Direct adenovirus-mediated IGF-I gene transduction of synovium induces persisting synovial fluid IGF-I ligand elevations

Goodrich, Laurie R.; Brower-Toland, Brent D.; Warnick, L. D.; Robbins, Paul D.; Evans, Christopher H.; Nixon, Alan J.

doi:10.1038/sj.gt.3302757

Cited by 31 publications

(30 citation statements)

References 53 publications

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“…Many different viral vectors including retrovirus, 8 lentivirus, 9 and adenovirus 2 have been investigated for use in OA; however, a significant impediment has been the substantial immune response, which limits transduction and transgene expression. 2 Adeno-associated virus (AAV) may be a promising alternative as it is nonpathogenic, transduces dividing and nondividing cells and enables long-term transgene expression.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown that articular tissues, including synoviocytes and chondrocytes, can be transduced through direct intraarticular (IA) injection. [2][3][4] Gene therapy techniques, which provide long-term in situ expression of repair-enhancing genes, would be superior to repeated injections or depots of peptide that are transient.…”

Section: Introductionmentioning

confidence: 99%

“…2 Adeno-associated virus (AAV) may be a promising alternative as it is nonpathogenic, transduces dividing and nondividing cells and enables long-term transgene expression. 10 Both rAAV2 and rAAV5 have been shown to effectively transduce equine synoviocytes and chondrocytes in our laboratory, 11 and by others.…”

Section: Introductionmentioning

confidence: 99%

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Humoral and Cell-Mediated Immune Response, and Growth Factor Synthesis After Direct Intraarticular Injection of rAAV2-IGF-I and rAAV5-IGF-I in the Equine Middle Carpal Joint

et al. 2015

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Intraarticular (IA) administration of viral vectors expressing a therapeutic transgene is an attractive treatment modality for osteoarthritis (OA) as the joint can be treated as a contained unit. Humoral and cell-mediated immune responses in vivo can limit vector effectiveness. Transduction of articular tissues has been investigated; however, the immune response to IA vectors remains largely unknown. We hypothesized that IA rAAV2 and rAAV5 overexpressing insulin-like growth factor-I (IGF-I) would result in long-term IGF-I formation but would also induce neutralizing antibodies (NAb) and anti-capsid effector T cells. Twelve healthy horses were assigned to treatment (rAAV2 or rAAV5) or control (saline) groups. Middle carpal joints were injected with 5 · 10 11 vector genomes/joint. Synovial fluid was analyzed for changes in composition, NAb titers, immunoglobulin isotypes, proinflammatory cytokines, and IGF-I. Serum was analyzed for antibody titers and cytokines. A T cell restimulation assay was used to assess T cell responses. Injection of rAAV2-or rAAV5-IGF-I did not induce greater inflammation compared with saline. Synovial fluid IGF-I was significantly increased in both rAAV2-and rAAV5-IGF-I joints by day 14 and remained elevated until day 56; however, rAAV5 achieved the highest concentrations. A capsid-specific T cell response was not noted although all virus-treated horses had increased NAbs in serum and synovial fluid after treatment. Taken together, our data show that IA injection of rAAV2-or rAAV5-IGF-I does not incite a clinically detectable inflammatory or cell-mediated immune response and that IA gene therapy using minimally immunogenic vectors represents a clinically relevant tool for treating articular disorders including OA.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Humoral and Cell-Mediated Immune Response, and Growth Factor Synthesis After Direct Intraarticular Injection of rAAV2-IGF-I and rAAV5-IGF-I in the Equine Middle Carpal Joint

et al. 2015

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“…Adenovirus is used to transfer GF genes (TGF-β, FGF-2, IGF-1, BMPs and Growth and differentiation factor 5, GDF-5) into cells [8,20,25,[40][41][42][43][44][45][46][47][48][49]. Genes, in encapsuled viral [24] vector, can be injected directly in vivo [50,51] or through decalcified cortical bone matrix (DCBM) as scaffold that contains the viral particles [52]. Indian hedgehog homolog (iHH) and SOXs genes employ adenovirus for transport into MSCs both in vitro [53,54] and in vivo [55,56].…”

Section: Viral Vectormentioning

confidence: 99%

“…Direct injection is mainly employed for the delivery of anti-inflammatory cytokines such as IL10 and IL1ra into a joint affected by rheumatoid arthritis, OA and full-thickness defects [12,57,67,68,78]. Even GFs, such as IGF1 and BMPs are delivered with this modality in arthritis, full-thickness and osteochondral defects [50,51,57,63]. In the direct procedures, the most employed vectors are adenovirus, rAAV or scAAV [50, 51, 57, 63, 67, 68], followed by plasmid [12] and Lentivirus [78] (Table 1).…”

Section: Direct Proceduresmentioning

confidence: 99%

Gene therapy for chondral and osteochondral regeneration: is the future now?

Bellavia

Veronesi

Carina

et al. 2017

Cell. Mol. Life Sci.

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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

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