30 results on '"Madry, Henning"'
Search Results
2. Locally Directed Recombinant Adeno- Associated Virus–Mediated IGF-1 Gene Therapy Enhances Osteochondral Repair and Counteracts Early Osteoarthritis In Vivo.
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Peifer, Carolin, Oláh, Tamás, Venkatesan, Jagadeesh K., Goebel, Lars, Orth, Patrick, Schmitt, Gertrud, Zurakowski, David, Menger, Michael D., Laschke, Matthias W., Cucchiarini, Magali, and Madry, Henning
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KNEE osteoarthritis ,GENE therapy ,REPEATED measures design ,DATA analysis ,COMPUTED tomography ,KRUSKAL-Wallis Test ,IN vivo studies ,MULTIVARIATE analysis ,DESCRIPTIVE statistics ,IMMUNOHISTOCHEMISTRY ,EXPERIMENTAL design ,GENE expression ,ARTICULAR cartilage injuries ,SHEEP ,PAIN management ,ANALYSIS of variance ,STATISTICS ,ONE-way analysis of variance ,STAINS & staining (Microscopy) ,HEALTH outcome assessment ,DATA analysis software ,FACTOR analysis ,CONNECTIVE tissue growth factor ,VIRUSES ,REGRESSION analysis - Abstract
Background: Restoration of osteochondral defects is critical, because osteoarthritis (OA) can arise. Hypothesis: Overexpression of insulin-like growth factor 1 (IGF-1) via recombinant adeno-associated viral (rAAV) vectors (rAAV-IGF-1) would improve osteochondral repair and reduce parameters of early perifocal OA in sheep after 6 months in vivo. Study Design: Controlled laboratory study. Methods: Osteochondral defects were created in the femoral trochlea of adult sheep and treated with rAAV-IGF-1 or rAAV- lacZ (control) (24 defects in 6 knees per group). After 6 months in vivo, osteochondral repair and perifocal OA were assessed by well-established macroscopic, histological, and immunohistochemical scoring systems as well as biochemical and micro–computed tomography evaluations. Results: Application of rAAV-IGF-1 led to prolonged (6 months) IGF-1 overexpression without adverse effects, maintaining a significantly superior overall cartilage repair, together with significantly improved defect filling, extracellular matrix staining, cellular morphology, and surface architecture compared with rAAV- lacZ. Expression of type II collagen significantly increased and that of type I collagen significantly decreased. Subchondral bone repair and tidemark formation were significantly improved, and subchondral bone plate thickness and subarticular spongiosa mineral density returned to normal. The OA parameters of perifocal structure, cell cloning, and matrix staining were significantly better preserved upon rAAV-IGF-1 compared with rAAV- lacZ. Novel mechanistic associations between parameters of osteochondral repair and OA were identified. Conclusion: Local rAAV-mediated IGF-1 overexpression enhanced osteochondral repair and ameliorated parameters of perifocal early OA. Clinical Relevance: IGF-1 gene therapy may be beneficial in repair of focal osteochondral defects and prevention of perifocal OA. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Gene Therapy
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Madry, Henning, Orth, Patrick, Venkatesan, Jagadeesh K., Tao, Ke, Goebel, Lars, Cucchiarini, Magali, Gobbi, Alberto, editor, Espregueira-Mendes, João, editor, Lane, John G., editor, and Karahan, Mustafa, editor
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- 2017
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4. Effects of rAAV-mediated FGF-2 gene transfer and overexpression upon the chondrogenic differentiation processes in human bone marrow aspirates
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Frisch, Janina, Venkatesan, Jagadeesh K., Rey-Rico, Ana, Zawada, Adam M., Schmitt, Gertrud, Madry, Henning, and Cucchiarini, Magali
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- 2016
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5. Use of Tissue Engineering Strategies to Repair Joint Tissues in Osteoarthritis: Viral Gene Transfer Approaches
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Cucchiarini, Magali and Madry, Henning
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- 2014
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6. Tissue-Engineering Strategies to Repair Joint Tissue in Osteoarthritis: Nonviral Gene-Transfer Approaches
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Madry, Henning and Cucchiarini, Magali
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- 2014
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7. Nonviral gene transfer to human meniscal cells. Part I: transfection analyses and cell transplantation to meniscus explants
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Lee, Hsiao-Ping, Kaul, Gunter, Cucchiarini, Magali, and Madry, Henning
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- 2014
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8. Nonviral gene transfer into human meniscal cells. Part II: effect of three-dimensional environment and overexpression of human fibroblast growth factor 2
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Lee, Hsiao-Ping, Rey-Rico, Ana, Cucchiarini, Magali, and Madry, Henning
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- 2014
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9. Advanced Gene Therapy Strategies for the Repair of ACL Injuries.
