Self-Complementary Adeno-Associated Virus–Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model

Levings, Rachael S. Watson; Smith, Andrew D.; Broome, T.A.; Rice, Brett L.; Gibbs, Eric P.; Myara, David A.; Hyddmark, E. Viktoria; Nasri, Elham; Zarezadeh, Ali; Levings, Padraic P.; Lü, Yuan; White, Margaret; Dacanay, E. Anthony; Foremny, Gregory B.; Evans, Christopher H.; Morton, Alison J.; Winter, Mathew; Dark, Michael J.; Nickerson, David M.; Colahan, Patrick T.; Ghivizzani, Steven C.

doi:10.1089/humc.2017.143

Cited by 35 publications

(44 citation statements)

References 37 publications

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“…There are many serotypes of AAV and appropriate rAAV vectors are chosen for specific applications based on tissue tropism and transduction efficiency 13–16 . In horses, rAAVs have predominantly been used for intra‐articular delivery of anti‐inflammatory or anabolic genes such as IL1‐RA, 14,15,17,18 IGF‐1, 19,20 and most recently, IL‐10 21 …”

Section: Introductionmentioning

confidence: 99%

Detection of intra‐articular gene therapy in horses using quantitative real time PCR in synovial fluid and plasma

Haughan

Jiang

Stefanovski

et al. 2020

Drug Testing and Analysis

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Gene therapy promotes the expression of missing or defective genes and can be curative following administration of a single dose. Gene therapy is prohibited in equine athletes by regulatory bodies due to the high potential for abuse and novel analytical methods are needed for detection. The goal of this study was to detect the administration of an experimental gene therapy: a recombinant adeno‐associated viral vector (rAAV) carrying a transgene for the anti‐inflammatory cytokine IL‐10 (rAAV‐IL10). Twelve horses were randomly assigned to receive an intra‐articular injection of rAAV‐IL10 or phosphate buffered saline (vehicle) into a middle carpal joint. Plasma and synovial fluid were collected on days 0, 1, 2, 4, 7, 14, 28, 56, and 84. Primer pairs were designed to detect two unique regions of rAAV. Using quantitative real time PCR, both sets of primers detected rAAV for 14–28 days in joints and up to 4 days in plasma, in all six treated horses. In synovial fluid, rAAV was detected on day 56 in 4/6 horses by both primer sets, and on day 84 in 1/6 horses by one primer set. In plasma, rAAV was detected for 7 days in 5/6 horses, 14 days in 2/6 horses, and 28 days in 1/6 horses by one primer set, and was detected for up to 14 days in 1/6 horses by the other primer set. This study is the first to validate that quantitative real time PCR can be used to systemically detect the local administration of a gene therapy product to horses.

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Section: Introductionmentioning

confidence: 99%

Detection of intra‐articular gene therapy in horses using quantitative real time PCR in synovial fluid and plasma

Haughan

Jiang

Stefanovski

et al. 2020

Drug Testing and Analysis

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“…Consequently, horses diagnosed with OA are often retired or euthanised.There is a broad spectrum of treatments for equine OA. Most of them are anti-inflammatory and pain-relieving without a true disease-modifying effect, although regenerative medicine in regard to equine OA is a rapidly evolving area [5][6][7][8]. Two of the drug groups most commonly used for treating the symptoms related to equine OA are nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroids, often in combination.…”

mentioning

confidence: 99%

Identification and Quantification of Transient Receptor Potential Vanilloid 1 (TRPV1) in Equine Articular Tissue

