Since its inception in 1999, the Alliance for Lupus Research (ALR) has become the largest private source of funds for lupus research in the world. This year, the ALR is proud to announce that it has increased its annual grant support significantly. This increase has been due, in part, to an approximate $1.75 million commitment to a Special Initiative focused on genetics. The SLE Genetics Initiative is designed to accelerate the search for genes that put people at risk for developing systemic lupus erythematosus (SLE or lupus).
The ALR also continues to fund the very successful Target Identification in Lupus (TIL) program. This grant focuses on several critical areas of research that will yield important information for developing new, more targeted and effective therapies for lupus.
Through these important research efforts, the ALR continues its commitment to support research into the prevention, treatment and cure of lupus.
Over the past year, the ALR has embarked on the journey of reviewing the global needs for lupus research. Beginning steps have already made an important impact on redefining the ALR Research Program. One important outcome of this new and still ongoing strategic process is the launch of the first-ever consortium of lupus researchers, whose members have agreed to join forces and pool resources in the field of genetics. Members of the International SLE Genetics (SLEGEN) Consortium first gathered at an ALR-sponsored lupus genetics summit held in New York City in July 2004. After additional meetings and discussions, the group submitted a research proposal to the ALR that was reviewed and critiqued by an independent committee of scientific experts. This research proposal has resulted in the first Special Initiative being funded by the ALR.
Summary:
A major obstacle in the search for lupus susceptibility genes has been the inability of individual research teams to assemble the very large numbers of patient samples and develop the technologies that are essential for identifying genes responsible for complex genetic diseases. The SLEGEN Initiative will facilitate the search for lupus genes by pooling patient samples from the newly formed International SLE Genetics Consortium, supported by the ALR, which includes many scientists working on the genetics of human SLE. Members of the SLEGEN Consortium will contribute genetic material (DNA) collected worldwide from patients with lupus.
This project will also take advantage of revolutionary advances in the technologies for rapidly analyzing large numbers of DNA samples. These technologies will allow researchers to identify differences in the frequency of thousands of genetic variants known as SNPs (single nucleotide polymorphisms or snips) between the genomes of people who have lupus and those who do not (controls). In this study, a dense SNP-based screen will be performed on a newly available SNP chip. Analyzing the data on the SNP markers, whose locations in the genome are known, will enable researchers to identify regions of the genome containing genes involved in lupus susceptibility that are shared by patients but not controls, and that can be grouped by characteristics such as ethnicity and clinical features of the disease.
What this study means for people with lupus: By analyzing DNA sequences from large numbers of affected individuals and controls, scientists can hone in on the areas of individual chromosomes where genes involved in lupus susceptibility are likely to be found. This project will launch a new era in the search for genes in human lupus, setting the stage for future cooperative efforts in the SLEGEN Consortium. Identifying the genes involved in lupus will provide a better understanding of the disease process, which will lead to better treatments. It may also lead to improved diagnosis and prevention of lupus and make it possible to target particular treatments to those individuals most likely to benefit.
In 2005, the ALR has committed funding to 22 Target Identification in Lupus (TIL) grants: eight new research grants, two renewed grants that were launched in 2002, and twelve continuing grants started last year. Most TIL investigators are receiving research grants of approximately $500,000 over two years, while renewed grants are for as much as $1 million for two years. The research areas addressed by the TIL grants are susceptibility, pathogenesis (disease development), clinical assessment and therapy.
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Marta E. Alarcón-Riquelme, MD, PhD Uppsala University Uppsala, Sweden |
Summary: Evidence suggests that genetic factors play an important role in the development of lupus. Through genetic analyses of DNA samples from a large number of families in which one or more individuals have lupus, Dr. Alarcón-Riquelme and her colleagues have identified a specific variation in a gene known as PDCD1 that is associated with susceptibility to lupus. The PDCD1 gene is responsible for production of the PD-1 protein, which is found in several types of immune system cells. This study will provide information about the PD-1 protein and the molecular pathway in which it participates, and on how this pathway contributes to the development of lupus. Dr. Alarcón-Riquelme will also use family-based genetic approaches (similar to those used to identify the PDCD1 lupus susceptibility gene) to search for additional genes involved in lupus susceptibility.
