Gene therapy for human osteoarthritis: principles and clinical translation

ABSTRACT

Introduction: Osteoarthritis (OA) is the most prevalent chronic joint disease. Its key feature is a progressive articular cartilage loss. Gene therapy for OA aims at delivering gene-based therapeutic agents to the osteoarthritic cartilage, resulting in a controlled, site-specific, long-term presence to rebuild the damaged cartilage.

Areas covered: An overview is provided of the principles of gene therapy for OA based on a PubMed literature search. Gene transfer to normal and osteoarthritic cartilage in vitro and in animal models in vivo is reviewed. Results from recent clinical gene therapy trials for OA are discussed and placed into perspective.

Expert opinion: Recombinant adeno-associated viral (rAAV) vectors enable to directly transfer candidate sequences in human articular chondrocytes in situ, providing a potent tool to modulate the structure of osteoarthritic cartilage. However, few preclinical animal studies in OA models have been performed thus far. Noteworthy, several gene therapy clinical trials have been carried out in patients with end-stage knee OA based on the intraarticular injection of human juvenile allogeneic chondrocytes overexpressing a cDNA encoding transforming growth factor-beta-1 via retroviral vectors. In a recent placebo-controlled randomized trial, clinical scores were improved compared with placebo. These translational results provide sufficient reason to proceed with further clinical testing of gene transfer protocols for the treatment of OA.

KEYWORDS:

• Articular cartilage
• chondrocyte
• clinical trials
• gene therapy
• human osteoarthritis
• vectors

Article highlights

• Gene therapy is a promising therapeutic approach for structural modification of osteoarthritis (OA).

• Principles of OA gene therapy are examined.

• Gene transfer has been chiefly used to promote cartilage regeneration.

• Significant progress has been achieved in the safety and efficiency of viral and nonviral gene delivery methods.

• Encouraging preliminary results have been reported from recent clinical gene therapy trials in knee OA.

• The main challenge for the clinical applications of gene therapy remains ensuring safety while guaranteeing effectiveness.

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Declaration of interest

Funding was received from two academic sources; the Deutsche Forschungsgemeinschaft and the Deutsche Arthrose-Hilfe. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.