Gene transfer to human joints: Progress toward a gene therapy of arthritis

Evans, Christopher H.; Robbins, Paul D.; Ghivizzani, Steven C.; Wasko, Mary Chester; Tomaino, Matthew M.; Kang, Richard W.; Muzzonigro, Thomas A.; Vogt, Molly T.; Elder, Elaine M.; Whiteside, Theresa L.; Watkins, Simon C.; Herndon, James H.

doi:10.1073/pnas.0502854102

Cited by 195 publications

(120 citation statements)

References 28 publications

(22 reference statements)

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“…In a separate study using mice that constitutively express human TNF␣, treatment with TNF mAb prevented further cartilage damage in older mice and actually promoted cartilage repair in younger mice (7-8 weeks of age) (50). Clinical trials have also shown the promise of IL-1Ra gene therapy for the treatment of arthritis (51). In our study, we provide evidence that IL-1Ra and TNF mAb may have beneficial effects on the meniscus, specifically for integrative meniscal repair in an inflammatory microenvironment.…”

Section: Discussionmentioning

confidence: 56%

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

McNulty

Moutos

Weinberg

et al. 2007

Arthritis & Rheumatism

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Objective. To examine the hypotheses that increasing concentrations of interleukin-1 (IL-1) or tumor necrosis factor ␣ (TNF␣) inhibit the integrative repair of the knee meniscus in an in vitro model system, and that inhibitors of these cytokines will enhance repair.Methods. Explants (8 mm in diameter) were harvested from porcine medial menisci. To simulate a full-thickness defect, a 4-mm-diameter core was removed and reinserted. Explants were cultured for 14, 28, or 42 days in the presence of 0-1,000 pg/ml of IL-1 or TNF␣. Explants were also cultured in the presence of IL-1 or TNF␣ with IL-1 receptor antagonist (IL-1Ra) or TNF monoclonal antibody (mAb). At the end of the culture period, biomechanical testing, cell viability, and histologic analyses were performed to quantify the extent of repair.Results. Mechanical testing revealed increased repair strength, cell accumulation, and tissue formation at the interface over time under control conditions. Pathophysiologic concentrations of both IL-1 and TNF␣ significantly decreased repair strength, cell migration, and tissue formation at the interface. The addition of IL-1Ra or TNF mAb to explants prevented the effects of IL-1 or TNF␣, respectively. Conclusion. Our findings document that physiologically relevant concentrations of IL-1 and TNF␣ inhibit meniscal repair in vitro and therefore may also inhibit meniscal repair during arthritis or following joint injury. The finding that IL-1Ra and TNF mAb promoted integrative meniscal repair in an inflammatory microenvironment suggests that intraarticular delivery of IL-1Ra and/or TNF mAb may be useful clinically to promote meniscal healing following injury.

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Section: Discussionmentioning

confidence: 56%

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

McNulty

Moutos

Weinberg

et al. 2007

Arthritis & Rheumatism

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“…33 Following genetic labeling of chondrocytes with GFP using a retroviral vector, Mierisch et al 34 observed a reduction of GFP-labeled chondrocytes from 100% of the initial density to 15% by 4 weeks after implantation into rabbit osteochondral defects. In our study, residual GFP expression was seen through 2 months in monolayer culture and through the 21-day study period in three-dimensional pellet culture.…”

Section: Aav-transduced Human Cells Improve Cartilage Repairmentioning

confidence: 99%

Adeno-associated viral gene transfer of transforming growth factor-β1 to human mesenchymal stem cells improves cartilage repair

et al. 2007

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Bone marrow cells are routinely accessed clinically for cartilage repair. This study was performed to determine whether adeno-associated virus (AAV) effectively transduces human bone marrow-derived mesenchymal stem cells (hMSC) in vitro, whether AAV infection interferes with hMSC chondrogenesis and whether AAV-transforming growth factor-beta-1 (TGF-b1)-transduced hMSC can improve cartilage repair in vivo. Adult hMSC were transduced with AAVgreen fluorescent protein (GFP) or AAV-transforming growth factor b1 (TGFb1) and studied in pellet cultures. For in vivo studies, AAV-GFP and AAV-TGF-b1-transduced hMSCs were implanted into osteochondral defects of 21 athymic rats. GFP was detected using fluorescent microscopy.Cartilage repair was assessed using gross and histological analysis at 4, 8 and 12 weeks. In pellet culture, GFP expression was visualized in situ through 21 days in vitro. In vivo GFP transgene expression was observed by in situ fluorescent surface imaging in 100% of GFP implanted defects at 2 , 67% at 8 and 17% at 12 weeks. Improved cartilage repair was observed in osteochondral defects implanted with AAV-TGF-b1-transduced hMSC at 12 weeks (P ¼ 0.0047). These results show that AAV is a suitable vector for gene delivery to improve the cartilage repair potential of human mesenchymal stem cells.

