Advances in research on targeted gene therapy for nonunion of fracture_West China Medical Journal

Authors：

WANG Ning ¹ , CHEN Junyi ¹ , ZHU Lunjing ¹ , DUAN Jiangtao ¹ , PENG Chenfei ² ,  BEI Chaoyong ¹

1. Department of Orthopedics for Limb Trauma, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541000, P. R. China;
2. Department of Orthopedics, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi 541000, P. R. China;

Corresponding author：

BEI Chaoyong, Email: beichy2008@126.com

Keywords：

Gene delivery; Fracture nonunion; Gene therapy; Gene-activated matrix; Genetically engineered cells

DOI：

10.7507/1002-0179.201910049

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Clinically, fracture nonunion often leads to pain and disability in patients. Fracture nonunion often requires additional surgery to restore skeletal muscle function, so the treatment of fracture nonunion has always been a difficult point in the field of orthopedics. In recent years, with the development of genetic engineering, the technology of using gene to treat fracture nonunion has been widely studied. A large number of experiments have confirmed that the target genes encoding growth factors related to fracture healing are introduced into target cells through different delivery methods in vivo or in vitro, thereby expressing specific growth factors can promote fracture healing, which provides a new way for treating fracture nonunion. This article will discuss the research status of different delivery methods of osteogenic genes, as well as their advantages and disadvantages, in order to provide a theoretical basis for targeted gene therapy for fracture nonunion.

Citation： WANG Ning, CHEN Junyi, ZHU Lunjing, DUAN Jiangtao, PENG Chenfei, BEI Chaoyong. Advances in research on targeted gene therapy for nonunion of fracture. West China Medical Journal, 2020, 35(1): 89-92. doi: 10.7507/1002-0179.201910049 Copy

