Gene Therapy Approaches for Treating Rheumatoid Arthritis

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Clinical Orthopaedics and Related Research 2000; 379:S288-S299

Gene Therapy Approaches for Treating Rheumatoid Arthritis

C. Ghivizzani, PhD *; J. Oligino, PhD **; ph C. Glorioso,

PhD **; D. Robbins, PhD **; H. , PhD *

Current gene therapy approaches for treating rheumatoid arthritis have made

use of gene transfer technology as an improved delivery system for emerging

proteins and other biologicals whose activities may have therapeutic value.

Preclinical research has focused on two primary directions, evaluation of

methods of gene delivery and identification of gene products with

antiarthritic potential. Although there are reports involving systemic gene

delivery, the bulk of effort has focused on local, intraarticular

administration using ex vivo and in vivo methods. Viral-based vectors,

including adenovirus, adeno-associated virus and herpes simplex virus have

the greatest efficiency of gene delivery after intraarticular injection and

are capable of generating relevant levels of gene products in several animal

models of disease. However, there are limitations to existing generations of

these systems that currently preclude their clinical application. Those gene

products found to be efficacious in animal models of rheumatoid arthritis

include proteins that specifically block the activity of the primary

inflammatory cytokines, and include interleukin-1 receptor antagonist and

soluble receptors for tumor necrosis factor and interleukin-1. Delivery and

expression of genes encoding certain cytokines such as interleukins -4, -10,

and -13 and viral interleukin-10, that block synthesis of inflammatory

mediators and downregulate aspects of cellular and humoral immune pathways

have been found beneficial. Although significant progress has been made,

leading to Phase I clinical trials, there remain several hurdles to the

routine practice of gene therapy for treatment of rheumatoid arthritis.