DNA-Like Drugs Target Systemic Lupus Erythematosus

A potential new treatment for systemic lupus erythematosus (SLE) has been demonstrated in a mouse model of this chronic autoimmune syndrome.

Investigators from the University of Iowa (Ames, USA) and at Boston University School of Medicine (MA, USA) worked with lupus-prone MRL-Faslpr/lpr mice as well as with isolated mouse and human cell lines growing in tissue culture.

The investigators treated the mice and cell lines with novel DNA-like compounds called R inhibitory oligonucleotides (INH-ODNs). These short chains of nucleotides had previously been shown to inhibit the activation of autoimmune B-cells by blocking intracellular nucleic acid-sensing receptors, Toll-like receptor (TLR) 7 and TLR9, which play important roles in the pathogenesis of SLE.

Results published in the May 28, 2009, issue of the journal Arthritis Research and Therapy revealed that in the mouse model the compounds demonstrated significant effectiveness by delaying death and reducing kidney damage. The INH-ODNs had 10- to 30-fold higher inhibitory potency when autoreactive B cells were activated through the B-cell receptor (BCR) and associated TLR7 or TLR9 than when stimulation occurred via non-BCR-engaged TLR7/9. Inhibition of TLR9 required the presence of both CCT and GGG triplets in an INH-ODN, whereas the inhibition of the TLR7 pathway appeared to be sequence-independent but dependent on the phosphorothioate backbone.

"The increased potency of class R inhibitory oligonucleotides for certain cells involved in lupus flare-ups could help patients by providing specific inhibition, yet allowing them to generate a protective immune response when needed,” said first author Dr. Petar Lenert, assistant professor of internal medicine at the University of Iowa. "With further testing, we hope that class R inhibitory oligonucleotides may become another weapon in the fight against lupus.”

Related Links:
University of Iowa
Boston University School of Medicine