016.12.008","article-title":"Diverse role of survival motor neuron protein","volume":"1860","author":"Singh","year":"2017","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0092-8674(00)81632-3","article-title":"A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing","volume":"95","author":"Pellizzoni","year":"1998","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.cell.2011.06.043","article-title":"Structure of a key intermediate of the SMN complex reveals Gemin2\u2019s crucial function in snRNP assembly","volume":"146","author":"Zhang","year":"2011","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.celrep.2013.11.012","article-title":"SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3\u2032-end formation of histone mRNAs","volume":"5","author":"Tisdale","year":"2013","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fayzullina, S., and Martin, L.J. (2014). Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093329"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.1093\/nar\/gkq271","article-title":"GEMIN2 promotes accumulation of RAD51 at double-strand breaks in homologous recombination","volume":"38","author":"Takizawa","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_25","first-page":"6986","article-title":"Genetic inhibition of JNK3 ameliorates spinal muscular atrophy","volume":"24","author":"Genabai","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1083\/jcb.201004016","article-title":"Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling","volume":"192","author":"Sen","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1083\/jcb.200304128","article-title":"Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons","volume":"163","author":"Rossoll","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_28","first-page":"804","article-title":"SMN affects membrane remodelling and anchoring of the protein synthesis machinery","volume":"129","author":"Gabanella","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1093\/hmg\/9.16.2451","article-title":"Animal models of spinal muscular atrophy","volume":"9","author":"Monani","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1128\/MCB.01262-08","article-title":"Regulation of SMN protein stability","volume":"29","author":"Burnett","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.nmd.2018.01.003","article-title":"Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases","volume":"28","author":"Calucho","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Butchbach, M.E. (2016). Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front. Mol. Biosci., 3.","DOI":"10.3389\/fmolb.2016.00007"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ajhg.2009.08.002","article-title":"A positive modifier of spinal muscular atrophy in the SMN2 gene","volume":"85","author":"Prior","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.pcl.2015.03.010","article-title":"Spinal muscular atrophies","volume":"62","author":"Darras","year":"2015","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1750-1172-6-71","article-title":"Spinal muscular atrophy","volume":"6","author":"Mercuri","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ncl.2015.07.004","article-title":"Spinal Muscular Atrophy","volume":"33","author":"Kolb","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1090-3798(99)80012-9","article-title":"Very severe spinal muscular atrophy (SMA type 0): An expanding clinical phenotype","volume":"3","author":"Dubowitz","year":"1999","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3233\/JND-160177","article-title":"Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients","volume":"3","author":"Grotto","year":"2016","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1126\/science.166.3903.393","article-title":"Enzyme from calf thymus degrading the RNA moiety of DNA-RNA Hybrids: Effect on DNA-dependent RNA polymerase","volume":"166","author":"Stein","year":"1969","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17181","DOI":"10.1074\/jbc.M311683200","article-title":"Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs","volume":"279","author":"Wu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1073\/pnas.75.1.285","article-title":"Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide","volume":"75","author":"Stephenson","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nchembio.939","article-title":"Synthetic oligonucleotides recruit ILF2\/3 to RNA transcripts to modulate splicing","volume":"8","author":"Rigo","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6900","DOI":"10.1093\/nar\/gkz500","article-title":"mRNA levels can be reduced by antisense oligonucleotides via no-go decay pathway","volume":"47","author":"Liang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11560","DOI":"10.1093\/nar\/gkab954","article-title":"Targeting 3\u2032 and 5\u2032 untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression","volume":"49","author":"Li","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gene.2012.07.083","article-title":"Function of alternative splicing","volume":"514","author":"Kelemen","year":"2013","journal-title":"Gene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrd3625","article-title":"RNA therapeutics: Beyond RNA interference and antisense oligonucleotides","volume":"11","author":"Kole","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"232","DOI":"10.31662\/jmaj.2021-0019","article-title":"Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy","volume":"4","author":"Matsuo","year":"2021","journal-title":"JMA J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.nmd.2015.07.002","article-title":"Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum","volume":"25","author":"Musumeci","year":"2015","journal-title":"Neuromuscul. Disord."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.omtn.2017.03.001","article-title":"Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease","volume":"7","author":"Bergsma","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43856-023-00419-1","article-title":"Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders","volume":"4","author":"Lauffer","year":"2024","journal-title":"Commun. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.1093\/nar\/gkw236","article-title":"The delivery of therapeutic oligonucleotides","volume":"44","author":"Juliano","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nbt.3779","article-title":"Cellular uptake and trafficking of antisense oligonucleotides","volume":"35","author":"Crooke","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41573-020-0075-7","article-title":"Advances in oligonucleotide drug delivery","volume":"19","author":"Roberts","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/oli.1.2000.10.117","article-title":"Phosphorothioate oligodeoxynucleotides: What is their origin and what is unique about them?","volume":"10","author":"Eckstein","year":"2000","journal-title":"Antisense Nucleic Acid Drug Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1089\/nat.2014.0506","article-title":"Phosphorothioates, essential components of therapeutic oligonucleotides","volume":"24","author":"Eckstein","year":"2014","journal-title":"Nucleic Acid Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev.pa.36.040196.000543","article-title":"Progress in antisense oligonucleotide therapeutics","volume":"36","author":"Crooke","year":"1996","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1002\/cbdv.201100081","article-title":"An overview of sugar-modified oligonucleotides for antisense therapeutics","volume":"8","author":"Prakash","year":"2011","journal-title":"Chem. Biodivers."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9352","DOI":"10.1021\/bi200904e","article-title":"Stability and mismatch discrimination of locked nucleic acid-DNA duplexes","volume":"50","author":"Owczarzy","year":"2011","journal-title":"Biochemistry"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Dhuri, K., Bechtold, C., Quijano, E., Pham, H., Gupta, A., Vikram, A., and Bahal, R. (2020). Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J. Clin. Med., 9.","DOI":"10.3390\/jcm9062004"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0169-328X(97)00048-X","article-title":"End-capped antisense oligodeoxynucleotides effectively inhibit gene expression in vivo and offer a low-toxicity alternative to fully modified phosphorothioate oligodeoxynucleotides","volume":"47","author":"Hebb","year":"1997","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.3390\/molecules14031304","article-title":"Gene knockdowns in adult animals: PPMOs and vivo-morpholinos","volume":"14","author":"Moulton","year":"2009","journal-title":"Molecules"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.ajhg.2008.01.014","article-title":"Antisense masking of an hnRNP A1\/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice","volume":"82","author":"Hua","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hua, Y., Vickers, T.A., Baker, B.F., Bennett, C.F., and Krainer, A.R. (2007). Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050073"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/gt.2017.34","article-title":"How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy","volume":"24","author":"Singh","year":"2017","journal-title":"Gene Ther."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Sintusek, P., Catapano, F., Angkathunkayul, N., Marrosu, E., Parson, S.H., Morgan, J.E., Muntoni, F., and Zhou, H. (2016). Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155032"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1101\/gad.1941310","article-title":"Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model","volume":"24","author":"Hua","year":"2010","journal-title":"Genes Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"72ra18","DOI":"10.1126\/scitranslmed.3001777","article-title":"Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy","volume":"3","author":"Passini","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature10485","article-title":"Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model","volume":"478","author":"Hua","year":"2011","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1093\/hmg\/ddr600","article-title":"A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse","volume":"21","author":"Porensky","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1089\/hum.2012.211","article-title":"A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice","volume":"24","author":"Zhou","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1212\/WNL.0000000000002445","article-title":"Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy","volume":"86","author":"Chiriboga","year":"2016","journal-title":"Neurology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1016\/S0140-6736(16)31408-8","article-title":"Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study","volume":"388","author":"Finkel","year":"2016","journal-title":"Lancet"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/jcph.884","article-title":"Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations","volume":"57","author":"Luu","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40265-017-0711-7","article-title":"Nusinersen: First Global Approval","volume":"77","author":"Hoy","year":"2017","journal-title":"Drugs"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/mus.26001","article-title":"Making sense of antisense oligonucleotides: A narrative review","volume":"57","author":"Goyal","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"100373","DOI":"10.1016\/j.cotox.2022.100373","article-title":"Nephrotoxicity of marketed antisense oligonucleotide drugs","volume":"32","author":"Wu","year":"2022","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.addr.2015.01.008","article-title":"Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides","volume":"87","author":"Geary","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1093\/nar\/gkt066","article-title":"The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides","volume":"41","author":"Ming","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrneurol.2017.148","article-title":"Antisense oligonucleotides: The next frontier for treatment of neurological disorders","volume":"14","author":"Rinaldi","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/nat.2022.0061","article-title":"Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides","volume":"33","author":"Goyenvalle","year":"2023","journal-title":"Nucleic Acid Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1007\/s12325-022-02376-y","article-title":"Adherence and Persistence to Nusinersen for Spinal Muscular Atrophy: A US Claims-Based Analysis","volume":"40","author":"Fox","year":"2023","journal-title":"Adv. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/0092-8674(88)90263-2","article-title":"Cellular uptake of the tat protein from human immunodeficiency virus","volume":"55","author":"Frankel","year":"1988","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/0092-8674(88)90262-0","article-title":"Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein","volume":"55","author":"Green","year":"1988","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0092-8674(89)90417-0","article-title":"Mutational analysis of HIV-1 Tat minimal domain peptides: Identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression","volume":"58","author":"Green","year":"1989","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e202300236","DOI":"10.1002\/cmdc.202300236","article-title":"Cell Penetrating Peptides: Classification, Mechanisms, Methods of Study, and Applications","volume":"18","author":"Gori","year":"2023","journal-title":"ChemMedChem"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.bcp.2005.10.048","article-title":"Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide","volume":"71","author":"Lindgren","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/nbt1201-1173","article-title":"A peptide carrier for the delivery of biologically active proteins into mammalian cells","volume":"19","author":"Morris","year":"2001","journal-title":"Nat. Biotechnol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7980","DOI":"10.1016\/j.biomaterials.2013.07.014","article-title":"A pH-responsive \u03b1-helical cell penetrating peptide-mediated liposomal delivery system","volume":"34","author":"Zhang","year":"2013","journal-title":"Biomaterials"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/mt.2011.284","article-title":"Cell-penetrating peptides as versatile vehicles for oligonucleotide delivery","volume":"20","author":"Margus","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Chavda, V.P., Solanki, H.K., Davidson, M., Apostolopoulos, V., and Bojarska, J. (2022). Peptide-Drug Conjugates: A New Hope for Cancer Management. Molecules, 27.","DOI":"10.3390\/molecules27217232"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/cbdd.12055","article-title":"The future of peptide-based drugs","volume":"81","author":"Craik","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3389\/fphar.2020.00697","article-title":"Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application","volume":"11","author":"Xie","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.tibs.2015.10.004","article-title":"Mechanism Matters: A Taxonomy of Cell Penetrating Peptides","volume":"40","author":"Kauffman","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"D1098","DOI":"10.1093\/nar\/gkv1266","article-title":"CPPsite 2.0: A repository of experimentally validated cell-penetrating peptides","volume":"44","author":"Agrawal","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Borrelli, A., Tornesello, A.L., Tornesello, M.L., and Buonaguro, F.M. (2018). Cell Penetrating Peptides as Molecular Carriers for Anti-Cancer Agents. Molecules, 23.","DOI":"10.3390\/molecules23020295"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.tips.2010.11.005","article-title":"Biological responses towards cationic peptides and drug carriers","volume":"32","author":"Verdurmen","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jconrel.2017.02.029","article-title":"The effect of nanoparticle size and NLS density on nuclear targeting in cancer and normal cells; impaired nuclear import and aberrant nanoparticle intracellular trafficking in glioma","volume":"253","author":"Tammam","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1074\/jbc.M509813200","article-title":"Mechanism of uptake of C105Y, a novel cell-penetrating peptide","volume":"281","author":"Rhee","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1016\/S0968-0896(02)00340-1","article-title":"A cell-penetrating peptide from a novel pVII-pIX phage-displayed random peptide library","volume":"10","author":"Gao","year":"2002","journal-title":"Bioorganic Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1021\/cb100423u","article-title":"An unusual cell penetrating peptide identified using a plasmid display-based functional selection platform","volume":"6","author":"Gao","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3892\/br.2016.639","article-title":"Cell-penetrating peptides: Possible transduction mechanisms and therapeutic applications","volume":"4","author":"Guo","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/psc.1408","article-title":"Antimicrobial activity, bactericidal mechanism and LPS-neutralizing activity of the cell-penetrating peptide pVEC and its analogs","volume":"17","author":"Nan","year":"2011","journal-title":"J. Pept. