Gene Therapy for Chondral and Osteochondral Regeneration: is the Future Now?

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2017 Sep 3

PMID 28864934

Citations 27

Authors

Daniele Bellavia

F Veronesi

V Carina

V Costa

L Raimondi

A De Luca

R Alessandro

M Fini

G Giavaresi

Affiliations

Soon will be listed here.

Abstract

Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis.

Citing Articles

Bioadhesive and Injectable Hydrogels and Their Correlation with Mesenchymal Stem Cells Differentiation for Cartilage Repair: A Mini-Review.

Kovac J, Priscakova P, Gbelcova H, Heydari A, Ziaran S Polymers (Basel). 2023; 15(21).

PMID: 37959908 PMC: 10648146. DOI: 10.3390/polym15214228.

A Review of the Role of Bioreactors for iPSCs-Based Tissue-Engineered Articular Cartilage.

Reina-Mahecha A, Beers M, van der Veen H, Zuhorn I, van Kooten T, Sharma P Tissue Eng Regen Med. 2023; 20(7):1041-1052.

PMID: 37861960 PMC: 10645985. DOI: 10.1007/s13770-023-00573-6.

Regeneration of articular cartilage defects: Therapeutic strategies and perspectives.

Guo X, Xi L, Yu M, Fan Z, Wang W, Ju A J Tissue Eng. 2023; 14:20417314231164765.

PMID: 37025158 PMC: 10071204. DOI: 10.1177/20417314231164765.

Timing Expression of miR203a-3p during OA Disease: Preliminary In Vitro Evidence.

Costa V, De Fine M, Raimondi L, Bellavia D, Cordaro A, Carina V Int J Mol Sci. 2023; 24(5).

PMID: 36901745 PMC: 10002134. DOI: 10.3390/ijms24054316.

CTGF as a multifunctional molecule for cartilage and a potential drug for osteoarthritis.

Yang Z, Li W, Song C, Leng H Front Endocrinol (Lausanne). 2022; 13:1040526.

PMID: 36325449 PMC: 9618584. DOI: 10.3389/fendo.2022.1040526.

References

Nishida K, Doita M, Takada T, Kakutani K, Miyamoto H, Shimomura T . Sustained transgene expression in intervertebral disc cells in vivo mediated by microbubble-enhanced ultrasound gene therapy. Spine (Phila Pa 1976). 2006; 31(13):1415-9. DOI: 10.1097/01.brs.0000219945.70675.dd. View

Montemurro T, Vigano M, Budelli S, Montelatici E, Lavazza C, Marino L . How we make cell therapy in Italy. Drug Des Devel Ther. 2015; 9:4825-34. PMC: 4548721. DOI: 10.2147/DDDT.S80403. View

Knedla A, Riepl B, Lefevre S, Kistella S, Grifka J, Straub R . The therapeutic use of osmotic minipumps in the severe combined immunodeficiency (SCID) mouse model for rheumatoid arthritis. Ann Rheum Dis. 2008; 68(1):124-9. DOI: 10.1136/ard.2007.086116. View

Matsumoto T, Cooper G, Gharaibeh B, Meszaros L, Li G, Usas A . Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arthritis Rheum. 2009; 60(5):1390-405. PMC: 4879830. DOI: 10.1002/art.24443. View

An C, Cheng Y, Yuan Q, Li J . IGF-1 and BMP-2 induces differentiation of adipose-derived mesenchymal stem cells into chondrocytes-like cells. Ann Biomed Eng. 2010; 38(4):1647-54. DOI: 10.1007/s10439-009-9892-x. View

Tao K, Frisch J, Rey-Rico A, Venkatesan J, Schmitt G, Madry H . Co-overexpression of TGF-β and SOX9 via rAAV gene transfer modulates the metabolic and chondrogenic activities of human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 2016; 7:20. PMC: 4736112. DOI: 10.1186/s13287-016-0280-9. View

