Table 1.
Interleukins.
| References | Objectives | Study design | Disease models | Delivery methods | Targets | Effects |
|---|---|---|---|---|---|---|
| Pelletier et al. (16) | Evaluate the therapeutic effect of IL-1Ra on progression of OA lesions | Preclinical in vivo | Dog ACLT section and partial synovectomy of the knee | Retrovirally transduced synovial fibroblasts | IL-1Ra | Reduced progression of experimentally induced OA lesions after intraarticular injection of transduced synovial cells |
| Baragi et al. (17) | Demonstrate the chondroprotective effect of IL-1ra | Preclinical in vitro and ex vivo | Human articular OA chondrocytes and OA cartilage explants | Adenovirus: Ad.RSV hIL-1ra | IL-1Ra | Adherence and viability of transduced chondrocytes on surface of hyaline cartilage; protection of OA cartilage from Il-1β-induced matrix degradation |
| Nixon et al. (18) | Investigate the disease-modifying properties of IL-1Ra gene therapy | Preclinical in vivo | Mouse ACLT model | Helper-dependent adenovirus: HdAd-mIL-1Ra | IL-1Ra | Prevention and treatment of surgically induced OA: improved histologic scores, fewer osteophytes; higher cartilage volume and surface |
| Horse osteochondral fragment model | Helper-dependent adenovirus: HdAd-eqIL-1Ra | Improvement in pain: improved lameness, range of motion and effusion; better cartilage status; improved synovial membrane status; fewer osteophytes | ||||
| Deng et al. (19) | Evaluate the potential of loaded nanomicelles to treat articlular inflammation in in vivo TMJOA model | Preclinical in vivo | Rat MIA model | Polyplex nanomicelles | IL-1Ra | Reduced pain behavior; less cartilage degradation; lower Mankin score; reduced surface fibrosis; reduced OA progression; downregulation of pro-inflammatory cytokines |
| Senter et al. (20) | Assess efficacy, biodistribution and safety of HDAd-ratIL-1Ra as well as biodistribution of FX201 (human equivalent) | Preclinical in vivo | Rat ACLT model | Helper-dependent adenovirus: HDAd-ratIL-1Ra and FX201 (HDAd-hIL-1Ra) | IL-1Ra | HDAd-ratIL-1Ra decreased OA-induced joint damage; HDAd-ratIL-1Ra and FX201 mainly localized to knee joint; HDAd-ratIL-1Ra well-tolerated |
| Fernandes et al. (21) | Determine the effect of IL-1Ra through a lipoplex on structural changes in in vivo OA model | Preclinical in vivo | Rabbit menisectomy model | IL-1Ra plasmid (Lipoplex) | IL-1Ra | Reduced width of osteophytes and size of macroscopic lesions (dose-dependent); reduced severity of histologic cartilage lesions; presence of IL-1Ra in the synovium and cartilage of injected rabbits |
| Zhang et al. (22) | Evaluate the efficiency of chitosan-EGFP nanoparticles for gene therapy of OA | Preclinical in vivo | Rabbit medial collateral ligament excision and medial menisectomy model of OA | Chitosan-EGFP nanoparticles | IL-1Ra or IL-10 | Less severe lesions after treatment with IL-1Ra; (no expression of IL-10, therefore effect was not studied) |
| Deng et al. (23) | Development of a new nanoparticle made of chitosan (CS)/hyaluronic acid (HA)/plasmid-DNA | Preclinical in vitro | Rat IL-1β-treated synoviocytes | CS/HA/pDNA nanoparticles | IL-1Ra | Increased IL-1Ra expression and decreased MMP-3, MMP-13, COX-2 and iNOS expression in IL-1β-induced synoviocytes |
| Frisbie et al. (24) | Evaluate the utility of the equine IL-1Ra gene therapy in a equine OA model | Preclinical in vitro | Equine synoviocytes | Adenovirus: Ad-EqIL-1a | IL-1Ra | Dose dependent increase of IL-1Ra after transduction of equine synoviocytes; inhibit PGE2 production in response to human IL-1α |
| Preclinical in vivo | Equine OA model | Improvement in clinical parameters of pain, disease activity, preservation of articular cartilage, beneficial effects on histologic parameters of synovial membrane and articular cartilage | ||||