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Amini, Mahnaz, Venkatesan, Jagadeesh K., Liu, Wei, Leroux, Amélie, Nguyen, Tuan Ngoc, Madry, Henning, Migonney, Véronique, and Cucchiarini, Magali
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ANTERIOR cruciate ligament injuries ,GENE therapy ,ANTERIOR cruciate ligament ,DRUG delivery systems ,GENETIC transformation - Abstract
The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes are never fully satisfactory in terms of long-lasting, complete, and safe repair. Gene therapy, based on the transfer of therapeutic genetic sequences via a gene vector, is a potent tool to durably and adeptly enhance the processes of ACL repair and has been reported for its workability in various experimental models relevant to ACL injuries in vitro, in situ, and in vivo. As critical hurdles to the effective and safe translation of gene therapy for clinical applications still remain, including physiological barriers and host immune responses, biomaterial-guided gene therapy inspired by drug delivery systems has been further developed to protect and improve the classical procedures of gene transfer in the future treatment of ACL injuries in patients, as critically presented here. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Thermosensitive Hydrogel Based on PEO-PPO-PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno-Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects
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Madry, Henning, Gao, Liang, Rey-Rico, Ana, Venkatesan, Jagadeesh K., Müller-Brandt, Kathrin, Cai, Xiaoyu, Goebel, Lars, Schmitt, Gertrud, Speicher-Mentges, Susanne, Zurakowski, David, Menger, Michael D., Laschke, Matthias W., and Cucchiarini, Magali
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biomaterial-guided therapy ,tissue engineering ,rAAV ,cartilage defects ,gene therapy - Published
- 2021
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11. Scaffold-Mediated Gene Delivery for Osteochondral Repair
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Madry, Henning, Venkatesan, Jagadeesh Kumar, Carballo-Pedrares, Natalia, Rey-Rico, Ana, and Cucchiarini, Magali
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lcsh:Pharmacy and materia medica ,Gene therapy ,tissue engineering ,Osteochondral repair ,lcsh:RS1-441 ,Tissue engineering ,Controlled delivery ,Review ,osteochondral repair ,gene therapy ,controlled delivery - Abstract
Osteochondral defects involve both the articular cartilage and the underlying subchondral bone. If left untreated, they may lead to osteoarthritis. Advanced biomaterial-guided delivery of gene vectors has recently emerged as an attractive therapeutic concept for osteochondral repair. 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Pn== , solid scaffolds, and hybrid materials. The data show that a site-specific delivery of therapeutic gene vectors in the context of acellular or cellular strategies allows for a spatial and temporal control of osteochondral neotissue composition in vitro. In vivo, implantation of acellular hydrogels loaded with nonviral or viral vectors has been reported to significantly improve osteochondral repair in translational defect models. These advances support the concept of scaffold-mediated gene delivery for osteochondral repair.
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- 2021
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12. rAAV-Mediated sox9 Overexpression Improves the Repair of Osteochondral Defects in a Clinically Relevant Large Animal Model Over Time In Vivo and Reduces Perifocal Osteoarthritic Changes.
- Author
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Lange, Cliff, Madry, Henning, Venkatesan, Jagadeesh K., Schmitt, Gertrud, Speicher-Mentges, Susanne, Zurakowski, David, Menger, Michael D., Laschke, Matthias W., and Cucchiarini, Magali
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BIOLOGICAL models , *BIOCHEMISTRY , *STATISTICS , *IN vivo studies , *DNA , *SHEEP , *ANIMAL experimentation , *IMMUNOHISTOCHEMISTRY , *REGRESSION analysis , *MANN Whitney U Test , *GENE expression , *TREATMENT effectiveness , *PHENOMENOLOGY , *TOMOGRAPHY , *GENE therapy , *OSTEOARTHRITIS , *DESCRIPTIVE statistics , *RESEARCH funding , *TRANSCRIPTION factors , *ARTICULAR cartilage , *HISTOLOGY , *DATA analysis software , *DATA analysis , *ALGORITHMS - Abstract
Background: Gene transfer of the transcription factor SOX9 with clinically adapted recombinant adeno-associated virus (rAAV) vectors offers a powerful tool to durably enhance the repair process at sites of osteochondral injuries and counteract the development of perifocal osteoarthritis (OA) in the adjacent articular cartilage. Purpose: To examine the ability of an rAAV sox9 construct to improve the repair of focal osteochondral defects and oppose perifocal OA development over time in a large translational model relative to control gene transfer. Study Design: Controlled laboratory study. Methods: Standardized osteochondral defects created in the knee joints of adult sheep were treated with rAAV-FLAG-h sox9 relative to control (reporter) rAAV- lacZ gene transfer. Osteochondral repair and degenerative changes in the adjacent cartilage were monitored using macroscopic, histological, immunohistological, and biochemical evaluations after 6 months. The microarchitecture of the subchondral bone was assessed by