What this study means for people with lupus: Finding genes involved in lupus susceptibility and learning how they contribute to disease development will provide information that could lead to new, more targeted treatments and bring us closer to a cure. In addition, such knowledge might someday enable doctors to tailor treatments to individual patients according to the particular genetic risk factors a person has for the disease.
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Timothy W. Behrens, MD University of Minnesota Minneapolis, Minnesota |
Summary: With previous support from the ALR, Dr. Behrens’ laboratory has shown that the activity of a group of genes regulated by interferons (proteins that have potent effects on the immune system) is dramatically increased in blood cells from lupus patients. These findings, together with additional evidence from several other laboratories, suggest that the interferon pathway may be an important target for new lupus therapies. Dr. Behrens will continue studies to identify additional genes that are abnormally regulated in lupus patients. He will use the results of these studies to develop a novel, gene-based diagnostic test for lupus and to develop laboratory tests that can predict disease flares and other adverse events in lupus patients. Dr. Behrens will also work with colleagues in academia and industry to develop potential therapies that block the actions of interferon that lead to abnormal gene activity in lupus and will conduct preliminary tests of these compounds that would set the stage for initial testing in lupus patients.
What this study means for people with lupus: Dr. Behrens’ research should lead to the development of more accurate diagnostic tests for lupus and provide doctors with better ways to monitor and predict disease activity that could help guide therapy. These studies may also lead to the development of novel therapies that block the harmful actions of interferon in people with lupus without impairing interferon’s normal, virus-fighting effects.
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John B. Harley, MD, PhD Oklahoma Medical Research Foundation and University of Oklahoma Oklahoma City, Oklahoma |
Summary: A great deal of scientific evidence indicates that our genes are important in determining who does and does not develop lupus. By studying almost 500 families in which two or more relatives have lupus, Dr. Harley and his coworkers have obtained strong evidence for several specific regions of DNA in the human genome, each of which contains a gene that can contribute a small amount to the disease. Scientists think that different gene combinations may work together to cause lupus in different individuals. In a few of the regions found so far to contribute to lupus, researchers have identified the specific genes that are responsible. The remaining genetic effects are confined to pieces of DNA known to contain a gene conferring risk for lupus, but researchers do not yet know the specific culprits from among the thousands of possibly responsible genes. Dr. Harley’s research team will apply new technologies and advances in human genomics to identify as many of these genes as is possible, and failing this goal, to get as close to them as they can. As the search for these genes proceeds, Dr. Harley will collaborate with other lupus researchers to investigate whether specific DNA sequences he finds that are strongly associated with these genes can be used as “genetic biomarkers” in tests to aid in the diagnosis, prognosis, and treatment of lupus.
What this study means for people with lupus: Finding the genes that contribute to lupus and then figuring out how they work to create the disease will provide opportunities for new strategies of diagnosis, therapy, and prevention. As part of the search for these genes, Dr. Harley will identify biomarkers that could enable improved diagnosis and monitoring of lupus and help guide decisions on the treatment of individual patients.
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Mary-Claire King, PhD University of Washington Seattle, Washington |
Summary: This genomics project will examine how DNA sequences and gene expression differ between people with lupus and people of the same age and sex without the disease. Dr. King, who is known for her work on the genetic basis of complex human diseases (diseases that result from an interplay of multiple genetic and environmental factors), will study genes that are suspects for involvement in lupus on the basis of studies of mouse models of the disease or of clinical findings in patients. Among these suspect genes for lupus are those involved in interferon production and in pathways regulated by interferon—a substance that has various effects on the immune system. Dr. King and her colleagues will examine variations in these genes in lupus patients and controls (people without lupus) from the U.S. and from areas of the world such as China, where lupus is exceptionally common.
What this study means for people with lupus: Identifying genes that are involved in susceptibility to lupus should lead to new insights on the causes of the disease. This work may also enable individually tailored therapy by identifying genetic differences among lupus patients that are associated with different responses to therapies. Ultimately, identifying the specific genetic lesions associated with lupus will enable the development of therapies designed to biochemically correct the consequences of those errors.
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Edward K. Wakeland, PhD University of Texas Southwestern Medical Center Dallas, Texas |
Summary: Dr. Wakeland will use a novel strain of lupus-prone mice to identify a gene that suppresses the development of systemic autoimmunity and fatal lupus nephritis (kidney disease). This gene, known as Sles1, can completely suppress the development of lupus-like disease in a mouse strain that normally dies by the age of 9 months. The Sles1 gene does not affect normal immune functions, but specifically suppresses the development of autoimmune responses similar to those that occur in people with SLE. Dr. Wakeland and his colleagues have localized the Sles1 gene to a very small region of the genome and will use a variety of genetic strategies to specifically identify the disease-suppressing gene. They will then pinpoint the particular molecular pathways and immune mechanisms that the gene affects to suppress fatal lupus in mice.
