Local injections of small interfering RNA (siRNA) can shut down tumor necrosis factor alpha (TNF-α) production in the joints of mice with collagen-induced arthritis (CIA), according to a preliminary study in the April issue of Arthritis & Rheumatism.¹

"These results offer promise for the use of siRNA as a new strategy for therapeutic intervention in rheumatoid arthritis and may serve as a tool to study arthritis disease pathways through loss-of-function phenotypes," the researchers conclude.

RNA interference (RNAi) is a normal cellular mechanism by which genes are down regulated in a sequence-specific fashion. Artificial introduction of small double-stranded RNA molecules (siRNA) into cells or tissues triggers this mechanism, allowing for the targeted silencing of nearly any gene. The considerable therapeutic promise of this technique has not been realized, in part because of the difficulty presented by technical issues such as inducing the uptake of siRNA by cells in vivo. In the current study, electroporation was used to stimulate the transfer of siRNA into joint tissue.

Electroporation of siRNA with sequence specificity to TNF-α into the joints of mice with CIA strongly inhibited inflammation. By contrast, electroporation of nonspecific siRNA or injection of siRNA against TNF-α without electroporation failed to produce therapeutic effects, the study showed.

The new study demonstrates "the prospects for siRNA to really help improve treatment for patients with many serious diseases, including arthritis," says study author Martin C. Woodle, PhD, the chief scientific officer of Intradigm Co. in Rockville, Maryland. Intradigm is the manufacturer of the novel siRNA therapy used in the study. "We think working locally in the joint is very attractive and we can get a much better effect," than with systemic therapies, he tells CIAOMed.

"Local administration allows us a better opportunity to maximize activity and diminish adverse systemic effects," he says. Still, many questions remain. "We don't know about the duration of treatment, appropriate timing of repeated doses, or how long the effects will last," Dr. Woodle says.

 

DNA versus RNA

Those attempting to use DNA in gene therapy approaches have encountered significant difficulty. "DNA is a large molecule" and must enter the nucleus to affect the function of the cell, "but siRNA doesn't need to get into the nucleus," Dr. Woodle explains.

It may be possible to block more than one proinflammatory cytokine at a time with siRNA technology. For example, targeting TNF-α, Interleukin-1 (IL-1) and IL-4 may have a much greater effect than with the same of amount of RNA. Additionally, siRNA is a more potent and selective way of regulating gene expression than antisense RNA.

"With arthritis, this is clearly a very exciting area," Dr. Woodle says, describing the specificity of RNAi and siRNA therapy. "Because of the endogenous mechanism it's probably about as clean of a selection as possible."

Reference:

Schiffelers RM, Xu J, Storm G et al. Effects of Treatment with Small Interfering RNA on Joint Inflammation in Mice With Collagen-Induced Arthritis. Arthritis Rheum. 2005;52:1314-1318.