micro–computed tomography. Results: Effective, prolonged sox9 overexpression via rAAV was significantly achieved in the defects after 6 months versus rAAV- lacZ treatment. The application of rAAV-FLAG-h sox9 improved the individual parameters of defect filling, matrix staining, cellular morphology, defect architecture, surface architecture, subchondral bone, and tidemark as well as the overall score of cartilage repair in the defects compared with rAAV- lacZ. The overexpression of sox9 led to higher levels of proteoglycan production, stronger type II collagen deposition, and reduced type I collagen immunoreactivity in the sox9 - versus lacZ -treated defects, together with decreased cell densities and DNA content. rAAV-FLAG-h sox9 enhanced semiquantitative histological subchondral bone repair, while the microstructure of the incompletely restored subchondral bone in the sox9 defects was not different from that in the lacZ defects. The articular cartilage adjacent to the sox9 -treated defects showed reduced histological signs of perifocal OA changes versus rAAV- lacZ. Conclusion: rAAV-mediated sox9 gene transfer enhanced osteochondral repair in sheep after 6 months and reduced perifocal OA changes. These results underline the potential of rAAV-FLAG-h sox9 as a therapeutic tool to treat cartilage defects and afford protection against OA. Clinical Relevance: The delivery of therapeutic rAAV sox9 to sites of focal injuries may offer a novel, convenient tool to enhance the repair of osteochondral defects involving both the articular cartilage and the underlying subchondral bone and provide a protective role by reducing the extent of perifocal OA. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Biological effects of FGF-2 and IGF-I Co-overexpression in human bone marrow-derived mesenchymal stem cells via rAAV vector administration
- Author
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Böhm, Teresa, Venkatesan, Jagadeesh K., Rey-Rico, Ana, Schmitt, Gertrud, Madry, Henning, and Cucchiarini, Magali
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ddc: 610 ,viruses ,regenerative medicine ,610 Medical sciences ,Medicine ,cartilage ,gene therapy - Abstract
Objectives: Gene-based modification of bone marrow-derived mesenchymal stem cells (MSCs)is an attractive approach to treat articular cartilage defects. Here, we tested the benefits of co-delivering rAAV-FGF-2 and rAAV-IGF-I in human MSCs as a tool to enhance the cartilage repair. Methods: rAAV-lacZ[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)
- Published
- 2018
14. rAAV-Mediated Human FGF-2 Gene Therapy Enhances Osteochondral Repair in a Clinically Relevant Large Animal Model Over Time In Vivo.
- Author
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Morscheid, Yannik P., Venkatesan, Jagadeesh K., Schmitt, Gertrud, Orth, Patrick, Zurakowski, David, Speicher-Mentges, Susanne, Menger, Michael D., Laschke, Matthias W., Cucchiarini, Magali, and Madry, Henning
- Subjects
BIOCHEMISTRY ,STATISTICAL significance ,IN vivo studies ,SHEEP ,SPECTROPHOTOMETERS ,ANALYSIS of variance ,GROWTH factors ,ANIMAL experimentation ,TIME ,IMMUNOHISTOCHEMISTRY ,REGRESSION analysis ,MANN Whitney U Test ,PAIRED comparisons (Mathematics) ,PHENOMENOLOGY ,GENE therapy ,GENE expression profiling ,REPEATED measures design ,DESCRIPTIVE statistics ,ARTICULAR cartilage injuries ,ARTICULAR cartilage ,HISTOLOGY ,DATA analysis software ,ALGORITHMS - Abstract
Background: Osteochondral defects, if left untreated, do not heal and can potentially progress toward osteoarthritis. Direct gene transfer of basic fibroblast growth factor 2 (FGF-2) with the clinically adapted recombinant adeno-associated viral (rAAV) vectors is a powerful tool to durably activate osteochondral repair processes. Purpose: To examine the ability of an rAAV-FGF-2 construct to target the healing processes of focal osteochondral injury over time in a large translational model in vivo versus a control gene transfer condition. Study Design: Controlled laboratory study. Methods: Standardized osteochondral defects created in the knee joints of adult sheep were treated with an rAAV human FGF-2 (hFGF-2) vector by direct administration into the defect relative to control (reporter) rAAV- lacZ gene transfer. Osteochondral repair was monitored using macroscopic, histological, immunohistological, and biochemical methods and by micro–computed tomography after 6 months. Results: Effective, localized prolonged FGF-2 overexpression was achieved for 6 months in vivo relative to the control condition without undesirable leakage of the vectors outside the defects. Such rAAV-mediated hFGF-2 overexpression significantly increased the individual histological parameter "percentage of new subchondral bone" versus lacZ treatment, reflected in a volume of mineralized bone per unit volume of the subchondral bone plate that was equal to a normal osteochondral unit. Also, rAAV-FGF-2 significantly improved the individual histological parameters "defect filling,""matrix staining," and "cellular morphology" and the overall cartilage repair score versus the lacZ treatment and led to significantly higher cell densities and significantly higher type II collagen deposition versus lacZ treatment. Likewise, rAAV-FGF-2 significantly decreased type I collagen expression within the cartilaginous repair tissue. Conclusion: The current work shows the potential of direct rAAV-mediated FGF-2 gene therapy to enhance osteochondral repair in a large, clinically relevant animal model over time in vivo. Clinical Relevance: Delivery of therapeutic (hFGF-2) rAAV vectors in sites of focal injury may offer novel, convenient tools to enhance osteochondral repair in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