What this study means for people with lupus: Identifying the Sles1 gene in mice and finding the molecular and cellular processes that it influences should provide new targets for lupus therapies and may lead to the development of drugs that can suppress the disease without impairing the immune system’s normal functions. Interestingly, genetic analyses in human populations support the possibility that variations in a human version of the Sles1 gene may be involved in susceptibility to SLE.
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Franck Barrat, PhD Dynavax Technologies, Inc. Berkeley, California |
Summary: Interferon-alpha (IFN-alpha) is a substance normally involved in the immune response to viral infections. Research indicates that people with SLE have abnormally elevated serum levels of IFN-alpha that correlate with disease severity. Although the cause of this increase is still not fully understood, growing evidence links IFN-alpha production with the activation of a rare type of immune cell in the blood—the plasmacytoid dendritic cells (PDCs). Recent studies suggest that clusters of autoantibodies and molecules from the body’s own cells, known as immune complexes, can trigger IFN-alpha production in much the same way as a virus does, through the activation of specific receptors known as Toll-like receptors (TLRs). Dr. Barrat and his colleagues believe that interfering with the activation of PDCs by these Toll-like receptors will reduce the amount of IFN-alpha in the circulation and therefore reduce symptoms of lupus. The goal of this project is to evaluate a novel class of Toll-like receptor inhibitors composed of short pieces of DNA that block IFN-alpha production in PDCs by both viruses and immune complexes. Dr. Barrat and his colleagues will do experiments to better understand how these new TLR inhibitors work and how they might be used to treat lupus, including studies in mice with lupus-like disease.
What this study means for people with lupus: Decreasing IFN-alpha levels in SLE patients is predicted to reduce the symptoms of the disease. By specifically inhibiting the cells that produce IFN-alpha in response to either viruses or immune complexes, the approach being evaluated by Dr. Barrat could lead to a new and more specific treatment for lupus.
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Richard Bucala, MD, PhD Yale University New Haven, Connecticut |
Summary: Although the exact cause of lupus is unknown, researchers have learned a fair amount about the processes by which the disease damages the body. For instance, certain types of immune system proteins called cytokines normally help protect against infection, but when they are overproduced—as in lupus—they provide signals that trigger tissue damage. One cytokine that is overproduced in people with lupus is known as MIF, and it is a critical regulator of the body’s immune response. Dr. Bucala and his colleagues discovered that the human gene for MIF exists in variant forms, with some individuals producing high levels of MIF and others producing only small amounts. In this project, Dr. Bucala will determine whether people with lupus who have forms of the MIF gene that are associated with higher levels of the MIF protein have a more damaging immune system response. He will also test the potential benefit of blocking the actions of MIF in lupus-prone mice, using both a drug-like molecule that could be given orally and an antibody-based approach that would have to be given intravenously to human patients.
What this study means for people with lupus: Dr. Bucala’s work will provide information on whether blocking the actions of MIF could be a useful new strategy for treating lupus, and may accelerate the development of such therapies for use in humans. His study will also show whether patients who have a particular version of the MIF gene may be at high risk for organ damage, which could help guide individual treatment decisions and indicate who might be more responsive to therapies that target MIF.
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Philip L. Cohen, MD University of Pennsylvania Philadelphia, PA |
Summary: The constant birth and death of cells in the body is essential for the renewal of tissues and continued health. When cells die, specialized white blood cells called macrophages normally engulf, digest, and eliminate them from the body. If macrophages cannot efficiently recognize or digest dying cells, lingering cell debris may trigger autoantibody production and lead to harmful immune responses against tissues in the body, as occurs in lupus. Indeed, increasing evidence suggests that an impaired ability to eliminate dying cells swiftly from the circulation may play a role in the development of lupus. Dr. Cohen will investigate whether a series of antibodies developed in his laboratory that target and bind a protein called mer—one of the key receptors used to recognize dying cells—can boost the elimination of dying cells and reduce the inflammation associated with this process. After initial test tube and mouse experiments, Dr. Cohen will test the effects of the most promising mer-binding antibodies in mice with lupus-like disease.
