Direct Gene Therapy for Bone Regeneration: Gene Delivery, Animal Models, and Outcome Measures

Pelled, Gadi; Ben-Arav, Ayelet; Hock, Colleen; Reynolds, David G.; Yazıcı, Cemal; Zilberman, Yoram; Gazit, Zulma; Awad, Hani A.; Gazit, Dan; Schwarz, Edward M.

doi:10.1089/ten.teb.2009.0156

Cited by 55 publications

(56 citation statements)

References 81 publications

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“…Nevertheless, inconsistent results due to single outliers failed to show statistically significant differences. This insignificant therapeutic effect was found in numerous studies, which demonstrated non-viral gene transfer as a safe but relative inefficient strategy to increase bone growth [10,12,13]. Results of this study highlight the importance of promoting non-viral gene transfer by alternative methods.…”

Section: Discussionmentioning

confidence: 64%

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Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Kaipel

Schützenberger

Hofmann

et al. 2014

International Orthopaedics (SICOT)

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PURPOSE: Treatment of large segmental bone defects still is a challenge in clinical routine.Application of Gene-activated matrices (GAMs) based on fibrin, BMP 2/7 plasmids and nonviral transfection reagents (cationic polymers) could be an innovative treatment strategy to overcome this problem.The aim of this study was to determine the therapeutic efficacy of fibrin GAMs with or without additional transfection reagents for bone morphogenic protein (BMP)2 and BMP7 plasmid co-delivery in a rat femur non-union model. METHODS:In this experimental study a critical size femoral defect was created in 27 rats. At 4 weeks after the surgery animals were separated into 4 groups and underwent a second operation. Fibrin clots containing BMP2 and BMP7 plasmids with and without cationic polymer were implanted into the femoral defect. Fibrin clots containing recombinant human (rh) BMP2 served as positive and clots without supplement as negative controls.RESULTS: At 8 weeks animals which received GAMs containing the cationic polymer and BMP 2/7 plasmids showed decreased bone volume compared to animals treated with GAMs and BMP2/7 only. Application of BMP2 and BMP7 plasmids in fibrin GAMs without cationic polymer lead to variable results. Animals which received rhBMP 2 protein showed increased bone volume and osseous unions were achieved in 2 out of 6 animals.2 CONCLUSIONS: Cationic polymers decrease therapeutic efficiency of fibrin GAM based BMP2/7 plasmid co-delivery in bone regeneration. Non-viral gene transfer of BMP2/7 plasmids needs alternative promoters (e.g. by sonoporation, electroporation) to promise beneficial clinical effects.

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Section: Discussionmentioning

confidence: 64%

“…Viral delivery of DNA vectors to the target tissue was shown to be highly effective but could result in a fatal immune response of the host [10,11]. In contrast non-viral gene transfer using plasmids is regarded as a relatively safe but inefficient strategy [12,13].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Kaipel

Schützenberger

Hofmann

et al. 2014

International Orthopaedics (SICOT)

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“…The use of viral and non-viral vectors for tissue engineering has been reviewed elsewhere [47][48][49] but advantages and disadvantages of the particular expression systems are important to note. Viral vectors -as the name suggests -are derived from viruses (i.e.…”

Section: General Aspects Of Various Dna Delivery Methodsmentioning

confidence: 99%

How to use BMP-2 for clinical applications? A review on pros and cons of existing delivery strategies

Mumcuoglu¹,

Siverino²,

Tabisz³

et al. 2017

J Transl Sci

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“…In situ transfection indicates that miRNAs exist within the scaffold structure prior to the addition of cells; these scaffolds are implanted "cell-free" in the tissue void, where they will interact with the resident and homing cells to regenerate such defects. [105] The scaffold acts as a depot for the complexes and then infiltrating cells establish contact with these along the structure of the scaffolds to internalize them and become transfected. On the contrary, ex situ transfection consists in first administering the miRNA treatment to a controlled cell population, which is then mixed with or seeded onto the relevant scaffold.…”

Section: Scaffolds For Microrna Deliverymentioning

confidence: 99%

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

Curtin

Castaño

O’Brien

2017

Adv Healthcare Materials

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The field of "regenerative medicine" (RM) was conceptually developed to aid the body's natural capacity to self-repair, a capacity which is impaired with age and in cases of disease or injury. [1] RM is a vast and multifaceted area of medicine, often microRNA-based therapies are an advantageous strategy with applications in both regenerative medicine (RM) and cancer treatments. microRNAs (miRNAs) are an evolutionary conserved class of small RNA molecules that modulate up to one third of the human nonprotein coding genome. Thus, synthetic miRNA activators and inhibitors hold immense potential to finely balance gene expression and reestablish tissue health. Ongoing industrysponsored clinical trials inspire a new miRNA therapeutics era, but progress largely relies on the development of safe and efficient delivery systems. The emerging application of biomaterial scaffolds for this purpose offers spatiotemporal control and circumvents biological and mechanical barriers that impede successful miRNA delivery. The nascent research in scaffold-mediated miRNA therapies translates know-how learnt from studies in antitumoral and genetic disorders as well as work on plasmid (p)DNA/siRNA delivery to expand the miRNA therapies arena. In this progress report, the state of the art methods of regulating miRNAs are reviewed. Relevant miRNA delivery vectors and scaffold systems applied to-date for RM and cancer treatment applications are discussed, as well as the challenges involved in their design. Overall, this progress report demonstrates the opportunity that exists for the application of miRNA-activated scaffolds in the future of RM and cancer treatments.Regenerative Medicine

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Direct Gene Therapy for Bone Regeneration: Gene Delivery, Animal Models, and Outcome Measures

Cited by 55 publications

References 81 publications

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

Evaluation of fibrin-based gene-activated matrices for BMP2/7 plasmid codelivery in a rat nonunion model

How to use BMP-2 for clinical applications? A review on pros and cons of existing delivery strategies

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

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