15. rAAV-based genetic modification of human bone marrow aspirates seeded in 3D woven poly(epsilon-caprolactone) scaffolds
- Author
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Cucchiarini Madry, Magali, Frisch, Janina, Rey-Rico, Ana, Venkatesan, Jagadeesh K., Schmitt, Gertrud, Moutos, Franklin, Guilak, Farshid, and Madry, Henning
- Subjects
Cartilage ,Tissue Engineering ,ddc: 610 ,Gene Therapy ,610 Medical sciences ,Medicine ,Regenerative Medicine - Abstract
Objectives: Bone marrow aspirates are attractive platforms to deliver candidate genes to enhance the repair of cartilage defects. Yet, aspirates may not have a sufficient integrity to support joint loading in a defect repair site. Here, we tested the ability of rAAV vectors to modify human bone marrow[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)
- Published
- 2015
16. Influence of IGF-I overexpression via rAAV gene transfer upon the chondrogenic differentiation potential of human bone marrow aspirates
- Author
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Frisch, Janina, Rey Rico, Ana, Venkatesan, Jagadeesh K., Schmitt, Gertrud, Madry, Henning, and Cucchiarini Madry, Magali
- Subjects
Bone Marrow Aspirates ,ddc: 610 ,viruses ,Cartilage Repair ,Gene Therapy ,610 Medical sciences ,Medicine ,IGF-I - Abstract
Objectives: Implantation of bone marrow aspirates modified by recombinant adeno-associated viral (rAAV) vectors is a promising approach to improve the healing of articular cartilage defects. In the present study, we investigated the effects of prolonged overexpression of the mitogenic and pro-anabolic[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)
- Published
- 2015
17. Effects of static versus dynamic culture conditions upon the chondrogenic differentiation potential of human bone marrow aspirates following rAAV-mediated overexpression of sox9
- Author
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Venkatesan, Jagadeesh K., Rey-Rico, Ana, Frisch, Janina, Schmitt, Gertrud, Madry, Henning, and Cucchiarini, Magali
- Subjects
Cartilage ,ddc: 610 ,Gene Therapy ,610 Medical sciences ,Medicine ,Regenerative Medicine - Abstract
Objectives: Gene-based modification of bone marrow aspirates is an attractive approach to treat articular cartilage defects. Here, we examined the potential of rAAV-mediated sox9 gene transfer to enhance the chondrogenic differentiation processes in human bone marrow aspirates under dynamic versus static[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)
- Published
- 2015
18. Effects of TGF-β Overexpression via rAAV Gene Transfer on the Early Repair Processes in an Osteochondral Defect Model in Minipigs.
- Author
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Cucchiarini, Magali, Asen, Ann-Kathrin, Goebel, Lars, Venkatesan, Jagadeesh K., Schmitt, Gertrud, Zurakowski, David, Menger, Michael D., Laschke, Matthias W., and Madry, Henning
- Subjects
ANALYSIS of variance ,ANIMAL experimentation ,COMPUTED tomography ,CONFIDENCE intervals ,GENE expression ,GENE therapy ,HISTOLOGICAL techniques ,IMMUNOHISTOCHEMISTRY ,PROBABILITY theory ,STAINS & staining (Microscopy) ,STATISTICS ,SWINE ,TRANSFORMING growth factors-beta ,ARTICULAR cartilage injuries ,STATISTICAL power analysis ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics ,IN vivo studies - Abstract
Background: Application of the chondrogenic transforming growth factor beta (TGF-β) is an attractive approach to enhance the intrinsic biological activities in damaged articular cartilage, especially when using direct gene transfer strategies based on the clinically relevant recombinant adeno-associated viral (rAAV) vectors. Purpose: To evaluate the ability of an rAAV–TGF-β construct to modulate the early repair processes in sites of focal cartilage injury in minipigs in vivo relative to control (reporter lacZ gene) vector treatment. Study Design: Controlled laboratory study. Methods: Direct administration of the candidate rAAV–human TGF-β (hTGF-β) vector was performed in osteochondral defects created in the knee joint of adult minipigs for macroscopic, histological, immunohistochemical, histomorphometric, and micro–computed tomography analyses after 4 weeks relative to control (rAAV-lacZ) gene transfer. Results: Successful overexpression of TGF-β via rAAV at this time point and in the conditions applied here triggered the cellular and metabolic activities within the lesions relative to lacZ gene transfer but, at the same time, led to a noticeable production of type I and X collagen without further buildup on the subchondral bone. Conclusion: Gene therapy via direct, local rAAV–hTGF-β injection stimulates the early reparative activities in focal cartilage lesions in vivo. Clinical Relevance: Local delivery of therapeutic (TGF-β) rAAV vectors in focal defects may provide new, off-the-shelf treatments for cartilage repair in patients in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. Peripheral blood aspirates overexpressing IGF-I via rAAV gene transfer undergo enhanced chondrogenic differentiation processes.
