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Home / Equine Research Bank / Hum Gene Ther Clin Dev / Gene Therapy for Osteoarthritis: Pharmacokinetics of Intra-A...
Human gene therapy. Clinical development2018; 29(2); 90-100; doi: 10.1089/humc.2017.142

Gene Therapy for Osteoarthritis: Pharmacokinetics of Intra-Articular Self-Complementary Adeno-Associated Virus Interleukin-1 Receptor Antagonist Delivery in an Equine Model.

Abstract: Toward the treatment of osteoarthritis (OA), the authors have been investigating self-complementary adeno-associated virus (scAAV) for intra-articular delivery of therapeutic gene products. As OA frequently affects weight-bearing joints, pharmacokinetic studies of scAAV gene delivery were performed in the joints of the equine forelimb to identify parameters relevant to clinical translation in humans. Using interleukin-1 receptor antagonist (IL-1Ra) as a secreted therapeutic reporter, scAAV vector plasmids containing codon-optimized cDNA for equine IL-1Ra (eqIL-1Ra) were generated, which produced eqIL-1Ra at levels 30- to 50-fold higher than the native sequence. The most efficient cDNA was packaged in AAV2.5 capsid, and following characterization in vitro, the virus was injected into the carpal and metacarpophalangeal joints of horses over a 100-fold dose range. A putative ceiling dose of 5 × 1012 viral genomes was identified that elevated the steady-state eqIL-1Ra in the synovial fluids of injected joints by >40-fold over endogenous levels and was sustained for at least 6 months. No adverse effects were seen, and eqIL-1Ra in serum and urine remained at background levels throughout. Using the 5 × 1012 viral genome dose of scAAV, and green fluorescent protein as a cytologic marker, the local and systemic distribution of vector and transduced cells following intra-articular injection scAAV.GFP were compared in healthy equine joints and in those with late-stage, naturally occurring OA. In both cases, 99.7% of the vector remained within the injected joint. Strikingly, the pathologies characteristic of OA (synovitis, osteophyte formation, and cartilage erosion) were associated with a substantial increase in transgenic expression relative to tissues in healthy joints. This was most notable in regions of articular cartilage with visible damage, where foci of brilliantly fluorescent chondrocytes were observed. Overall, these data suggest that AAV-mediated gene transfer can provide relatively safe, sustained protein drug delivery to joints of human proportions.
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Publication Date: 2018-06-06 PubMed ID: 29869540PubMed Central: PMC6007808DOI: 10.1089/humc.2017.142Google Scholar: Lookup
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  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the use of a genetically engineered virus (scAAV) for delivering drugs into the joints affected by osteoarthritis (OA) in horses. The study produced promising results, with the therapy enhancing the production of an anti-inflammatory agent in the affected joints without causing adverse effects.

Research Overview

  • The study is centered on osteoarthritis, a degenerative joint disease common in both humans and horses. The researchers’ focus was on the development of a new treatment method.
  • The method utilizes a self-complementary adeno-associated virus (scAAV) for the delivery of therapeutic genes directly to the afflicted joints. AAV2.5 is a hybrid virus specifically engineered for gene therapy, and it was used in this research.
  • Interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein, was the therapeutic gene product used. A custom-made scAAV was used, with plasmids containing optimized codes for creating an equine version of IL-1Ra (eqIL-1Ra).

Methodology and Results

  • After creating the requisite scAAV.eqIL-1Ra, it was injected into the carpal and metacarpophalangeal joints of horses at various doses to study its effects.
  • A dose limit was established, beyond which no additional therapeutic benefits were observed. This dose, 5×10 viral genomes, caused a >40-fold increase in the level of eqIL-1Ra in the joints compared to natural levels.
  • The elevated levels were maintained for at least 6 months, with no side effects reported. Additionally, levels of eqIL-1Ra in the blood and urine were unaffected, implying that the therapy remained localized to the afflicted joints.
  • Another derivative of the scAAV (scAAV.GFP) with green fluorescent protein was used to compare the distribution and absorption of the virus in healthy and diseased joints. Findings showed that almost all of the scAAV remained in the affected joint. In diseased joints, there was considerable increase in visible, fluorescent chondrocytes where cartilage damage was evident, indicating that the virus targeted areas with greater damage more effectively.

Concluding Remarks

  • In conclusion, the study demonstrated that using AAV for gene therapy provides a targeted, effective, and safe treatment for degenerative joint diseases like OA.
  • Although this research was horse-centric, due to the similar characteristics of human and equine OA, these findings bode well for translating this therapy for treating human patients. However, more work is needed, including human trials, to verify the therapy’s safety and effectiveness in humans.

Cite This Article

APA
Watson Levings RS, Broome TA, Smith AD, Rice BL, Gibbs EP, Myara DA, Hyddmark EV, Nasri E, Zarezadeh A, Levings PP, Lu Y, White ME, Dacanay EA, Foremny GB, Evans CH, Morton AJ, Winter M, Dark MJ, Nickerson DM, Colahan PT, Ghivizzani SC. (2018). Gene Therapy for Osteoarthritis: Pharmacokinetics of Intra-Articular Self-Complementary Adeno-Associated Virus Interleukin-1 Receptor Antagonist Delivery in an Equine Model. Hum Gene Ther Clin Dev, 29(2), 90-100. https://doi.org/10.1089/humc.2017.142

Publication

Human gene therapy. Clinical development
ISSN: 2324-8645
NlmUniqueID: 101607433
Country: United States
Language: English
Volume: 29
Issue: 2
Pages: 90-100

Researcher Affiliations

Watson Levings, Rachael S
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Broome, Ted A
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Smith, Andrew D
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Rice, Brett L
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Gibbs, Eric P
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Myara, David A
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Hyddmark, E Viktoria
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Nasri, Elham
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Zarezadeh, Ali
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Levings, Padraic P
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Lu, Yuan
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
White, Margaret E
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Dacanay, E Anthony
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Foremny, Gregory B
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Evans, Christopher H
  • 3 Rehabilitation Medicine Research Center, Mayo Clinic , Rochester, Minnesota.
Morton, Alison J
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Winter, Mathew
  • 4 Department of Small Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Dark, Michael J
  • 5 Department of Infectious Diseases and Pathology, University of Florida , Gainesville, Florida.
Nickerson, David M
  • 6 Department of Statistics and Actuarial Science, University of Central Florida , Orlando, Florida.
Colahan, Patrick T
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Ghivizzani, Steven C
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.

MeSH Terms

  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics
  • Horses
  • Humans
  • Injections, Intra-Articular
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy

Conflict of Interest Statement

C.H.E. and S.C.G. are inventors on several patents and patent applications describing cell- and gene-based therapies for arthritis and connective tissue disorders.

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