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“…The safety of intraarticular IL-1Ra delivery has also been demonstrated in human clinical trials using single injections of 150 mg (15). As an alternative to the high and frequent dosing required for intraarticular protein delivery, animal studies have investigated IL-1Ra gene delivery via injection of either gene (16) or transfected cells (17), and exploratory clinical trials of such gene therapy have been performed in RA patients (18) and in OA patients (19).…”

mentioning

confidence: 99%

Development and characterization of a fusion protein between thermally responsive elastin‐like polypeptide and interleukin‐1 receptor antagonist: Sustained release of a local antiinflammatory therapeutic

Shamji

Betre

Kraus

et al. 2007

Arthritis & Rheumatism

140

111

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Objective. Interleukin-1 receptor antagonist (IL1Ra) has been evaluated for the intraarticular treatment of osteoarthritis. Such administration of proteins may have limited utility because of their rapid clearance and short half-life in the joint. The fusion of a drug to elastin-like polypeptides (ELPs) promotes the formation of aggregating particles that form a "drug depot" at physiologic temperatures, a phenomenon intended to prolong the presence of the drug. The purpose of this study was to develop an injectable drug depot composed of IL-1Ra and ELP domains and to evaluate the properties and bioactivity of the recombinant ELP-IL-1Ra fusion protein.Methods. Fusion proteins between IL-1Ra and 2 distinct sequences and molecular weights of ELP were overexpressed in Escherichia coli. Environmental sensitivity was demonstrated by turbidity and dynamic light scattering as a function of temperature. IL-1Ra domain activity was evaluated by surface plasmon resonance, and in vitro antagonism of IL-1-mediated lymphocyte and thymocyte proliferation, as well as IL-1-induced tumor necrosis factor ␣ (TNF␣) expression and matrix metalloproteinase 3 (MMP-3) and ADAMTS-4 messenger RNA expression in human intervertebral disc fibrochondrocytes. IL-1Ra immunoreactivity was assessed before and after proteolytic degradation of the ELP partner.Results. Both fusion proteins underwent supramolecular aggregation at subphysiologic temperatures and slowly resolubilized at 37°C. Interaction with IL-1 receptor was slower in association but equivalent in dissociation as compared with the commercial antagonist. Anti-IL-1 activity was demonstrated by inhibition of lymphocyte and thymocyte proliferation and by decreased TNF␣ expression and ADAMTS-4 and MMP-3 transcription by fibrochondrocytes. ELP domain proteolysis liberated a peptide of comparable size and immunoreactivity as the commercial IL-1Ra. This peptide was more bioactive against lymphocyte proliferation, nearly equivalent to the commercial antagonist.Conclusion. The ELP-IL-1Ra fusion protein proved to retain the characteristic ELP inverse phasetransitioning behavior as well as the bioactivity of the IL-1Ra domain. This technology represents a novel drug carrier designed to prolong the presence of bioactive peptides following intraarticular delivery.Interleukin-1 (IL-1) has been implicated as a mediator of anabolic and catabolic processes in the progression of osteoarthritis (OA). IL-1 is a 17-kd protein that stimulates both synoviocytes and chondrocytes to secrete proteases and other

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Gene transfer to human joints: Progress toward a gene therapy of arthritis

Cited by 195 publications

References 28 publications

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

Adeno-associated viral gene transfer of transforming growth factor-β1 to human mesenchymal stem cells improves cartilage repair

Development and characterization of a fusion protein between thermally responsive elastin‐like polypeptide and interleukin‐1 receptor antagonist: Sustained release of a local antiinflammatory therapeutic

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