Osteoarthritis gene therapy

Evans, Christopher H.; Gouze, Jean Noël; Gouze, Elvire; Robbins, Paul D.; Ghivizzani, Steven C.

doi:10.1038/sj.gt.3302196

Cited by 140 publications

(113 citation statements)

References 121 publications

(120 reference statements)

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“…Most of the AAV transduction occurred in the intra-articular soft tissues covered with synovial cells, with limited articular chondrocyte transduction. This is consistent with other studies, as vector penetration through the dense cartilage extracellular matrix is restricted (Goater et al, 2000;Evans et al, 2004). However, high-level expression of transgene product was possible from the soft tissues.…”

Section: Introductionsupporting

confidence: 82%

“…Hence, a successful delivery strategy for adequate levels of therapeutic molecules in a localized manner is critically important. Gene therapy strategies, therefore, have gained a lot of attention for arthritis treatment (Goater et al, 2000;Evans et al, 2004). Numerous vectors are available for in vivo gene transfer, such as naked DNA, retrovirus, adenovirus, etc.…”

Section: Discussionmentioning

confidence: 99%

“…OA, whether idiopathic or posttraumatic, develops over many years and patients frequently need chronic treatment. Common medications for OA include nonselective, nonsteroidal, anti-inflammatory drugs (NSAIDs) (Recommendations for the Medical Management, 2000; Evans et al, 2004). Daily long-term use of these drugs, however, is not without significant complications.…”

Section: Introductionmentioning

confidence: 99%

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Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

et al. 2013

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A single intra-articular injection of adeno-associated virus (AAV) results in stable and controllable transgene expression in normal rat knees. Because undamaged joints are unlikely to require treatment, the study of AAV delivery in joint injury models is crucial to potential therapeutic applications. This study tests the hypotheses that persistent and controllable AAV-transgene expression are (1) highly localized to the cartilage when AAV is injected postinjury and (2) localized to the intra-articular soft tissues when AAV is injected preinjury. Two AAV injection time points, postinjury and preinjury, were investigated in osteochondral defect and anterior cruciate ligament transection models of joint injury. Rats injected with AAV tetracycline response element (TRE)-luciferase received oral doxycycline for 7 days. Luciferase expression was evaluated longitudinally for 6 months. Transgene expression was persistent and controllable with oral doxycycline for 6 months in all groups. However, the location of transgene expression was different: postinjury AAV-injected knees had luciferase expression highly localized to the cartilage, while preinjury AAV-injected knees had more widespread signal from intraarticular soft tissues. The differential transgene localization between preinjury and postinjury injection can be used to optimize treatment strategies. Highly localized postinjury injection appears advantageous for treatments targeting repair cells. The more generalized and controllable reservoir of transgene expression following AAV injection before anterior cruciate ligament transection (ACLT) suggests an intriguing concept for prophylactic delivery of joint protective factors to individuals at high risk for early osteoarthritis (OA). Successful external control of intra-articular transgene expression provides an added margin of safety for these potential clinical applications.

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Section: Introductionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

et al. 2013

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“…However, the limitations of the virus vectors include induction of the host immune response, whereas retroviral vectors require dividing cells for integration. In addition, there is a small chance that viral vectors may integrate randomly into the host genome, posing a risk of neoplastic transformation or infectionassociated toxicity [6,8,22]. To avoid such adverse effects, a shorter or lower-level transgene expression might be sufficient and thus more appropriate for these potent differentiation factors.…”

Section: Discussionmentioning

confidence: 99%

Treating Human Meniscal Fibrochondrocytes with hIGF-1 Gene by Liposome

Zhang

Leng

Wang

et al. 2009

Clin Orthop Relat Res

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The menisci are intraarticular fibrocartilaginous structures essential to the normal function of the knee that lack the ability to self-repair. Human meniscal fibrochondrocytes may respond to beneficial genes like human insulin growth factor-1 (hIGF-1) and the meniscal cell may be a feasible donor for gene therapy. To explore this possibility, we amplified the hIGF-1 gene sequence in full length and cloned it into a bicistronic plasmid. This gene was then transfected into cultured human meniscal fibrochondrocytes by the liposome FuGene 6. Green fluorescence was expressed in part of the cells 6 hours after transfection and increased gradually, with a peak concentration of the hIGF-1 in the supernatants to 22.68 ng/mL 56 hours after transfection. Phenotypes of some cells changed and the proliferation accelerated after transfection. Flow cytometry analysis demonstrated upregulation of cell numbers in the G2 and S stages after hIGF-1 gene introduction. We conclude the hIGF-1 gene can be transfected into the human meniscal cell efficiently by liposome and it causes accelerated proliferation and differentiation. Within 10 days after transfection, the cytokine appears to be secreted into supernatants with the bioactivity and promotes the proliferation of the NIH 3T3 cell line.

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“…Anti-TNFα, PEGylated soluble TNFα (Fox & Stephens, 2010); (Frisbie et al, 2002); (Evans et al, 2004); (Meijer et al, 2003) (Zafarullah et al, 2003); (Martel-Pelletier, 1999); (Furman et al, 2006); (Fukui et al, 2001); (Evans et al, 2004); (Elsaid et al, 2009) Matrix protection…”

Section: Irap/ Il-1ramentioning

confidence: 99%