Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides.
Autor: | Dastpeyman M; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia., Sharifi R; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia., Amin A; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia., Karas JA; School of Chemistry, The University of Melbourne, VIC 3010, Australia; The Bio21 Institute, University of Melbourne, 30 Flemington Rd., VIC 3010, Australia., Cuic B; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia., Pan Y; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia., Nicolazzo JA; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia., Turner BJ; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia; The Perron Institute for Neurological and Translational Science, Queen Elizabeth Medical Centre, Nedlands, Western Australia 6150, Australia., Shabanpoor F; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: fazel.shabanpoor@unimelb.edu.au. |
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Jazyk: | angličtina |
Zdroj: | International journal of pharmaceutics [Int J Pharm] 2021 Apr 15; Vol. 599, pp. 120398. Date of Electronic Publication: 2021 Feb 26. |
DOI: | 10.1016/j.ijpharm.2021.120398 |
Abstrakt: | Antisense oligonucleotides (ASOs) are an emerging class of gene-specific therapeutics for diseases associated with the central nervous system (CNS). However, ASO delivery across the blood-brain barrier (BBB) to their CNS target cells remains a major challenge. Since ASOs are mainly taken up into the brain capillary endothelial cells interface through endosomal routes, entrapment in the endosomal compartment is a major obstacle for efficient CNS delivery of ASOs. Therefore, we evaluated the effectiveness of a panel of cell-penetrating peptides (CPPs) bearing several endosomal escape domains for the intracellular delivery, endosomal release and antisense activity of FDA-approved Spinraza (Nusinersen), an ASO used to treat spinal muscular atrophy (SMA). We identified a CPP, HA2-ApoE(131-150), which, when conjugated to Nusinersen, showed efficient endosomal escape capability and significantly increased the level of full-length functional mRNA of the survival motor neuron 2 (SMN2) gene in SMA patient-derived fibroblasts. Treatment of SMN2 transgenic adult mice with this CPP-PMO conjugate resulted in a significant increase in the level of full-length SMN2 in the brain and spinal cord. This work provides proof-of-principle that integration of endosomal escape domains with CPPs enables higher cytosolic delivery of ASOs, and more importantly enhances the efficiency of BBB-permeability and CNS activity of systemically administered ASOs. (Copyright © 2021 Elsevier B.V. All rights reserved.) |
Databáze: | MEDLINE |
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