- Author
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Frisch, Janina, Orth, Patrick, Rey‐Rico, Ana, Venkatesan, Jagadeesh Kumar, Schmitt, Gertrud, Madry, Henning, Kohn, Dieter, and Cucchiarini, Magali
- Subjects
ARTICULAR cartilage injuries ,CHONDROGENESIS ,SOMATOMEDIN C ,GENETIC overexpression ,GENETIC transformation ,CELL differentiation - Abstract
Implantation of peripheral blood aspirates induced towards chondrogenic differentiation upon genetic modification in sites of articular cartilage injury may represent a powerful strategy to enhance cartilage repair. Such a single-step approach may be less invasive than procedures based on the use of isolated or concentrated MSCs, simplifying translational protocols in patients. In this study, we provide evidence showing the feasibility of overexpressing the mitogenic and pro-anabolic insulin-like growth factor I (IGF-I) in human peripheral blood aspirates via rAAV-mediated gene transfer, leading to enhanced proliferative and chondrogenic differentiation (proteoglycans, type-II collagen, SOX9) activities in the samples relative to control (reporter rAAV- lacZ) treatment over extended periods of time (at least 21 days, the longest time-point evaluated). Interestingly, IGF-I gene transfer also triggered hypertrophic, osteo- and adipogenic differentiation processes in the aspirates, suggesting that careful regulation of IGF-I expression may be necessary to contain these events in vivo. Still, the current results demonstrate the potential of targeting human peripheral blood aspirates via therapeutic rAAV transduction as a novel, convenient tool to treat articular cartilage injuries. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
20. Hydrogel-Based Controlled Delivery Systems for Articular Cartilage Repair.
- Author
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Rey-Rico, Ana, Madry, Henning, and Cucchiarini, Magali
- Subjects
- *
BIOLOGICAL products , *BIOTECHNOLOGY , *DNA , *DRUG administration , *PHARMACEUTICAL gels , *GENE therapy , *GENETIC techniques , *GROWTH factors , *MEDICAL technology , *ARTICULAR cartilage injuries , *TISSUE engineering - Abstract
Delivery of bioactive factors is a very valuable strategy for articular cartilage repair. Nevertheless, the direct supply of such biomolecules is limited by several factors including rapid degradation, the need for supraphysiological doses, the occurrence of immune and inflammatory responses, and the possibility of dissemination to nontarget sites that may impair their therapeutic action and raise undesired effects. The use of controlled delivery systems has the potential of overcoming these hurdles by promoting the temporal and spatial presentation of such factors in a defined target. Hydrogels are promising materials to develop delivery systems for cartilage repair as they can be easily loaded with bioactive molecules controlling their release only where required. This review exposes the most recent technologies on the design of hydrogels as controlled delivery platforms of bioactive molecules for cartilage repair. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
21. TGF-β gene transfer and overexpression via rAAV vectors stimulates chondrogenic events in human bone marrow aspirates.
- Author
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Frisch, Janina, Rey‐Rico, Ana, Venkatesan, Jagadeesh Kumar, Schmitt, Gertrud, Madry, Henning, and Cucchiarini, Magali
- Subjects
BONE marrow examination ,TRANSFORMING growth factors ,GENETIC transformation ,GENETIC overexpression ,CELL differentiation ,IN vivo studies - Abstract
Genetic modification of marrow concentrates may provide convenient approaches to enhance the chondrogenic differentiation processes and improve the repair capacities in sites of cartilage defects following administration in the lesions. Here, we provided clinically adapted recombinant adeno-associated virus ( rAAV) vectors to human bone marrow aspirates to promote the expression of the potent transforming growth factor beta ( TGF-β) as a means to regulate the biological and chondrogenic activities in the samples in vitro. Successful TGF-β gene transfer and expression via rAAV was reached relative to control ( lacZ) treatment (from 511.1 to 16.1 pg rh TGF-β/mg total proteins after 21 days), allowing to durably enhance the levels of cell proliferation, matrix synthesis, and chondrogenic differentiation. Strikingly, in the conditions applied here, application of the candidate TGF-β vector was also capable of reducing the hypertrophic and osteogenic differentiation processes in the aspirates, showing the potential benefits of using this particular vector to directly modify marrow concentrates to generate single-step, effective approaches that aim at improving articular cartilage repair in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
22. Overexpression of TGF-β via rAAV-Mediated Gene Transfer Promotes the Healing of Human Meniscal Lesions Ex Vivo on Explanted Menisci.