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/sj.mt.6300346","article-title":"Characterization of a novel cytotoxic cell-penetrating peptide derived from p14ARF protein","volume":"16","author":"Johansson","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.bbrc.2006.07.065","article-title":"N-terminal peptides from unprocessed prion proteins enter cells by macropinocytosis","volume":"348","author":"Magzoub","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.drudis.2012.03.002","article-title":"Cell-penetrating peptides: Classes, origin, and current landscape","volume":"17","author":"Milletti","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0014-5793(97)01123-X","article-title":"Extensive cellular uptake into endothelial cells of an amphipathic beta-sheet forming peptide","volume":"415","author":"Oehlke","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jconrel.2013.11.020","article-title":"Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery","volume":"174","author":"Wang","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3762\/bjnano.11.10","article-title":"Internalization mechanisms of cell-penetrating peptides","volume":"11","author":"Ruseska","year":"2020","journal-title":"Beilstein J. Nanotechnol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"15300","DOI":"10.1074\/jbc.M401604200","article-title":"Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors","volume":"280","author":"Richard","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"17640","DOI":"10.1038\/srep17640","article-title":"Delivery of cell-penetrating peptide-peptide nucleic acid conjugates by assembly on an oligonucleotide scaffold","volume":"5","author":"Zhao","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"McClorey, G., and Banerjee, S. (2018). Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020051"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bpj.2009.03.059","article-title":"Alternative mechanisms for the interaction of the cell-penetrating peptides penetratin and the TAT peptide with lipid bilayers","volume":"97","author":"Yesylevskyy","year":"2009","journal-title":"Biophys. J."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.1007\/s00253-018-8889-5","article-title":"Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells","volume":"102","author":"Islam","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.bbamem.2005.10.004","article-title":"Interactions of amphipathic CPPs with model membranes","volume":"1758","author":"Deshayes","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/jbm.a.34859","article-title":"Cell-penetrating peptides: Achievements and challenges in application for cancer treatment","volume":"102","author":"Shin","year":"2014","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3980","DOI":"10.1021\/acs.biochem.9b00413","article-title":"Chimeras of Cell-Penetrating Peptides Demonstrate Synergistic Improvement in Antisense Efficacy","volume":"58","author":"Fadzen","year":"2019","journal-title":"Biochemistry"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1021\/bc0501045","article-title":"Arginine-rich peptide conjugation to morpholino oligomers: Effects on antisense activity and specificity","volume":"16","author":"Nelson","year":"2005","journal-title":"Bioconjugate Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"6418","DOI":"10.1093\/nar\/gkn671","article-title":"Improved cell-penetrating peptide-PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle","volume":"36","author":"Ivanova","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1089\/nat.2012.0404","article-title":"Systemic delivery of a Peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy","volume":"23","author":"Leger","year":"2013","journal-title":"Nucleic Acid Ther."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.ebiom.2019.06.036","article-title":"Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases","volume":"45","author":"Tsoumpra","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/nat.2016.0657","article-title":"FDA Approves Eteplirsen for Duchenne Muscular Dystrophy: The Next Chapter in the Eteplirsen Saga","volume":"27","author":"Krieg","year":"2017","journal-title":"Nucleic Acid Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2147\/DDDT.S97635","article-title":"Eteplirsen in the treatment of Duchenne muscular dystrophy","volume":"11","author":"Lim","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1038\/mt.2011.79","article-title":"Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice","volume":"19","author":"Yin","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1038\/mtna.2012.30","article-title":"Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment","volume":"1","author":"Betts","year":"2012","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e2112546119","DOI":"10.1073\/pnas.2112546119","article-title":"Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy","volume":"119","author":"Lim","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1093\/nar\/29.19.3965","article-title":"Nuclear antisense effects of neutral, anionic and cationic oligonucleotide analogs","volume":"29","author":"Sazani","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/71709","article-title":"A mouse model for spinal muscular atrophy","volume":"24","author":"Chang","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Mitrpant, C., Porensky, P., Zhou, H., Price, L., Muntoni, F., Fletcher, S., Wilton, S.D., and Burghes, A.H. (2013). Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062114"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"25658","DOI":"10.1038\/srep25658","article-title":"Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier","volume":"6","author":"Ozmen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.clinthera.2014.02.004","article-title":"Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy \u03947 mouse model phenotype","volume":"36","author":"Nizzardo","year":"2014","journal-title":"Clin. Ther."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/11\/2658\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:53:36Z","timestamp":1760108016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/11\/2658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,4]]},"references-count":131,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["molecules29112658"],"URL":"https:\/\/doi.org\/10.3390\/molecules29112658","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,4]]}}}