1.	de VF, Klop C, van ST, et al. The epidemiology of mortality after fragility fracture in England and Wales. Osteoporos Int, 2016, 27(Suppl 2): 619.
2.	Zura R, Xiong Z, Einhorn T, et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg, 2016, 151(11): e162775.
3.	Tay WH, de Steiger R, Richardson M, et al. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury, 2014, 45(10): 1653-1658.
4.	Bhargava R, Sankhla S, Gupta A, et al. Percutaneous autologus bone marrow injection in the treatment of delayed or nonunion. Indian J Orthop, 2007, 41(1): 67-71.
5.	Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol, 2007, 211(1): 27-35.
6.	Kimelman Bleich N, Kallai I, Lieberman JR, et al. Gene therapy approaches to regenerating bone. Adv Drug Deliv Rev, 2012, 64(12): 1320-1330.
7.	Ginn SL, Alexander IE, Edelstein ML, et al. Gene therapy clinical trials worldwide to 2012- an update. J Gene Med, 2013, 15(2): 65-77.
8.	刘亚军, 张先启, 官建中. 骨折愈合的基因治疗进展. 医学综述, 2015(10): 1796-1799.
9.	周桢杰, 李强, 李诗鹏, 等. 慢病毒介导骨形态发生蛋白 2 和血管内皮生长因子 165 双基因转染促进骨髓间充质干细胞向成骨细胞分化. 中国组织工程研究, 2018, 22(25): 3950-3955.
10.	卫亚琳, 牟代勇, 廉静, 等. BMP2 诱导 MEFs 成骨分化中 Notch 信号的作用及机制研究. 中国细胞生物学学报, 2018, 40(4): 478-489.
11.	Wu CC, Wang F, Rong S, et al. Enhancement of osteogenesis of rabbit bone marrow derived mesenchymal stem cells by transfection of human BMP-2 and EGFP recombinant adenovirus via Wnt signaling pathway. Exp Ther Med, 2018, 16(5): 4030-4036.
12.	范少鹏, 李晓辉, 时彩霞, 等. 慢病毒介导 BMP-2 过表达质粒转染骨髓间充质干细胞联合丝素蛋白支架向成骨细胞转化的实验研究. 中国骨伤, 2019, 32(9): 853-860.
13.	Liu F, Ferreira E, Porter RM, et al. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Eur Cell Mater, 2015, 30: 118-130.
14.	Seamon J, Wang X, Cui F, et al. Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res, 2013, 2013: 737580.
15.	王小志, 何惠宇, 杨楠, 等. 基因转染骨髓间充质干细胞复合同种异体骨修复绵羊极限骨缺损. 中国组织工程研究, 2013(47): 8141-8148.
16.	Tian K, Qi M, Wang L, et al. Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. J Orthop Surg Res, 2015, 10: 86.
17.	Persons DA. Lentiviral vector gene therapy: effective and safe?. Mol Ther, 2010, 18(5): 861-862.
18.	Alaee F, Sugiyama O, Virk MS, et al. Suicide gene approach usinga dual-expression lentiviral vector to enhance the safety of ex vivo gene therapy for bone repair. Gene Ther, 2014, 21(2): 139-147.
19.	陈宁, 蒋林彬, 粟谋, 等. 双基因 pCDNA 3.1-NGF-IRES-BMP2 真核质粒转染大鼠 BMSCs 诱导成骨的研究. 中国矫形外科杂志, 2016, 24(4): 345-351.
20.	朱伦井, 贝朝涌, 段江涛, 等. 脂质体和慢病毒介导 P75 神经生长因子受体及神经生长因子转染骨髓间充质干细胞的效果比较. 中国组织工程研究, 2019, 23(21): 3302-3308.
21.	Kimelman-Bleich N, Pelled G, Zilberman Y, et al. Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Mol Ther, 2011, 19(1): 53-59.
22.	Shapiro G, Kallai I, Sheyn D, et al. Ultrasound - mediated transgene expression in endogenous stem cells recruited to bone injury sites. Polym Adv Technol, 2014, 25(5): 525-531.
23.	Bez M, Sheyn D, Tawackoli W, et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med, 2017, 9(390): eaal3128.
24.	Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A, 1996, 93(12): 5753-5758.
25.	D’Mello SR, Elangovan S, Hong L, et al. A pilot study evaluating combinatorial and simultaneous delivery of polyethylenimine-plasmid DNA complexes encoding for VEGF and PDGF for bone regeneration in calvarial bone defects. Curr Pharm Biotechnol, 2015, 16(7): 655-660.
26.	Bozo IY, Deev RV, Drobyshev AY, et al. World’s first clinical case of gene-activated bone substitute application. Case Rep Dent, 2016, 2016: 8648949.
27.	马跃刚, 李强, 陶旋, 等. 慢病毒介导骨形态发生蛋白 2 和血管内皮生长因子 165 双基因转染骨髓间充质干细胞复合脱钙松质骨治疗兔股骨头坏死. 中国组织工程研究, 2019, 23(33): 5275-5280.
28.	Ren T, Li L, Cai X, et al. Engineered polyethylenimine/graphene oxide nanocomposite for nuclear localized gene delivery. Polymer Chemistry, 2012, 3(9): 2561-2569.
29.	Jin H, Zhang K, Qiao C, et al. Efficiently engineered cell sheet using a complex of polyethylenimine-alginate nanocomposites plus bone morphogenetic protein 2 gene to promote new bone formation. Int J Nanomedicine, 2014, 9: 2179-2190.
30.	Turgeman G, Pittman DD, Müller R, et al. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med, 3(3): 240-251.
31.	赵航, 马慧娟, 王超. 骨质疏松症相关基因研究进展. 实用老年医学, 2019, 33(6): 523-527.
32.	Yanagihara K, Uchida S, Ohba S, et al. Treatment of bone defects by transplantation of genetically modified mesenchymal stem cell spheroids. Mol Ther Methods Clin Dev, 2018, 9: 358-366.
33.	Pelled G, Sheyn D, Tawackoli W, et al. BMP6-engineered MSCs induce vertebral bone repair in a pig model: a pilot study. Stem Cells Int, 2016, 2016: 6530624.