What this study means for people with lupus: If Dr. Cohen’s approach shows promise in mice with lupus-like disease, this study could lead to the development of new therapies that accelerate the elimination of dying cells and prevent lupus exacerbations (disease flares) or reduce autoantibody production. This approach may provide a safer and more specific way than currently available treatments to control harmful immune responses in people with lupus.
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Mariana J. Kaplan, MD University of Michigan Ann Arbor, Michigan |
Summary: The risk of cardiovascular complications due to premature atherosclerosis (hardening of the arteries) is as much as 50 times higher in young women with SLE than in the general population. Conventional risk factors for heart disease do not account for this increased tendency. Instead, immune alterations characteristic of lupus appear to be responsible for the high rate of heart disease. Dr. Kaplan and her coworkers have found that lupus patients have increased death of the cells that line the interior of blood vessels, called endothelial cells, and that this increased cell death correlates with abnormal blood vessel function. However, they do not know what is killing these cells and whether the body can replace the dying cells with new endothelial cells in an efficient way. The main goal of this research project is to study the mechanisms by which endothelial cells are dying at an accelerated pace in lupus by looking at the role of different pathways and cells of the immune system in killing these cells. Dr. Kaplan also plans to test whether certain drugs or other treatment approaches might prevent accelerated endothelial cell death in lupus.
What this study means for people with lupus: The results of this research may provide important insights into what causes accelerated cardiovascular disease in lupus. They may also show whether specific therapeutic interventions can be designed to prevent this potentially fatal condition in people with the disease.
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Jerome Langer, PhD UMDNJRobert Wood Johnson Medical School Piscataway, New Jersey |
Summary: The causes of lupus and the factors relating to its progression are largely unknown. However, a growing body of evidence suggests that a type of immune system protein called interferon-alpha is a possible actor in the disease process. Alpha interferons are the body’s first natural defense against viruses. Normally, the body produces them only when stimulated by a signal such as a viral infection. Because recent evidence implicates abnormally elevated levels of alpha interferons in the cause or progression of lupus, it is important to develop ways to block the action of interferons. Dr. Langer will design and synthetically create novel interferon variants using molecular biology techniques and will evaluate them in laboratory tests for their ability to act as blockers of the body’s normal interferons. He will then test the ability of interferon variants that block the action of normal interferons to prevent or reduce disease in several types of laboratory mice in which interferons have been shown to promote lupus-like autoimmune disease.
What this study means for people with lupus: If the novel interferon variants created by Dr. Langer can block lupus-like disease in mice, these substances will provide researchers with powerful tools for studying how interferon is involved in lupus. Importantly, these molecules may also serve as a basis for new treatments for human lupus.
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Chandra Mohan, MD, PhD University of Texas Southwestern Medical Center Dallas, Texas |
Summary: Lupus is a complex disease caused by the interaction of multiple genetic and environmental factors. Genetic studies in mice that develop lupus-like disease have helped researchers identify at least three distinct stages of disease development. By studying genetically simplified mouse models of lupus, Dr. Mohan and his colleagues have identified specific regions in the mouse genome that contain one or more genes responsible for each of these three stages. They have also identified the particular types of cells that are affected in these three successive stages of disease development. In this study, Dr. Mohan will build on these findings to define in detail the molecular pathways involved in the different stages of disease development. To achieve these goals, he will use a powerful approach known as microarray analysis.
What this study means for people with lupus: These studies will identify key pathways and molecules involved in the development of lupus. Through this detailed analysis in simplified mouse models of the disease, Dr. Mohan expects to uncover potential targets for new therapies that could then be pursued further in studies of people with lupus.
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Chaim Putterman, MD Albert Einstein College of Medicine Bronx, New York |
Summary: TWEAK is a newly identified molecule that can cause inflammation and may play a role in lupus. TWEAK levels are increased in mice with lupus-like disease and in one type of white blood cell (T cells) from lupus patients. Dr. Putterman and his colleagues have recently found that the TWEAK receptor (known as Fn14)—a molecule on the surface of cells with which TWEAK must interact to carry out its effects—is present on certain kidney cells in lupus-prone mice. Treatment of these kidney cells with TWEAK triggers the production of substances that are important in kidney inflammation (nephritis) in lupus. In this project, Dr. Putterman will investigate the role of TWEAK and Fn-14 in the development of lupus and lupus kidney disease in mice and humans. He will also explore whether a novel antibody that targets TWEAK and blocks its actions may be helpful in treating kidney disease or other complications of SLE in lupus-prone mice.