Braucke

Frederiksen

Berg

et al. 2020

Animals

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Joint pain and osteoarthritis (OA) are some of the most common causes of lameness in horses, and most of the available treatments focus on symptomatic relief without a disease-modifying effect. TRPV1 is a potential target for treating joint diseases, including OA, and the present study aims to investigate if the TRPV1 receptor is present in equine articular tissue and determine whether the number of receptors is upregulated in joint inflammation. Metacarpo/metatarsophalangeal (MCP/MTP) joints from 15 horses euthanised for reasons unrelated to this study were included. Based on synovial fluid analysis, macroscopic evaluation, and magnetic resonance imaging (MRI), joints were divided into two groups: healthy joints and joints with pathology. ELISA analysis was performed on synovial tissue harvested from all joints. TPRV1 was found in all joints. The mean concentration of TRPV1 compared to total protein in healthy joints (8.4 × 10 −7 ng/mL) and joints with pathology (12.9 × 10 −7 ng/mL) differed significantly (p = 0.01, t-test with Welch correction). Quantitative real-time reverse transcriptase PCR analysis was performed on RNA isolates from synovial tissue from all joints. TRPV1 mRNA expression ratio normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in healthy joints (0.16 (SD: 0.19)) and joints with pathology (0.24 (SD: 0.14)) did not differ significantly (p = 0.43, t-test with Welch correction). mRNA expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) was very low for both groups. In conclusion, TRPV1 was detected both on mRNA and the protein level, with a higher expression of TRPV1 in samples from joints with pathology. Future studies will determine the clinical potential of equine TRPV1 as a target in the management of joint pain and inflammation.Animals 2020, 10, 506 2 of 15 described aetiology is trauma-either as a single event or as a series of microtrauma. This will induce an inflammatory response, which, in turn, will drive the process of articular cartilage breakdown and remodelling of the surrounding bone [4]. Consequently, horses diagnosed with OA are often retired or euthanised.There is a broad spectrum of treatments for equine OA. Most of them are anti-inflammatory and pain-relieving without a true disease-modifying effect, although regenerative medicine in regard to equine OA is a rapidly evolving area [5][6][7][8]. Two of the drug groups most commonly used for treating the symptoms related to equine OA are nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroids, often in combination. NSAIDs are predisposing for gastrointestinal ulceration and are potentially nephrotoxic, and corticosteroids are potentially chondrotoxic [9][10][11][12]. In human medicine, so-called disease-modifying osteoarthritis drugs (DMOADs) are being investigated in an attempt to stop the disease progression, as well as being pain-relieving and anti-inflammatory. However, an effective disease-modifying drug has not yet been developed [13].Several authors point to the ...

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“…The OCF model was adapted to determine if the levels of equine IL-1Ra generated by AAV gene transfer were sufficient to mediate an appropriate biologic response [92]. Following creation of the osteochondral fracture, the OCF joints in the treated animals were injected with 5 × 10 12 vg AAV.eqIL-1Ra, while controls animals received an equal volume of saline.…”

Section: Aaveqil-1ra Delivery and Expression In The Ocf Modelmentioning

confidence: 99%

Gene Therapy for the Treatment of Equine Osteoarthritis

Levings¹,

Smith²,

Levings³

et al. 2020

Equine Science

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Osteoarthritis (OA) is the predominant cause of lameness in horses. As in humans, the clinical symptoms of equine OA are persistent pain and dysfunction of the affected joint. Its pathology is similarly marked by progressive deterioration of the articular cartilage, subchondral bone sclerosis, marginal osteophytes, soft tissue inflammation and joint effusion. Disease pathogenesis is mediated by elevated levels of inflammatory cytokines and proteolytic enzymes in the articular tissues and synovial fluid. Existing pharmacologic agents can alleviate OA joint pain; none are able to inhibit erosive disease progression. As several gene-based treatments for human disease have received approval by the Food and Drug Administration (FDA), the transition to veterinary medicine will almost certainly follow. Several viral vector systems have demonstrated highly efficient gene transfer to the equine joint, enabling expression of therapeutic transgenes at efficacious levels for well over a year. Because of its large size, the equine joint is well suited to studies of genebased therapies for arthritic disease. The forelimb joints are vulnerable to OA onset, and treatment and diagnostic modalities are the same in humans and horses. Here, we discuss the various gene-transfer approaches under investigation and the current progress toward the development an effective gene therapy for equine OA.

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Self-Complementary Adeno-Associated Virus–Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model

Cited by 35 publications

References 37 publications

Detection of intra‐articular gene therapy in horses using quantitative real time PCR in synovial fluid and plasma

Detection of intra‐articular gene therapy in horses using quantitative real time PCR in synovial fluid and plasma

Identification and Quantification of Transient Receptor Potential Vanilloid 1 (TRPV1) in Equine Articular Tissue

Gene Therapy for the Treatment of Equine Osteoarthritis

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