1. de VF, Klop C, van ST, et al. The epidemiology of mortality after fragility fracture in England and Wales. Osteoporos Int, 2016, 27(Suppl 2): 619.
2. Zura R, Xiong Z, Einhorn T, et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg, 2016, 151(11): e162775.
3. Tay WH, de Steiger R, Richardson M, et al. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury, 2014, 45(10): 1653-1658.
4. Bhargava R, Sankhla S, Gupta A, et al. Percutaneous autologus bone marrow injection in the treatment of delayed or nonunion. Indian J Orthop, 2007, 41(1): 67-71.
5. Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol, 2007, 211(1): 27-35.
6. Kimelman Bleich N, Kallai I, Lieberman JR, et al. Gene therapy approaches to regenerating bone. Adv Drug Deliv Rev, 2012, 64(12): 1320-1330.
7. Ginn SL, Alexander IE, Edelstein ML, et al. Gene therapy clinical trials worldwide to 2012- an update. J Gene Med, 2013, 15(2): 65-77.
8. 刘亚军, 张先启, 官建中. 骨折愈合的基因治疗进展. 医学综述, 2015(10): 1796-1799.
9. 周桢杰, 李强, 李诗鹏, 等. 慢病毒介导骨形态发生蛋白 2 和血管内皮生长因子 165 双基因转染促进骨髓间充质干细胞向成骨细胞分化. 中国组织工程研究, 2018, 22(25): 3950-3955.
10. 卫亚琳, 牟代勇, 廉静, 等. BMP2 诱导 MEFs 成骨分化中 Notch 信号的作用及机制研究. 中国细胞生物学学报, 2018, 40(4): 478-489.
11. Wu CC, Wang F, Rong S, et al. Enhancement of osteogenesis of rabbit bone marrow derived mesenchymal stem cells by transfection of human BMP-2 and EGFP recombinant adenovirus via Wnt signaling pathway. Exp Ther Med, 2018, 16(5): 4030-4036.
12. 范少鹏, 李晓辉, 时彩霞, 等. 慢病毒介导 BMP-2 过表达质粒转染骨髓间充质干细胞联合丝素蛋白支架向成骨细胞转化的实验研究. 中国骨伤, 2019, 32(9): 853-860.
13. Liu F, Ferreira E, Porter RM, et al. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Eur Cell Mater, 2015, 30: 118-130.
14. Seamon J, Wang X, Cui F, et al. Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res, 2013, 2013: 737580.
15. 王小志, 何惠宇, 杨楠, 等. 基因转染骨髓间充质干细胞复合同种异体骨修复绵羊极限骨缺损. 中国组织工程研究, 2013(47): 8141-8148.
16. Tian K, Qi M, Wang L, et al. Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene. J Orthop Surg Res, 2015, 10: 86.
17. Persons DA. Lentiviral vector gene therapy: effective and safe?. Mol Ther, 2010, 18(5): 861-862.
18. Alaee F, Sugiyama O, Virk MS, et al. Suicide gene approach usinga dual-expression lentiviral vector to enhance the safety of ex vivo gene therapy for bone repair. Gene Ther, 2014, 21(2): 139-147.
19. 陈宁, 蒋林彬, 粟谋, 等. 双基因 pCDNA 3.1-NGF-IRES-BMP2 真核质粒转染大鼠 BMSCs 诱导成骨的研究. 中国矫形外科杂志, 2016, 24(4): 345-351.
20. 朱伦井, 贝朝涌, 段江涛, 等. 脂质体和慢病毒介导 P75 神经生长因子受体及神经生长因子转染骨髓间充质干细胞的效果比较. 中国组织工程研究, 2019, 23(21): 3302-3308.
21. Kimelman-Bleich N, Pelled G, Zilberman Y, et al. Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Mol Ther, 2011, 19(1): 53-59.
22. Shapiro G, Kallai I, Sheyn D, et al. Ultrasound - mediated transgene expression in endogenous stem cells recruited to bone injury sites. Polym Adv Technol, 2014, 25(5): 525-531.
23. Bez M, Sheyn D, Tawackoli W, et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med, 2017, 9(390): eaal3128.
24. Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A, 1996, 93(12): 5753-5758.
25. D’Mello SR, Elangovan S, Hong L, et al. A pilot study evaluating combinatorial and simultaneous delivery of polyethylenimine-plasmid DNA complexes encoding for VEGF and PDGF for bone regeneration in calvarial bone defects. Curr Pharm Biotechnol, 2015, 16(7): 655-660.
26. Bozo IY, Deev RV, Drobyshev AY, et al. World’s first clinical case of gene-activated bone substitute application. Case Rep Dent, 2016, 2016: 8648949.
27. 马跃刚, 李强, 陶旋, 等. 慢病毒介导骨形态发生蛋白 2 和血管内皮生长因子 165 双基因转染骨髓间充质干细胞复合脱钙松质骨治疗兔股骨头坏死. 中国组织工程研究, 2019, 23(33): 5275-5280.
28. Ren T, Li L, Cai X, et al. Engineered polyethylenimine/graphene oxide nanocomposite for nuclear localized gene delivery. Polymer Chemistry, 2012, 3(9): 2561-2569.
29. Jin H, Zhang K, Qiao C, et al. Efficiently engineered cell sheet using a complex of polyethylenimine-alginate nanocomposites plus bone morphogenetic protein 2 gene to promote new bone formation. Int J Nanomedicine, 2014, 9: 2179-2190.
30. Turgeman G, Pittman DD, Müller R, et al. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med, 3(3): 240-251.
31. 赵航, 马慧娟, 王超. 骨质疏松症相关基因研究进展. 实用老年医学, 2019, 33(6): 523-527.
32. Yanagihara K, Uchida S, Ohba S, et al. Treatment of bone defects by transplantation of genetically modified mesenchymal stem cell spheroids. Mol Ther Methods Clin Dev, 2018, 9: 358-366.
33. Pelled G, Sheyn D, Tawackoli W, et al. BMP6-engineered MSCs induce vertebral bone repair in a pig model: a pilot study. Stem Cells Int, 2016, 2016: 6530624.

Previous Article
The role and advances of endometrial stem/progenitor cells in the pathogenesis of endometriosis
Next Article
Research progress on repeated peripheral magnetic stimulation for pain

West China Medical Journal

Advances in research on targeted gene therapy for nonunion of fracture

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content