What this study means for people with lupus: These studies may provide a better understanding of how the kidneys are targeted and damaged in people with lupus nephritis. They may also provide a new approach to treating lupus that could be tested in people with the disease.
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Stephen Tomlinson, PhD Medical University of South Carolina Charleston, South Carolina |
Summary: Complement is the term given to a collection of blood proteins that form an important part of the immune system. Under normal conditions, complement has various protective roles, such as defense against invading microorganisms and modulation of immune responses. However, in lupus, complement inappropriately targets tissues in the patient’s body and plays a key role in causing inflammation and tissue damage. This project will investigate the role of different parts of the complement system in the pathogenesis (development) of lupus. The goals are to develop novel types of therapies that will inhibit complement only at the site of tissue damage and to test the safety and effectiveness of these therapies in mouse models of lupus. Promising results have been obtained in experiments with systemic (body-wide) complement inhibitors for the treatment of inflammation, but their use for treating lupus may exacerbate symptoms, since complement is also involved in normal protective processes that are important in people with lupus.
What this study means for people with lupus: Strategies to target complement inhibitors to the site of complement-associated tissue damage could provide significant improvements in effectiveness and safety over systemic complement inhibitors. If therapeutic studies in mouse models of lupus are successful, Dr. Tomlinson and his colleagues will make plans to translate this approach for testing and use in lupus patients.
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Joseph M. Ahearn, MD University of Pittsburg Pittsburgh, Pennsylvania |
Summary: In preliminary studies funded in part by the ALR, Dr. Ahearn and his colleagues developed blood tests that show promise for more accurately diagnosing lupus and monitoring disease activity. These tests measure the levels of certain proteins that are deposited on the surface of red blood cells. The proteins are part of the complement system—a group of blood proteins that contribute to inflammation and tissue damage in lupus. In the next phase of this project, Dr. Ahearn and his coworkers will measure complement proteins on red blood cells in samples from a large number of people with lupus at multiple time points over a two-year period. This large clinical study will evaluate the ability of these blood tests to diagnose lupus and monitor disease activity, with the goal of developing the tests for routine use in settings such as a doctor’s office or medical laboratory.
What this study means for people with lupus: One of the main obstacles to developing better therapies for lupus is the lack of biomarkers for the disease—that is, biological molecules or other factors that can be used to measure the progress of disease and the effects of treatment. New biomarkers are also needed to improve the diagnosis of lupus. Dr. Ahearn’s study shows promise for yielding biomarkers that can increase the, accuracy of lupus diagnosis, provide better ways of measuring the response to therapies being tested in clinical trials for people with lupus, and allow earlier and more accurate detection of disease flares, enabling better treatment of the disease.
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Pojen P. Chen, PhD University of California, Los Angeles Los Angeles, California |
Summary: About 20 to 30 percent of people with lupus have a condition called antiphospholipid syndrome (APS), which is associated with recurrent miscarriage in women and abnormal blood clotting that can lead to heart attacks, strokes, and other serious problems. People with APS have autoantibodies directed against phospholipids—molecules that are a basic component of all tissues and organs. Yet only a minority of people with these antiphospholipid antibodies (aPL) will develop problems, and current diagnostic tests cannot accurately identify those patients who are at risk. Dr. Chen is continuing work to identify compounds that can be used to develop novel diagnostic tests for specific forms of aPL that put an individual at risk of disease complications. Scientists refer to these harmful forms of aPL as pathogenic (disease-causing) antibodies.
What this study means for people with lupus: Because most anti-clotting drugs are potentially hazardous, patients with antiphospholipid antibodies are usually not treated until after life-threatening events occur. Developing new diagnostic tests that can identify those people with aPL who are at risk for serious complications would enable physicians to start preventive treatment before problems occur.