| Goodrich et al. (25) | scAAVIL-1Ra dosing trial in an equine model | Preclinical in vivo | Skeletally mature horses | Adenoassociated virus: scAAV2IL-1ra | IL-1Ra | Transduction of the scAAV vector both in the synovial and cartilage tissues; no evidence of intra-articular toxicity; neutralizing ABs within 2 weeks of administration which persisted for the duration of the study but did not lower protein expression intra-articularly |
| Watson Levings et al. (26) | Generate pharmacokinetic profile of homologous gene delivery of scAAV.IL-1Ra | Preclinical in vivo | Naturally occurring OA in horses | Adenoassociated virus: sc-AAV.eqIL-1Ra | IL-1Ra | Safe and sustained drug delivery to joints |
| Watson Levings et al. (27) | Efficacy of local treatment with scAAV.IL-1Ra | Preclinical in vivo | Horse surgically induced osteochondral fragmentation (OCF) model | Adenoassociated virus: sc-AAV.eqIL-1Ra | IL-1Ra | Reduced forelimb lameness; reduced inflammation; enhanced repair of osteochondral injury; reduced joint effusion; reduced synovial proliferation |
| Glass et al. (28) | Evaluate the possibility to combine gene therapy and functional tissue engineering to develop engineered cartilage with inductible immunomodulatory properties | Preclinical in vitro | IL-1β-stimulated MSCs from human bone marrow | IL-1Ra lentivirus via scaffold | IL-1Ra | Engineered cartilage constructs are capable of inducible and tunable IL-1Ra production at therapeutically relevant concentrations; these constructs protect from the effects of IL-1 |
| Gabner et al. (29) | Evaluate IL-1Ra expression in equine MSCs | Preclinical in vitro | Equine OA chondrocytes co-culture | Lentivirus: pSEWNFKBIL-1Ra | IL-1Ra | Protective ability of the IL-1Ra protein (increased ACAN and COL2A1 and decreased IL-6, MMP-1 and MMP-13); upon TNF-α, a dose-dependent increase in IL-1Ra expression in MSC/IL-1Ra cells |
| Chen et al. (30) | Investigate the combinatorial effect of adenovirus-mediated overexpression of bFGF vs. IL-1Ra vs. IGF-1 on OA | Preclinical in vitro | Human articular OA chondrocytes | Adenovirus: AdbFGF; AdIL-1Ra; AdIGF-1 | bFGF •IL-1Ra •IGF-1 | Increased chondrocyte proliferation; increased GAG and type II collagen synthesis |
| Preclinical in vivo | Rabbit ACLT model | Protects from cartilage degradation: lower Mankin score; increased type II collagen and proteoglycan synthesis; better results with combinations | ||||
| Zhang et al. (31) | Evaluate the effect of using IL-1Ra and IL-10 together as gene therapy for OA | Preclinical in vivo | Rabbit medial collateral ligament excision and medial menisectomy model of OA | Retrovirus: PLXRN-IL-1Ra and PLXRN-IL-10 | IL-1Ra and IL-10 | Reduced cartilage lesions and decreased loss of proteoglycans after combined injection; no effect on synovitis |
| Haupt et al. (32) | Evaluate the combinatorial effect of adenovirus-mediated overexpression of IGF-1 and IL-1Ra in an OA culture model | Preclinical in vitro | IL-1β-stimulated horse cartilage explants and synovial membrane | Adenovirus: equine AdIGF-1; equine AdIL-1Ra | IGF-1 and IL-1Ra | Matrix synthesis stimulation and catabolics blockers, prevention matrix degradation by IL-1, protection and partial restoration of cartilage matrix |
| Zhang et al. (33) | Evaluate feasibility of gene therapy by co-injecting IL-1Ra and TGF-beta1 genes into joints together with liposomes | Preclinical in vivo | Rabbit medial collateral ligament excision and medial menisectomy model of OA | Lipofectamine transfection | IL-1Ra and TGF-β1 | Inhibited cartilage damage and prevention of osteophyte formation; increased Mankin score; normalization of choncdrocyte number and order; increased type II collagen expression and ECM deposition |
