News > November 29, 2007

By Lauren Dayton | Staff writer

New research from the Wake Forest University Baptist Medical Center may help doctors gain insight into the causes of and potential treatments for lupus. Lupus is a chronic inflammatory disease that affects various parts of the body, especially the skin, joints, blood and kidneys.

Dr. Nilamadham Mishra, a rheumatologist and researcher on the project, explained the two studies saying that one addresses premature atherosclerosis and the other addresses premature cell death. Atherosclerosis is an arterial disease where blood flow is obstructed by the accumulation of cholesterol. It can lead to a heart attack or stroke. It is the leading cause of disability and death in lupus patients, occurring prematurely in women of reproductive age (15 to 45 years old). Mishra’s previous research showed that in mice, atherosclerosis could be prevented when he administered histone deacetylase inhibitors. Histone deacetylase is an enzyme that allows histones to bind DNA, in this case, preventing the lupus symptom-inducing DNA from being transcribed. The most recent study investigated a specific one of the 18 types of histone deacetylase, HDAC9. In this study, the lupus mice exhibited high levels of HDAC9 and had correspondingly high cholesterol accumulation in their arteries. But when the mice were genetically engineered to lack HDAC9, those mice had lower levels of cholesterol accumulation than the lupus mice. Histones are the control center for cell expression, so any medication altering histones is altering the gene conditions responsible for lupus symptoms. By using histone deacetylase inhibitors, Mishra hopes to relieve lupus by “resetting the foundation of the epigenome.”

“This study suggests that specifically targeting HDAC9 without inhibiting other histone deacetylases will be helpful for atherosclerosis,” Mishra said in a press release.

The second study addressed cell death, which occurs at an increased rate in lupus patients. This cell death can cause deposits in the kidneys or brain and is believed to cause the inflammation associated with lupus symptoms. The project studied microRNA, the fine tuner of gene expression. It found that in a study of five patients with lupus and seven healthy people of the same ages and sex over a three month period, lupus patients exhibited elevated levels of microRNA miR-16. This elevated level of miR-16 is associated with increased cell death. “We have not previously understood why cells die at an increased rate,” Mishra said in the press release. “This new study suggests both a possible mechanism and treatment.”

Looking forward, the project’s goal is to use a histone deacetylase inhibitor in a clinical trial for humans. The Food and Drug Administration has already approved one called Zolinza, which was originally developed to treat a rare form of skin cancer.

Since the government has already approved the medication, Mishra hopes the study will begin within the year.

The pilot study will gauge what dosage of Zolinza the patients can handle. After that the group can conduct a long-term study of one to two years, pending a grant from the Alliance for Lupus Research. Mishra’s wife had lupus at age seven and experienced kidney disease, joint problems and a stroke. At 17 years old she had another stroke, which left her in a wheelchair with reduced speech abilities. Mishra, who grew up in Orissa, India (a city near Calcutta) came to the United States to do lupus research. Patients like his wife “are the reason we do lupus research, it’s personal,” Mishra said.

An estimated two million Americans have lupus and 90 percent of them are women, mostly of reproductive age. The disease is much more common in African-Americans and Hispanics than in Caucasians.

According to the press release, co-researchers on the project were: John Parks, Ph.D., Eric Olson, Ph.D., and Richard St. Clair, Ph.D., all with Wake Forest, and Kerri Keiger, Ph.D., and Emmanuel Labourier, Ph.D., both with Ambion Inc. in Austin, Tex.