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Advanced Technology for Gene Delivery with Homing Peptides to Spinal Cord through Systemic Circulation in Mice.

ABSTRACT: Homing peptides to the spinal cord were identified and isolated using phage display technology. In vivo biopanning was performed by intravenous systemic injection of a phage library to screen specific peptides targeting the spinal cord of mice. Analyses of the sequences of targeted phages yielded two candidate peptides targeting the spinal cord: SP1 (C-LHQSPHI-C) and SP2 (C-PTNNPRS-C). These peptides were synthesized and intravenously injected into mice to evaluate their tissue specificity and potential as gene delivery carriers. The complexes between SP1 or SP2 peptides and the plasmid vector expressing the reporter gene could induce gene transduction in the spinal cord through systemic injection without gene expression in the brain, liver, and kidney. In addition, intravenous injection of the complex between SP1 and the vectors induced interleukin-4 expression in the spinal cord, resulting in effective suppression of lipopolysaccharide-induced hyperalgesia. Therefore, intravenously administered spinal cord homing peptides complexed with a plasmid vector provided tissue-specific treatment featuring gene delivery to the CNS through systemic circulation. This novel method of gene delivery is feasible and has great potential for clinical application.

SUBMITTER: Terashima T

PROVIDER: S-EPMC6538929 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Advanced Technology for Gene Delivery with Homing Peptides to Spinal Cord through Systemic Circulation in Mice.

Terashima Tomoya T Ogawa Nobuhiro N Sato Toshiyuki T Katagi Miwako M Nakae Yuki Y Okano Junko J Maegawa Hiroshi H Kojima Hideto H

Molecular therapy. Methods & clinical development 20190510

Homing peptides to the spinal cord were identified and isolated using phage display technology. <i>In vivo</i> biopanning was performed by intravenous systemic injection of a phage library to screen specific peptides targeting the spinal cord of mice. Analyses of the sequences of targeted phages yielded two candidate peptides targeting the spinal cord: SP1 (C-LHQSPHI-C) and SP2 (C-PTNNPRS-C). These peptides were synthesized and intravenously injected into mice to evaluate their tissue specificit ...[more]

PMID: 31193742

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Project description:Proper selection and effective delivery of combination drugs targeting multiple pathophysiological pathways key to spinal cord injury (SCI) hold promise to address the thus far scarce clinical therapeutics for improving recovery after SCI. In this study, we aim to develop a clinically feasible way for targeted delivery of multiple drugs with different physiochemical properties to the SCI site, detail the underlying mechanism of neural recovery, and detect any synergistic effect related to combination therapy. Methods: Liposomes (LIP) modified with a scar-targeted tetrapeptide (cysteine-alanine-glutamine-lysine, CAQK) were first constructed to simultaneously encapsulate docetaxel (DTX) and brain-derived neurotrophic factor (BDNF) and then were further added into a thermosensitive heparin-modified poloxamer hydrogel (HP) with affinity-bound acidic fibroblast growth factor (aFGF-HP) for local administration into the SCI site (CAQK-LIP-GFs/DTX@HP) in a rat model. In vivo fluorescence imaging was used to examine the specificity of CAQK-LIP-GFs/DTX binding to the injured site. Multiple comprehensive evaluations including biotin dextran amine anterograde tracing and magnetic resonance imaging were used to detect any synergistic effects and the underlying mechanisms of CAQK-LIP-GFs/DTX@HP both in vivo (rat SCI model) and in vitro (primary neuron). Results: The multiple drugs were effectively delivered to the injured site. The combined application of GFs and DTX supported neuro-regeneration by improving neuronal survival and plasticity, rendering a more permissive extracellular matrix environment with improved regeneration potential. In addition, our combination therapy promoted axonal regeneration via moderation of microtubule function and mitochondrial transport along the regenerating axon. Conclusion: This novel multifunctional therapeutic strategy with a scar-homing delivery system may offer promising translational prospects for the clinical treatment of SCI.

Project description:BackgroundSpinal cord ischemic injury is a severe complication of aortic surgery. We hypothesized that cerebrospinal fluid (CSF) oxygenation with nanobubbles after reperfusion could ameliorate spinal cord ischemic injury.MethodsTwenty white Japanese rabbits were categorized into 4 groups of 5 rabbits each: sham group, with balloon catheter insertion into the aorta; ischemia group, with spinal cord ischemic injury by abdominal aortic occlusion; nonoxygenated group, with nonoxygenated artificial CSF irrigation after spinal cord ischemic injury; and oxygenated group, with oxygenated artificial CSF irrigation after spinal cord ischemic injury. At 48 hours after spinal cord ischemic injury, the modified Tarlov score to reflect hind limb movement was evaluated. The spinal cord was histopathologically examined by counting anterior horn cells, and microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses were performed.ResultsThe oxygenated group showed improved neurologic function compared with the ischemia and nonoxygenated groups (P < .01 and P = .019, respectively). Anterior horn neuron prevention in the sham, nonoxygenated, and oxygenated groups was confirmed (mean modified Tarlov score: sham, 9.2 ± 1.9; nonoxygenated, 10.2 ± 2.2; oxygenated, 10.4 ± 2.2; ischemia, 2.7 ± 2.7). Microarray analysis identified 644 genes with twofold or greater increased signals between the ischemia and sham groups. Thirty-three genes related to inflammatory response were enriched among genes differentially expressed between the oxygenated and ischemia groups. Interleukin (IL)-6 and tumor necrosis factor (TNF) expression levels were significantly lower in the oxygenated group compared with the ischemia group, while qRT-PCR showed lower IL-6 and TNF expression levels in the oxygenated group compared with the ischemia group (P < .05).ConclusionsCSF oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemic injury and suppress inflammatory responses in the spinal cord.

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Advanced Technology for Gene Delivery with Homing Peptides to Spinal Cord through Systemic Circulation in Mice.

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Advanced Technology for Gene Delivery with Homing Peptides to Spinal Cord through Systemic Circulation in Mice.

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