A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy

Zhang, Ge; Guo, Baosheng; Wu, Heng; Tang, Tao; Zhang, Bao-Ting; Zheng, Lizhen; He, Yang; Yang, Zhijun; Pan, Xiaohua; Chow, H. Lee; To, K.F.; Li, Yaping; Li, Dahu; Wang, Xinluan; Wang, Yixiang; Lee, Kwong-Man; Hou, Zhibo; Dong, Nan; Li, Gang; Leung, Kwok‐Sui; Hung, L.K.; He, Fuchu; Zhang, Lingqiang; Qin, Ling

doi:10.1038/nm.2617

Cited by 370 publications

(354 citation statements)

References 28 publications

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“…(39) Finite element analysis (FEA) was performed to simulate a compression test on the same ROI from the proximal base of the cylinder perpendicularly to the distal base using Image Processing Language (IPL) software provided by Scanco Medical, with assigned Young's modulus of 10 GPa and Poisson ratio of 0.3 for bone stiffness (N/mm) and the estimated failure load (N). (33,40) mCT-based angiography for evaluation of vascular architecture…”

Section: Sequential Fluorescence Labelingmentioning

confidence: 99%

“…(30,31) We hypothesize that blockade of aberrant VEGF-Src signaling can inhibit both the vascular component (as evidenced by persistent marrow edema) and the skeletal component (ie, persistent bone resorption) of the destructive repair, but preserve VEGF-induced neovascularization in SAON. (32) We aim to determine the role of VEGF in destructive repair by supplementing and neutralizing VEGF, respectively, and define the role of Src through blocking Src by means of in vivo gene knockdown technology-RNAi using siRNA (33) with and without supplement of VEGF in a rabbit SAON model. (30,34) …”

Section: Introductionmentioning

confidence: 99%

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Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Cao

Chen

et al. 2015

Journal of Bone and Mineral Research

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Vascular hyperpermeability and highly upregulated bone resorption in the destructive repair progress of steroid-associated osteonecrosis (SAON) are associated with a high expression of VEGF and high Src activity (Src is encoded by the cellular sarcoma [c-src] gene). This study was designed to prove our hypothesis that blocking the VEGF-Src signaling pathway by specific Src siRNA is able to prevent destructive repair in a SAON rabbit model. Destructive repair in SAON was induced in rabbits. At 2, 4, and 6 weeks after SAON induction, VEGF, anti-VEGF, Src siRNA, Src siRNAþVEGF, control siRNA, and saline were introduced via intramedullary injection into proximal femora for each group, respectively. Vascularization and permeability were quantified by dynamic contrast-enhanced (DCE) MRI. At week 6 after SAON induction, proximal femurs were dissected for micro-computed tomography (mCT)-based trabecular architecture with finite element analysis (FEA), mCT-based angiography, and histological analysis. Histological evaluation revealed that VEGF enhanced destructive repair, whereas anti-VEGF prevented destructive repair and Src siRNA and Src siRNAþVEGF prevented destructive repair and enhanced reparative osteogenesis. Findings of angiography and histomorphometry were consistent with those determined by DCE MRI. Src siRNA inhibited VEGF-mediated vascular hyperpermeability but preserved VEGF-induced neovascularization. Bone resorption was enhanced in the VEGF group and inhibited in the anti-VEGF, Src siRNA, Src siRNAþVEGF groups as determined by both 3D mCT and 2D histomorphometry. FEA showed higher estimated failure load in the Src siRNA and Src siRNAþVEGF groups when compared to the vehicle control group. Blockage of VEGF-Src signaling pathway by specific Src siRNA was able to prevent steroid-associated destructive repair while improving reconstructive repair in SAON, which might become a novel therapeutic strategy.

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Section: Sequential Fluorescence Labelingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Cao

Chen

et al. 2015

Journal of Bone and Mineral Research

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“…In a ground-breaking study, an siRNA against Pleckho1 (casein kinase-2 interacting protein-1) was delivered systemically using a novel carrier consisting of cationic lipid DOTAP with six repeat of a tripeptide aspartate-serine-serine. (97) Peptide-modified liposomes containing Pleckho1 siRNA led to an increase in bone mineral density compared with unmodified liposomes or free siRNA over the course of 9 weeks. Bone mineral density returned to normal levels in ovariectomized rats upon delivery of Pleckho1 siRNA in peptide-modified liposomes over a 13-week period.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 97%

Realizing the potential of gene-based molecular therapies in bone repair

Rose

Uludağ

2013

Journal of Bone and Mineral Research

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A better understanding of osteogenesis at genetic and biochemical levels is yielding new molecular entities that can modulate bone regeneration and potentially act as novel therapies in a clinical setting. These new entities are motivating alternative approaches for bone repair by utilizing DNA-derived expression systems, as well as RNA-based regulatory molecules controlling the fate of cells involved in osteogenesis. These sophisticated mediators of osteogenesis, however, pose unique delivery challenges that are not obvious in deployment of conventional therapeutic agents. Viral and nonviral delivery systems are actively pursued in preclinical animal models to realize the potential of the gene-based medicines. This article will summarize promising bone-inducing molecular agents on the horizon as well as provide a critical review of delivery systems employed for their administration. Special attention was paid to synthetic (nonviral) delivery systems because they are more likely to be adopted for clinical testing because of safety considerations. We present a comparative analysis of dose-response relationships, as well as pharmacokinetic and pharmacodynamic features of various approaches, with the purpose of clearly defining the current frontier in the field. We conclude with the authors' perspective on the future of genebased therapy of bone defects, articulating promising research avenues to advance the field of clinical bone repair. © 2013 American Society for Bone and Mineral Research. KEY WORDS: OSTEOGENESIS; BIOENGINEERING; MOLECULAR PATHWAYS; GENE-BASED THERAPYClinical Need for New Bone-Regeneration Strategies N early 2.2 million bone grafts are performed worldwide annually (1) and up to 20% of fractures are hampered by impaired healing. (2) The economic impact of nonunions is enormous, with the cost of spinal fusions alone reaching $20 billion annually. (3) The gold standard for repair of large segmental defects remains autologous grafts, where bone harvested from a non-weight-bearing site, usually the iliac crest, is used to repair defects. Bone grafts, however, are limited in several aspects, including potency of the grafts and the physiological detriment resulting from harvest surgery. Allografts are alternatively employed, where donor tissue is used to repair the defect, but the risk of disease transmission is always a concern. Allografts are extensively processed to reduce this risk, but osteopotency of the graft could be decreased in this way. (4) Demineralized bone matrix derived from decalcified bone can similarly act as a substitute; its potency, however, is variable and depends on the processing conditions. Synthetic scaffolds have been used to provide a hospitable environment for new bone formation. Scaffolds have been constructed from the organic (collagen) and inorganic (hydroxyapatite [HA]) components of bone, but such scaffolds are incapable of inducing osteogenesis on their own and they are more suitable for smaller defects.Osteogenic proteins are frequently employed to render ost...

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“…In this way often multiple genes are targeted at relatively low concentrations. Zhang et al 131 where able to target siRNA towards bone forming areas based on liposome surface properties. The targeted RNA stimulated osteoblast activity without interfering with bone resorption, so less bone remodeling and breakdown took place, leading to higher quantities of bone.…”

Section: Liposome-based Transfectionmentioning

confidence: 99%

Non-viral gene therapy for bone tissue engineering

Wegman

2013

Biotechnology and Genetic Engineering Reviews

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A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy

Cited by 370 publications

References 28 publications

Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits

Realizing the potential of gene-based molecular therapies in bone repair

Non-viral gene therapy for bone tissue engineering

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