Israeli and American scientists have made a significant step towards a cure for systemic lupus erythematosus (SLE), in which nine out of 10 patients are female. SLE is characterized by a wide profile of autoantibodies, causing inflammation and irreversible organ damage.
Most people with lupus develop the disease between the ages of 15 and 44, but the symptoms last lifelong. The Lupus Foundation of America estimates that 1.5 million Americans – and at least five million people worldwide – have a form of SLE, which strikes mostly women of childbearing age but also men, children, and teenagers.
People with lupus can experience significant symptoms, such as pain, extreme fatigue, hair loss, cognitive problems and physical impairments that affect every facet of their lives. Many also suffer from cardiovascular disease, strokes, disfiguring rashes and painful joints – and it can sometimes be fatal – but for others, there may be no visible symptoms.
The risk of developing SLE is, at least in part, genetic, but it is a complex genetic illness with no clear pattern of inheritance. Indeed, in some cases. Joint and muscle pain is often the first sign of lupus. This pain tends to occur on both sides of the body at the same time, particularly in the joints of the wrists, hands, fingers, and knees. The joints may look inflamed and feel warm to the touch.
During a recent 20-year period, the annual number of SLE deaths in the US rose from 879 to 1,406, and the number of lupus deaths per 10 million people rose from 39 to 52. Each year, the death rate has been more than five times higher for women than men, and more than three times higher for blacks than whites.
But there is hope. Researchers at Ben-Gurion University of the Negev in Beersheba, the Israeli National Institute for Biotechnology in the Negev (NIBN) and US National Institutes of Health have identified in mice the path mitochondrial DNA use to exit cells in order to trigger autoimmune diseases and how to block that escape route. The researchers demonstrated their concept relating to SLE and their findings in a recent issue of the prestigious journal Science.
Prof. Varda Shoshan-Barmatz in collaboration with a group from NIH, headed by Dr. Jay Chung, have had remarkable success in lupus mouse models so far and are beginning to take the next steps towards other diseases.
The team discovered a unique mechanism involving the mitochondrial protein voltage-dependent anion channel (VDAC1) in the exit of mitochondrial factors such as pro-cell death proteins and mitochondrial DNA (mtDNA) that trigger some autoimmune diseases. When VDAC1 is overexpressed, as found in several diseases, a large pore composed of several VDAC1 units is formed, allowing the release of pro-cell death factors and mtDNA.
Shoshan-Barmatz has developed a molecule called VBIT-4 that inhibits cell death and restores mitochondrial functions associated with several diseases. That novel molecule prevents the formation of the large pore caused by VDAC1 overexpression and thereby prevents the exit of these factors from the mitochondria. Without the release of these factors, cell death in diseases such as Alzheimer’s and Parkinson’s diseases or mtDNA release like in SLE is avoided.
Moreover, they showed that inhibition of VDAC1 by a small molecule newly developed by NIBN (covered by several patents), resulted in substantial improvement in pathological aspects of the disease
“Since the results thus far with lupus have been so promising, we believe that the molecule will be beneficial with regards to other diseases such as Alzheimer’s, Crohn’s and ulcerative colitis – as our preliminary results already support,” said Prof. Varda Shoshan-Barmatz of the BGU’s department of life sciences and the founding director of NIBN.
Mitiochrondrial DNA has also been found in the plasma of patients of other autoimmune diseases such as Colitis and Crohn’s diseases. This gives rise to new hope that this VDAC1-modulating molecule will lead to more therapies in an expanding list of other diseases that are associated with cell death or release of DNA from the mitochondria.
“Our breakthrough is identifying a new pathway for the exit of mitochondrial DNA that we can either trigger under controlled conditions or inhibit using our novel molecule that we specifically developed to prevent the formation of this pathway,” she continued.