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Virginia Pascual, MD Baylor Institute for Immunology Research Dallas, Texas |
Summary: SLE is characterized by periods of active disease, called flares, and periods of remission. Unfortunately, laboratory tests to predict the development of flares are not available. Using novel techniques to analyze gene activity in patient blood samples, Dr. Pascual and her colleagues have identified a series of genes that distinguish adults and children with lupus from both healthy individuals and people with other autoimmune diseases. The activity or expression of some of these genes—including genes that are regulated by interferon-alpha, a substance that has potent effects on the immune system—correlates with SLE disease activity better than any currently available markers of disease activity. The goals of this study are to further evaluate these genes as predictors of disease activity and to develop simple laboratory tests that could be used to detect these markers of disease in a clinical setting.
What this study means for people with lupus: Laboratory tests that can accurately predict and monitor lupus disease activity could be used to monitor the response to treatment and help evaluate novel therapies. Such tests could also help doctors decide when to treat patients more aggressively to prevent the development of disease flares, rather than treating after damage has occurred. These studies will also further researchers’ understanding of the basic mechanisms that cause lupus, which could lead to the development of new, more targeted therapies.
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Robert A. Eisenberg, MD University of Pennsylvania Philadelphia, Pennsylvania |
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R. John Looney, MD University of Rochester Rochester, New York |
Summary: Small pilot studies conducted separately by Drs. Eisenberg and Looney have shown that rituximab, a drug that has been used extensively to treat certain cancers, is reasonably well tolerated by SLE patients and may have some effectiveness in treating the disease. Rituximab is a genetically engineered antibody that targets B cells and eliminates them from the circulation. B cells are a type of white blood cell that plays a central role in the development of lupus. Based on the preliminary findings in SLE patients, a leading medical biotechnology company plans to conduct a formal clinical trial to test the effectiveness of this treatment in lupus patients with kidney involvement. In conjunction with this clinical trial, Drs. Eisenberg and Looney will conduct a number of immunological studies that will provide new information on the basic mechanisms of disease in SLE—in particular, the role of B cells—and on how depletion of B cells in lupus patients might be effective as a therapy.
What this study means for people with lupus: Previous ALR support for research on rituximab spurred the biotechnology industry’s interest in pursuing clinical trials of this drug for SLE. Knowledge gained from the studies by Drs. Eisenberg and Looney will be important in designing future treatment approaches for lupus. Their work will help determine how best to use rituximab, what other therapies that target B cells might be effective, and how these various approaches could be combined to yield the greatest benefits. These studies will enhance the value of the clinical trial for the patients involved and for all other SLE patients.
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Gary D. Glick, PhD University of Michigan Ann Arbor, Michigan |
Summary: As part of efforts to find better therapies for lupus, Dr. Glick’s laboratory screened a series of compounds to look for those that would specifically kill immune cells involved in lupus. These studies led to the discovery of a new compound, known as Bz-423, that is effective at treating kidney disease (nephritis) in two mouse models of human lupus. Unlike current lupus drugs, Bz-423 suppressed the autoimmune response in mice with lupus-like disease without adverse side effects. Subsequent studies showed how this compound kills cells and identified its cellular target. Although Bz-423 is effective, it has certain chemical properties that would make it difficult to use in humans. Therefore, the goal of Dr. Glick’s project is to design and synthesize compounds chemically related to Bz-423 that have optimized properties for human testing.
What this study means for people with lupus: Current therapies for lupus nephritis kill healthy cells along with those that cause disease. Developing chemically modified forms of Bz-423 that have improved properties for human use and retain their effectiveness would provide potential new drugs specific for lupus. After further testing, the most promising of these drug candidates could be evaluated in clinical trials in people with lupus.
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Nilamadhab Mishra, MD Wake Forest University Winston-Salem, North Carolina |
Summary: Studies in both mice and people with lupus suggest that the disease process may be associated with specific changes in the normal patterns of gene activity. Such changes may result in part from abnormalities in the actions of enzymes called histone deacetylases (HDACs), which cells use to turn certain genes on and off. In previous studies supported in part by the ALR, Dr. Mishra showed that two experimental drugs that inhibit the actions of HDACs have beneficial effects in mice with lupus-like kidney disease. These and other findings suggest that abnormal HDAC activity may play a role in lupus. In the next phase of this project, Dr. Mishra will do experiments to find out which of the many known HDACs play an important role in the disease process in mice. As part of this effort, he will test the effects of certain HDAC inhibitors in mice with lupus-like disease. These compounds selectively block the actions of only certain HDACs, and are already used to treat some human disorders.