- Author
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Cucchiarini, Magali, Schmidt, Katharina, Frisch, Janina, Kohn, Dieter, and Madry, Henning
- Subjects
DNA analysis ,BIOCHEMISTRY ,BIOLOGICAL models ,CELL physiology ,COLLAGEN ,ENZYME-linked immunosorbent assay ,GENE therapy ,GENETIC techniques ,GROWTH factors ,HISTOLOGICAL techniques ,IMMUNOHISTOCHEMISTRY ,PHENOMENOLOGY ,MENISCUS (Anatomy) ,PROBABILITY theory ,RESEARCH funding ,T-test (Statistics) ,TOTAL knee replacement ,BLIND experiment ,DESCRIPTIVE statistics ,IN vitro studies ,MANN Whitney U Test ,METABOLISM - Abstract
Background: Direct application of therapeutic gene vectors derived from the adeno-associated virus (AAV) might be beneficial to improve the healing of meniscal tears. Purpose: To test the ability of recombinant AAV (rAAV) to overexpress the potent transforming growth factor–b (TGF-b) in primary cultures of human meniscal fibrochondrocytes, in human meniscal explants, and in experimental human meniscal lesions as a new tool to enhance meniscal repair. Study Design: Controlled laboratory study. Methods: The effects of the candidate treatment on the proliferative and metabolic activities of meniscal cells were monitored in vitro for up to 21 days and in situ in intact and injured human menisci for up to 15 days using biochemical, immunohistochemical, histological, and histomorphometric analyses. Results: Efficient production of TGF-b via rAAV was achieved in vitro and in situ, both in the intact and injured meniscus. Application of the rAAV TGF-b vector stimulated the levels of cell proliferation and matrix synthesis (type I collagen) compared with control gene transfer in all systems tested, especially in situ in regions of poor healing capacity and in sites of meniscal injury. No adverse effects of the candidate treatment were observed at the level of osseous differentiation, as tested by immunodetection of type X collagen. Most remarkably, a significant reduction of the amplitude of meniscal tears was noted after TGF-b treatment, an effect that was associated with increased expression levels of the a–smooth muscle actin contractile marker. Conclusion: Overexpression of TGF-b via rAAV gene transfer is capable of modulating the reparative activities of human meniscal cells, allowing for the healing of meniscal lesions by convenient injection in sites of injury. Clinical Relevance: Direct gene-based approaches using rAAV have strong potential to develop new therapeutic options that aim at treating human meniscal defects. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
23. Advances and challenges in gene-based approaches for osteoarthritis.
- Author
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Madry, Henning and Cucchiarini, Magali
- Abstract
Osteoarthritis (OA), a paramount cause of physical disability for which there is no definitive cure, is mainly characterized by the gradual loss of the articular cartilage. Current nonsurgical and reconstructive surgical therapies have not met success in reversing the OA phenotype so far. Gene transfer approaches allow for a long-term and site-specific presence of a therapeutic agent to re-equilibrate the metabolic balance in OA cartilage and may consequently be suited to treat this slow and irreversible disorder. The distinct stages of OA need to be respected in individual gene therapy strategies. In this context, molecular therapy appears to be most effective for early OA. A critical step forward has been made by directly transferring candidate sequences into human articular chondrocytes embedded within their native extracellular matrix via recombinant adeno-associated viral vectors. Although extensive studies in vitro attest to a growing interest in this approach, data from animal models of OA are sparse. A phase I dose-escalating trial was recently performed in patients with advanced knee OA to examine the safety and activity of chondrocytes modified to produce the transforming growth factor β1 via intra-articular injection, showing a dose-dependent trend toward efficacy. Proof-of-concept studies in patients prior to undergoing total knee replacement may be privileged in the future to identify the best mode of translating this approach to clinical application, followed by randomized controlled trials. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
24. Application of Alginate Hydrogels for Next-Generation Articular Cartilage Regeneration.
- Author
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Liu, Wei, Madry, Henning, and Cucchiarini, Magali
- Subjects
- *
CARTILAGE regeneration , *ARTICULAR cartilage , *ALGINIC acid , *HYDROGELS , *GENE therapy , *SODIUM alginate - Abstract
The articular cartilage has insufficient intrinsic healing abilities, and articular cartilage injuries often progress to osteoarthritis. Alginate-based scaffolds are attractive biomaterials for cartilage repair and regeneration, allowing for the delivery of cells and therapeutic drugs and gene sequences. In light of the heterogeneity of findings reporting the benefits of using alginate for cartilage regeneration, a better understanding of alginate-based systems is needed in order to improve the approaches aiming to enhance cartilage regeneration with this compound. This review provides an in-depth evaluation of the literature, focusing on the manipulation of alginate as a tool to support the processes involved in cartilage healing in order to demonstrate how such a material, used as a direct compound or combined with cell and gene therapy and with scaffold-guided gene transfer procedures, may assist cartilage regeneration in an optimal manner for future applications in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
25. Improved Tissue Repair in Articular Cartilage Defects in Vivo by rAAV-Mediated Overexpression of Human Fibroblast Growth Factor 2
- Author
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Cucchiarini, Magali, Madry, Henning, Ma, Chunyan, Thurn, Tanja, Zurakowski, David, Menger, Michael D., Kohn, Dieter, Trippel, Stephen B., and Terwilliger, Ernest F.
