Journal article
Intra-Articular Adeno-Associated Virus-Mediated Proteoglycan 4 Gene Therapy for Preventing Posttraumatic Osteoarthritis
Human gene therapy, Vol.33(9-10), pp.529-540
01/07/2022
DOI: 10.1089/hum.2021.177
PMCID: PMC9142765
PMID: 34610749
Abstract
Lubricin, a glycoprotein encoded by the proteoglycan 4 (PRG4) gene, is an essential boundary lubricant that reduces friction between articular cartilage surfaces. The loss of lubricin subsequent to joint injury plays a role in the pathogenesis of posttraumatic osteoarthritis. In this study, we describe the development and evaluation of an adeno-associated virus (AAV)-based PRG4 gene therapy intended to restore lubricin in injured joints. The green fluorescent protein (GFP) gene was inserted the PRG4 gene to facilitate tracing the distribution of the transgene product (AAV-PRG4-GFP)
. Transduction efficiency of AAV-PRG4-GFP was evaluated in joint cells, and the conditioned medium containing secreted PRG4-GFP was used for shear loading/friction and viability tests.
transduction of joint tissues following intra-articular injection of AAV-PRG4-GFP was confirmed in the mouse stifle joint in a surgical model of destabilization of the medial meniscus (DMM), and chondroprotective activity was tested in a rabbit anterior cruciate ligament transection (ACLT) model.
studies showed that PRG4-GFP has lubricin-like cartilage-binding and antifriction properties. Significant cytoprotective effects were seen when cartilage was soaked in PRG4-GFP before cyclic shear loading (
= 3). Polymerase chain reaction and confocal microscopy confirmed the presence of PRG4-GFP DNA and protein, respectively, in a mouse DMM (
= 3 per group). In the rabbit ACLT model, AAV-PRG4-GFP gene therapy enhanced lubricin expression (
= 0.001 vs. AAV-GFP:
= 7-14) and protected the cartilage from degeneration (
= 0.014 vs. AAV-GFP:
= 9-10) when treatments were administered immediately postoperation, but efficacy was lost when treatment was delayed for 2 weeks. AAV-PRG4-GFP gene therapy protected cartilage from degeneration in a rabbit ACLT model; however, data from the ACLT model suggest that early intervention is essential for efficacy.
Details
- Title: Subtitle
- Intra-Articular Adeno-Associated Virus-Mediated Proteoglycan 4 Gene Therapy for Preventing Posttraumatic Osteoarthritis
- Creators
- Dongrim Seol - Department of Orthodontics, The University of Iowa, Iowa City, Iowa, USAHyeong Hun Choe - Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, Iowa, USAHongjun Zheng - Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USAMarc J Brouillette - Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, Iowa, USADouglas C Fredericks - Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, Iowa, USAEmily B Petersen - Department of Orthopedics and Rehabilitation, The University of Iowa, Iowa City, Iowa, USAIno Song - Department of Roy J. Carver Biomedical Engineering, The University of Iowa, Iowa City, Iowa, USALeela R J Chakka - Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, Iowa, USAAliasger K Salem - Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, Iowa, USAJames A Martin - Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.33(9-10), pp.529-540
- DOI
- 10.1089/hum.2021.177
- PMID
- 34610749
- PMCID
- PMC9142765
- NLM abbreviation
- Hum Gene Ther
- ISSN
- 1043-0342
- eISSN
- 1557-7422
- Language
- English
- Date published
- 01/07/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Orthodontics; Pharmaceutical Sciences and Experimental Therapeutics; Orthopedics and Rehabilitation; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9984217431502771
Metrics
108 Record Views