Gouze E, Pawliuk R, Pilapil C, Gouze J, Fleet C, Palmer G . In vivo gene delivery to synovium by lentiviral vectors. Mol Ther. 2002; 5(4):397-404. DOI: 10.1006/mthe.2002.0562. View

Li B, Li F, Ma L, Yang J, Wang C, Wang D . Poly(lactide-co-glycolide)/fibrin gel construct as a 3D model to evaluate gene therapy of cartilage in vivo. Mol Pharm. 2014; 11(7):2062-70. DOI: 10.1021/mp5000136. View

Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S . Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther. 2010; 17(6):779-89. DOI: 10.1038/gt.2010.16. View

10.

Frank K, Hogarth D, Miller J, Mandal S, Mease P, Samulski R . Investigation of the cause of death in a gene-therapy trial. N Engl J Med. 2009; 361(2):161-9. DOI: 10.1056/NEJMoa0801066. View

11.

Veronesi F, Giavaresi G, Tschon M, Borsari V, Aldini N, Fini M . Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2012; 22(2):181-92. DOI: 10.1089/scd.2012.0373. View

12.

Liang W, Zhu C, Liu F, Cui W, Wang Q, Chen Z . Integrin β1 Gene Therapy Enhances in Vitro Creation of Tissue-Engineered Cartilage Under Periodic Mechanical Stress. Cell Physiol Biochem. 2015; 37(4):1301-14. DOI: 10.1159/000430253. View

13.

Chen Z, Shi H, Sun S, Xu H, Cao D, Luo J . MicroRNA-181b suppresses TAG via target IRS2 and regulating multiple genes in the Hippo pathway. Exp Cell Res. 2016; 348(1):66-74. DOI: 10.1016/j.yexcr.2016.09.004. View

14.

Pagnotto M, Wang Z, Karpie J, Ferretti M, Xiao X, Chu C . Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 2007; 14(10):804-13. DOI: 10.1038/sj.gt.3302938. View

15.

Cherian J, Parvizi J, Bramlet D, Lee K, Romness D, Mont M . Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage. 2015; 23(12):2109-2118. DOI: 10.1016/j.joca.2015.06.019. View

16.

Liang Y, Duan L, Xiong J, Zhu W, Liu Q, Wang D . E2 regulates MMP-13 via targeting miR-140 in IL-1β-induced extracellular matrix degradation in human chondrocytes. Arthritis Res Ther. 2016; 18(1):105. PMC: 4863330. DOI: 10.1186/s13075-016-0997-y. View

17.

Goodrich L, Brower-Toland B, Warnick L, Robbins P, Evans C, Nixon A . Direct adenovirus-mediated IGF-I gene transduction of synovium induces persisting synovial fluid IGF-I ligand elevations. Gene Ther. 2006; 13(17):1253-62. DOI: 10.1038/sj.gt.3302757. View

18.

Zhang X, Zheng Z, Liu P, Ma Y, Lin L, Lang N . The synergistic effects of microfracture, perforated decalcified cortical bone matrix and adenovirus-bone morphogenetic protein-4 in cartilage defect repair. Biomaterials. 2008; 29(35):4616-29. DOI: 10.1016/j.biomaterials.2008.07.051. View

19.

Alcorn J, Merritt T, Farach-Carson M, Wang H, Hecht J . Ribozyme-mediated reduction of wild-type and mutant cartilage oligomeric matrix protein (COMP) mRNA and protein. RNA. 2009; 15(4):686-95. PMC: 2661830. DOI: 10.1261/rna.1335909. View

20.

Venkatesan J, Ekici M, Madry H, Schmitt G, Kohn D, Cucchiarini M . SOX9 gene transfer via safe, stable, replication-defective recombinant adeno-associated virus vectors as a novel, powerful tool to enhance the chondrogenic potential of human mesenchymal stem cells. Stem Cell Res Ther. 2012; 3(3):22. PMC: 3583131. DOI: 10.1186/scrt113. View