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：

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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.	劉亞軍, 張先啟, 官建中. 骨折愈合的基因治療進展. 醫學綜述, 2015(10): 1796-1799.
9.	周楨杰, 李強, 李詩鵬, 等. 慢病毒介導骨形態發生蛋白 2 和血管內皮生長因子 165 雙基因轉染促進骨髓間充質干細胞向成骨細胞分化. 中國組織工程研究, 2018, 22(25): 3950-3955.
10.	衛亞琳, 牟代勇, 廉靜, 等. BMP2 誘導 MEFs 成骨分化中 Notch 信號的作用及機制研究. 中國細胞生物學學報, 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.	范少鵬, 李曉輝, 時彩霞, 等. 慢病毒介導 BMP-2 過表達質粒轉染骨髓間充質干細胞聯合絲素蛋白支架向成骨細胞轉化的實驗研究. 中國骨傷, 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, 楊楠, 等. 基因轉染骨髓間充質干細胞復合同種異體骨修復綿羊極限骨缺損. 中國組織工程研究, 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.	陳寧, 蔣林彬, 粟謀, 等. 雙基因 pCDNA 3.1-NGF-IRES-BMP2 真核質粒轉染大鼠 BMSCs 誘導成骨的研究. 中國矯形外科雜志, 2016, 24(4): 345-351.
20.	朱倫井, 貝朝涌, 段江濤, 等. 脂質體和慢病毒介導 P75 神經生長因子受體及神經生長因子轉染骨髓間充質干細胞的效果比較. 中國組織工程研究, 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.	馬躍剛, 李強, 陶旋, 等. 慢病毒介導骨形態發生蛋白 2 和血管內皮生長因子 165 雙基因轉染骨髓間充質干細胞復合脫鈣松質骨治療兔股骨頭壞死. 中國組織工程研究, 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.	趙航, 馬慧娟, 王超. 骨質疏松癥相關基因研究進展. 實用老年醫學, 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. 劉亞軍, 張先啟, 官建中. 骨折愈合的基因治療進展. 醫學綜述, 2015(10): 1796-1799.
9. 周楨杰, 李強, 李詩鵬, 等. 慢病毒介導骨形態發生蛋白 2 和血管內皮生長因子 165 雙基因轉染促進骨髓間充質干細胞向成骨細胞分化. 中國組織工程研究, 2018, 22(25): 3950-3955.
10. 衛亞琳, 牟代勇, 廉靜, 等. BMP2 誘導 MEFs 成骨分化中 Notch 信號的作用及機制研究. 中國細胞生物學學報, 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. 范少鵬, 李曉輝, 時彩霞, 等. 慢病毒介導 BMP-2 過表達質粒轉染骨髓間充質干細胞聯合絲素蛋白支架向成骨細胞轉化的實驗研究. 中國骨傷, 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, 楊楠, 等. 基因轉染骨髓間充質干細胞復合同種異體骨修復綿羊極限骨缺損. 中國組織工程研究, 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. 陳寧, 蔣林彬, 粟謀, 等. 雙基因 pCDNA 3.1-NGF-IRES-BMP2 真核質粒轉染大鼠 BMSCs 誘導成骨的研究. 中國矯形外科雜志, 2016, 24(4): 345-351.
20. 朱倫井, 貝朝涌, 段江濤, 等. 脂質體和慢病毒介導 P75 神經生長因子受體及神經生長因子轉染骨髓間充質干細胞的效果比較. 中國組織工程研究, 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. 馬躍剛, 李強, 陶旋, 等. 慢病毒介導骨形態發生蛋白 2 和血管內皮生長因子 165 雙基因轉染骨髓間充質干細胞復合脫鈣松質骨治療兔股骨頭壞死. 中國組織工程研究, 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. 趙航, 馬慧娟, 王超. 骨質疏松癥相關基因研究進展. 實用老年醫學, 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.

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