Toward gene therapy in rheumatoid arthritis

ABSTRACT

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease of the joint, affecting 0.24% of the global population. Many patients only respond partially or not at all to current therapies while the systemic complications of immunosuppression associated with these treatments are unacceptable. Genetic therapies for RA have the potential to improve treatments by targeting delivery to the disease site, enhancing efficacy, and avoiding adverse effects.

Areas covered

The route of administration, delivery vector, nucleic acid type, and target gene must be carefully selected to develop an effective RA gene therapy. Drawing from examples of RA gene therapies investigated in animal models and clinical trials, this review discusses how these strategies may be used to translate RA gene therapy into the clinic.

Expert opinion

Existing RA treatments lack specificity to the joint. Genetic delivery systems can include targeting properties, such as disease-responsive promoters or cell-targeting moieties, to overcome this. Non-viral vectors, in particular, can be engineered easily to possess these properties and, unlike viral vectors, display low immunogenicity. Contrary to current drugs, gene therapy can be delivered intra-articularly, providing sustained levels of the therapeutic. Targeted vectors may also achieve this, but with a single systemic injection, simultaneously delivering the therapeutic to all affected joints.

KEYWORDS:

• Rheumatoid arthritis
• gene therapy
• viral vectors
• non-viral vectors
• targeted delivery
• intra-articular delivery
• systemic delivery

Article Highlights

• Gene therapy for RA can provide high and prolonged therapeutic gene expression at the disease site, whilst avoiding systemic side effect.

• Intra-articular delivery is possible, but arthritis is polyarticular, so multiple injections would be required. Alternatively, systemic delivery could target all joints with one injection.

• Viral vectors provide adequate efficacy, but safety and immunogenicity are of concern. Non-viral vectors are safer and new formulations may provide the desired efficacy in vivo.

• Including cell-targeting properties or inducible promoters into gene delivery vectors may improve the potency of the gene therapy, prevent off-target effects and make systemic delivery feasible.

Declaration of Interest

Emily Young declares involvement with Biotechnology and Biological Sciences Research Council [grant number BB/M009513/1], GOSH NIHR BRC. Stephen Hart declares receiving funding from Cystic Fibrosis Trust, Action Research, GOSH NIHR BRC. 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 apart from those disclosed.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/M009513/1]. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.