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Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis.

Authors
  • Stone, Adrianne1, 2
  • Grol, Matthew W1
  • Ruan, Merry Z C1
  • Dawson, Brian1
  • Chen, Yuqing1
  • Jiang, Ming-Ming1
  • Song, I-Wen1
  • Jayaram, Prathap3, 4
  • Cela, Racel1
  • Gannon, Francis5
  • Lee, Brendan H L1
  • 1 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
  • 2 2 Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas.
  • 3 3 H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.
  • 4 4 Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas.
  • 5 5 Department of Pathology, Baylor College of Medicine, Houston, Texas.
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Feb 01, 2019
Volume
30
Issue
2
Pages
225–235
Identifiers
DOI: 10.1089/hum.2018.106
PMID: 30070147
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone. Employing two surgical techniques to model mild, moderate and severe posttraumatic OA, we found that combined delivery of helper-dependent adenoviruses (HDVs), expressing IL-1Ra and PRG4, preserved articular cartilage better than either monotherapy in both models as demonstrated by preservation of articular cartilage volume and surface area. This improved protection was associated with increased expression of proanabolic and cartilage matrix genes together with decreased expression of catabolic genes and inflammatory mediators. In addition to improvements in joint tissues, this combinatorial gene therapy prolonged protection against thermal hyperalgesia compared to either monotherapy. Taken together, our results show that a combinatorial strategy is superior to monotherapeutic approaches for treatment of posttraumatic OA.

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