What this study means for people with lupus: By providing a better understanding of the role of HDACs in causing lupus-like disease, this study could lead to the development of new, more targeted treatments for human lupus that block the actions of specific HDACs and have fewer side effects. This study will also show whether certain HDAC inhibitors that have already been shown to be safe in humans have potential for treating people with lupus.
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Charles A. Nicolette, PhD Argos Therapeutics, Inc. Durham, North Carolina |
Summary: Currently, people with lupus are treated with a variety of drugs that have only partial benefit and have damaging side effects that limit their use. Lupus, particularly in children, can be an aggressive disease and better, more specific treatments with fewer side effects are urgently needed. Previous ALR-funded studies led by Dr. Jacques Banchereau (Baylor Institute for Immunology Research, Dallas, Texas) provide strong evidence that interferon-alpha—a protein that has multiple effects on the immune system—contributes to immune system abnormalities in adults and children with lupus. To translate this discovery into a useful product, antibodies have been developed that bind to and neutralize the biological activity of interferon-alpha from the blood of lupus patients in test-tube experiments. Dr. Nicolette, in collaboration with Dr. Banchereau and colleagues, is developing an antibody product suitable for human use that targets interferon-alpha and blocks its effects on immune cells. The ultimate aim of their study is to test the hypothesis that neutralizing interferon-alpha will provide significant relief to lupus patients, with an expectation that side effects will be far less than with current treatments.
What this study means for people with lupus: If initial studies with an antibody that blocks interferon-alpha activity in lupus patients yield promising results, they could lead to the development of a new, more specific and effective therapy for both young people and adults who have lupus.
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Michelle A. Petri, MD, MPH Johns Hopkins University Baltimore, Maryland |
Summary: Cardiovascular disease, specifically from atherosclerosis (hardening of the arteries), is a major cause of death and a serious longterm complication in people with lupus. Recent studies show that atherosclerosis develops earlier and progresses faster in lupus patients than in otherwise healthy people, and suggest that chronic inflammation may play a key role in the increased risk of atherosclerosis in these patients. Although a group of prescription drugs called statins are commonly used to reduce high cholesterol and prevent atherosclerosis in the general population, these drugs have never been specifically tested in people with lupus. This study will test the effectiveness of one statin drug, atorvastatin, in slowing the development and progression of atherosclerosis in lupus patients by comparing several measures of atherosclerosis in people taking the drug and people taking a placebo (inactive pill). Because research has recently shown that statins have anti-inflammatory effects in addition to lowering cholesterol, Dr. Petri will also examine whether atorvastatin has a beneficial effect on overall disease activity.
What this study means for people with lupus: If statins are shown to slow the progression of atherosclerosis in people with SLE, these drugs will provide an important approach to help prevent one of the most debilitating and life-threatening complications of the disease. Furthermore, the drugs may play a role in modifying the disease process as a whole, thereby offering a new option for treating the disease and its many other complications.
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Gregg J. Silverman, MD University of California, San Diego La Jolla, California |
Summary: In the first phase of this project, Dr. Silverman showed that a protein made by staphylococcus aureus (staph) bacteria acts as a selective B-cell toxin in mice, killing targeted B cells without harming other cells in the body. Preliminary studies also indicated that this bacterial protein, called staphylococcal protein A (SpA), could selectively target and eliminate B cells in non-human primates. B cells are white blood cells that normally help the immune system fight infections. They also play a central role in the development of lupus, producing antibodies that attack the body’s own tissues. In the second phase of this project, Dr. Silverman will study the detailed mechanisms by which SpA causes targeted B-cell death and examine whether SpA and rituximab act through common pathways to trigger the death of B cells. Rituximab is a genetically engineered antibody that also targets and kills B cells and is being examined as a potential therapy for lupus. However, researchers do not have a clear understanding of how rituximab works.
What this study means for people with lupus: Current therapies for lupus act mainly by suppressing the immune system, and they often result in increased susceptibility to infection or other adverse side effects. Because SpA attacks only certain B cells in the immune system in primates as well as mice, it might be used to selectively eliminate those B cells involved in lupus, leaving infection-fighting B cells unharmed. In addition, Dr. Silverman’s studies comparing how SpA and rituximab work to selectively target and kill B cells should provide insights that will help develop safe and practical new approaches for treating SLE.
To download a pdf of the 2005 ALR grant recipients, click here.
Target Identification in Lupus 2004
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