- Subjects
- *
CARTILAGE , *GROWTH factors , *LIGAMENTS , *CYTOKINES - Abstract
Abstract: Therapeutic gene transfer into articular cartilage is a potential means to stimulate reparative activities in tissue lesions. We previously demonstrated that direct application of recombinant adeno-associated virus (rAAV) vectors to articular chondrocytes in their native matrix in situ as well as sites of tissue damage allowed for efficient and sustained reporter gene expression. Here we test the hypothesis that rAAV-mediated overexpression of fibroblast growth factor 2 (FGF-2), one candidate for enhancing the repair of cartilage lesions, would lead to the production of a biologically active factor that would facilitate the healing of articular cartilage defects. In vitro, FGF-2 production from an rAAV-delivered transgene was sufficient to stimulate chondrocyte proliferation over a prolonged period of time. In vivo, application of the therapeutic vector significantly improved the overall repair, filling, architecture, and cell morphology of osteochondral defects in rabbit knee joints. Differences in matrix synthesis were also observed, although not to the point of statistical significance. This process may further benefit from cosupplementation with other factors. These results provide a basis for rAAV application to sites of articular cartilage damage to deliver agents that promote tissue repair. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
26. Functionalized hydrogels as smart gene delivery systems to treat musculoskeletal disorders.
- Author
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Enayati, Mohammadsaeid, Liu, Wei, Madry, Henning, Neisiany, Rasoul Esmaeely, and Cucchiarini, Magali
- Subjects
- *
MUSCULOSKELETAL system diseases , *HYDROGELS , *GENE therapy , *MUSCULOSKELETAL system , *TISSUE scaffolds , *THERAPEUTICS - Abstract
Despite critical advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy based on the delivery of therapeutic genetic sequences has strong value to offer effective, durable options to decisively manage such disorders. Furthermore, scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy, allowing for the spatiotemporal delivery of candidate genes to sites of injury. Among the many scaffolds for musculoskeletal research, hydrogels raised increasing attention in addition to other potent systems (solid, hybrid scaffolds) due to their versatility and competence as drug and cell carriers in tissue engineering and wound dressing. Attractive functionalities of hydrogels for musculoskeletal therapy include their injectability, stimuli-responsiveness, self-healing, and nanocomposition that may further allow to upgrade of them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. Such functionalized hydrogels may also be tuned to successfully transfer therapeutic genes in a minimally invasive manner in order to protect their cargos and allow for their long-term effects. In light of such features, this review focuses on functionalized hydrogels and demonstrates their competence for the treatment of musculoskeletal disorders using gene therapy procedures, from gene therapy principles to hydrogel functionalization methods and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are being discussed in the perspective of translation in patients. Despite advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy has strong value in offering effective, durable options to decisively manage such disorders. Scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy. Among many scaffolds for musculoskeletal research, hydrogels raised increasing attention. Functionalities including injectability, stimuli-responsiveness, and self-healing, tune them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. This review introduces functionalized hydrogels for musculoskeletal disorder treatment using gene therapy procedures, from gene therapy principles to functionalized hydrogels and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are discussed from the perspective of translation in patients. [Display omitted] • Gene therapy as a reliable treatment for musculoskeletal diseases was introduced. • Functionalized hydrogels as carriers for gene delivery were discussed. • Nanocomposite hydrogels may render intelligent platforms for delivery purposes. • Injectability, stimuli responsiveness, and self-healing were reviewed. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
27. Scaffold-Mediated Gene Delivery for Osteochondral Repair.
- Author
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Madry, Henning, Venkatesan, Jagadeesh Kumar, Carballo-Pedrares, Natalia, Rey-Rico, Ana, and Cucchiarini, Magali
- Subjects
- *
GENETIC vectors , *ARTICULAR cartilage , *VIRAL genes , *BONES , *GENES - Abstract
Osteochondral defects involve both the articular cartilage and the underlying subchondral bone. If left untreated, they may lead to osteoarthritis. Advanced biomaterial-guided delivery of gene vectors has recently emerged as an attractive therapeutic concept for osteochondral repair. The goal of this review is to provide an overview of the variety of biomaterials employed as nonviral or viral gene carriers for osteochondral repair approaches both in vitro and in vivo, including hydrogels, solid scaffolds, and hybrid materials. The data show that a site-specific delivery of therapeutic gene vectors in the context of acellular or cellular strategies allows for a spatial and temporal control of osteochondral neotissue composition in vitro. In vivo, implantation of acellular hydrogels loaded with nonviral or viral vectors has been reported to significantly improve osteochondral repair in translational defect models. These advances support the concept of scaffold-mediated gene delivery for osteochondral repair. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
28. Improved Chondrogenic Differentiation of rAAV SOX9-Modified Human MSCs Seeded in Fibrin-Polyurethane Scaffolds in a Hydrodynamic Environment.
