Efficient systemic CNS delivery of a therapeutic antisense oligonucleotide with a blood-brain barrier-penetrating ApoE-derived peptide.

Autor: Yeoh YQ; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia., Amin A; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia., Cuic B; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia., Tomas D; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia., Turner BJ; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia., Shabanpoor F; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia; School of Chemistry, University of Melbourne, VIC 3010, Australia. Electronic address: fazel.shabanpoor@unimelb.edu.au.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jun; Vol. 175, pp. 116737. Date of Electronic Publication: 2024 May 14.
DOI: 10.1016/j.biopha.2024.116737
Abstrakt: Antisense oligonucleotide (ASO) has emerged as a promising therapeutic approach for treating central nervous system (CNS) disorders by modulating gene expression with high selectivity and specificity. However, the poor permeability of ASO across the blood-brain barrier (BBB) diminishes its therapeutic success. Here, we designed and synthesized a series of BBB-penetrating peptides (BPP) derived from either the receptor-binding domain of apolipoprotein E (ApoE) or a transferrin receptor-binding peptide (THR). The BPPs were conjugated to phosphorodiamidate morpholino oligomers (PMO) that are chemically analogous to the 2'-O-(2-methoxyethyl) (MOE)-modified ASO approved by the FDA for treating spinal muscular atrophy (SMA). The BPP-PMO conjugates significantly increased the level of full-length SMN2 in the patient-derived SMA fibroblasts in a concentration-dependent manner with minimal to no toxicity. Furthermore, the systemic administration of the most potent BPP-PMO conjugates significantly increased the expression of full-length SMN2 in the brain and spinal cord of SMN2 transgenic adult mice. Notably, BPP8-PMO conjugate showed a 1.25-fold increase in the expression of full-length functional SMN2 in the brain. Fluorescence imaging studies confirmed that 78% of the fluorescently (Cy7)-labelled BPP8-PMO reached brain parenchyma, with 11% uptake in neuronal cells. Additionally, the BPP-PMO conjugates containing retro-inverso (RI) D-BPPs were found to possess extended half-lives compared to their L-counterparts, indicating increased stability against protease degradation while preserving the bioactivity. This delivery platform based on BPP enhances the CNS bioavailability of PMO targeting the SMN2 gene, paving the way for the development of systemically administered neurotherapeutics for CNS disorders.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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