| Wang et al. (34) | Determine the efficacy of local expression of IL-1Ra and sTNF-RI | Preclinical in vivo | Rabbit medial collateral ligament excision plus medial menisectomy OA model | Adenovirus: Ad-IL-1Ra and Ad-sTNF-RI | IL-1Ra and TNF-RI | Reduced cartilage lesions after IL-1Ra injection and combination, but not after sTNF-RI injection alone; reduced synovitis after combinatorial injection |
| Attur et al. (35) | Determine the effect of IL-1RII expression on modulating effects of IL-1beta | Preclinical in vitro | Human articular OA chondrocytes and synoviocytes | Adenovirus: AdRSVRII | IL-1RII | Dose-dependent decrease in response of OA chondrocytes and synoviocytes to IL-1beta (induction of NO, PGE2, IL-6, IL-8; production of IL-1beta and proteoglycan) protection of other cells in co-culture and transplant from effect of IL-1beta via sIL1-RII |
| Broeren et al. (36) | Determine the therapeutic potential of CXCL10p-IL10 in 3D micromass synovial membrane model that mimics early stage OA | Preclinical in vitro | Human OA synovial tissue | Lentivirus: CXCL10p-IL10 | IL-10 | Reduced IL-1β-induced secretion of IL-1β and IL-6 |
| Farrell et al. (37) | Evaluate the ability of hMSCS overexpressing vIL-10 to modulate the inflammation and alter OA disease progression | Preclinical in vivo | CIOA mouse model | Adenovirus: AdIL-10 | vIL-10 | A trend toward more damage in animals treated with hMSCs; reduced CD4 and CD8 T cells in the vIL-10-expressing hMSC group |
| Cameron et al. (38) | Investigate combinatorial effect of BM-MSCs and IL-10 overexpression | Preclinical in vitro | IL-1β/TNF-α-stimulated horse BM-MSCs and cartilage explant co-cultures | Adenoassociated virus: AAV-IL10 | IL-10 | Decreased T cell proliferation; decreased expression of inflammatory markers (IL-1beta, IL-6 and TNF-alpha) in stimulated cartilage explant co-cultures; no protection from ECM degradation |
| Watkins et al. (39) | Toxicology study of intra-articular hIL-10var pDNA in dogs | Preclinical in vivo | Healthy naive dogs | hIL-10var pDNA (transfection with Fugene 6) | IL-10 | Well-tolerated without toxicologic effects for up to 1.5 mg of plasmid |
| Efficacy of intra-articular hIL-10var pDNA in companion dogs | Naturally occurring OA in companion dogs | No adverse changes; decreased pain scores | ||||
| Lang et al. (40) | Optimization of a non-viral transfection system to evaluate Cox-2 controlled IL-4 expression for OA gene therapy | Preclinical in vitro | Equine chondrocytes | pN3.Cox2.IL-4 (different transfection agents) | IL-4 | Exogenous stimulation of chondrocytes transfected with pN3.Cox-2.IL-4 led to increased IL-4 expression and decreased IL-1β,−6,−8, MMP-1 and−3 expression |
| Song et al. (41) | Investigate whether IL-4 transfection and spheroid formation potentiates therapeutic effect of MSCs for OA | Preclinical in vitro | Rat IL-1β stimulated primary chondrocytes | IL-4 MSC spheroids (delivered via cationic liposomes) | IL-4 | Reduced IL-1beta induced apoptosis; lower production of osteoarthritic factors; higher production of cartilage ECM |
| Preclinical in vivo | Rat ACLT-MMx model | Enhanced attenuation of tissue regeneration; improved chondroprotective and anti-inflammatory effects; higher pain relief | ||||
| Broeren et al. (42) | Determine the effect of viral overexpression of TSG-6 in experimental OA | Preclinical in vitro | BM-derived cells differentiated into osteoclasts | Adenovirus: pShuttle-CMV-TSG-6 | TSG-6 | Inhibited osteoclast activity |
| Preclinical in vivo | Mouse CIOA model | No difference in protease activity or cartilage damage; increased ectopic bone formation | ||||
| Qiu et al. (43) | Investigate the effect of HA/CS/pCrmA on OA synoviocytes | Preclinical in vitro | IL-1β stimulated primary rat synoviocytes | Hyaluronic acid/chitosan (HA/CS) nanoparticles | pCrmA | Attenuated IL-1β mediated inflammation: normalization of increased MMP-3 and MMP-13 expression caused by IL-1β stimulation |