- Author
-
Venkatesan, Jagadeesh K., Gardner, Oliver, Rey-Rico, Ana, Eglin, David, Alini, Mauro, Stoddart, Martin J., Cucchiarini, Magali, and Madry, Henning
- Subjects
HYDRODYNAMICS ,GENE therapy ,MESENCHYMAL stem cells ,GENETIC transformation ,CHONDROGENESIS - Abstract
The repair of focal articular cartilage defects remains a problem. Combining gene therapy with tissue engineering approaches using bone marrow-derived mesenchymal stem cells (MSCs) may allow the development of improved options for cartilage repair. Here, we examined whether a three-dimensional fibrin-polyurethane scaffold provides a favorable environment for the effective chondrogenic differentiation of human MSCs (hMSCs) overexpressing the cartilage-specific SOX9 transcription factor via recombinant adeno-associated virus (rAAV) -mediated gene transfer cultured in a hydrodynamic environment in vitro. Sustained SOX9 expression was noted in the constructs for at least 21 days, the longest time point evaluated. Such spatially defined SOX9 overexpression enhanced proliferative, metabolic, and chondrogenic activities compared with control (reporter lacZ gene transfer) treatment. Of further note, administration of the SOX9 vector was also capable of delaying premature hypertrophic and osteogenic differentiation in the constructs. This enhancement of chondrogenesis by spatially defined overexpression of human SOX9 demonstrate the potential benefits of using rAAV-modified hMSCs seeded in fibrin-polyurethane scaffolds as a promising approach for implantation in focal cartilage lesions to improve cartilage repair. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
29. pNaSS-Grafted PCL Film-Guided rAAV TGF-β Gene Therapy Activates the Chondrogenic Activities in Human Bone Marrow Aspirates.
- Author
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Venkatesan, Jagadeesh K., Cai, Xiaoyu, Meng, Weikun, Rey-Rico, Ana, Schmitt, Gertrud, Speicher-Mentges, Susanne, Falentin-Daudré, Céline, Leroux, Amélie, Madry, Henning, Migonney, Véronique, and Cucchiarini, Magali
- Subjects
- *
BONE marrow , *TRANSFORMING growth factors-beta , *GENE therapy , *POLYCAPROLACTONE , *ARTICULAR cartilage , *VIRAL genes - Abstract
Scaffold-guided viral gene therapy is a novel, powerful tool to enhance the processes of tissue repair in articular cartilage lesions by the delivery and overexpression of therapeutic genes in a noninvasive, controlled release manner based on a procedure that may protect the gene vehicles from undesirable host immune responses. In this study, we examined the potential of transferring a recombinant adeno-associated virus (rAAV) vector carrying a sequence for the highly chondroregenerative transforming growth factor beta (TGF-β), using poly(ɛ-caprolactone) (PCL) films functionalized by the grafting of poly(sodium styrene sulfonate) (pNaSS) in chondrogenically competent bone marrow aspirates as future targets for therapy in cartilage lesions. Effective overexpression of TGF-β in the aspirates by rAAV was achieved upon delivery using pNaSS-grafted and ungrafted PCL films for up to 21 days (the longest time point evaluated), with superior levels using the grafted films, compared with respective conditions without vector coating. The production of rAAV-mediated TGF-β by pNaSS-grafted and ungrafted PCL films significantly triggered the biological activities and chondrogenic processes in the samples (proteoglycan and type-II collagen deposition and cell proliferation), while containing premature mineralization and hypertrophy relative to the other conditions, with overall superior effects supported by the pNaSS-grafted films. These observations demonstrate the potential of PCL film-assisted rAAV TGF-β gene transfer as a convenient, off-the-shelf technique to enhance the reparative potential of the bone marrow in patients in future approaches for improved cartilage repair. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
30. 676. Local Stimulation of Articular Cartilage Repair by Transplantation of Encapsulated Chondrocytes Overexpressing Human FGF-2 In Vivo
- Author
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Kaul, Gunter, Cucchiarini, Magali, Zurakowski, David, Trippel, StephenB., Kohn, Dieter, and Madry, Henning
- Subjects
- *
CARTILAGE cells , *ARTICULAR cartilage , *GENE therapy - Abstract
An abstract of the article "Local Stimulation of Articular Cartilage Repair by Transplantation of Encapsulated Chondrocytes Overexpressing Human FGF-2 In Vivo," by Gunter Kaul, Magali Cucchiarini, David Zurakowski, Stephen B. Trippel, Dieter Kohn and Henning Madry is presented.
- Published
- 2005
- Full Text
- View/download PDF
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