The strategic plan of the Alliance for Lupus Research (ALR) is focused on five critical areas of research that will yield important knowledge for developing new, more targeted and more effective therapies for systemic lupus erythematosus (SLE, or lupus): susceptibility, pathogenesis (disease development), inflammation and damage, clinical assessment, and treatment/therapies. Following are summaries of the 21 research grants currently funded by the ALR in these five areas.
The 2004 ALR grants program is the largest ever; it includes renewed support for seven research projects that were launched in 2000 and 2001, new awards to eight investigators, and continuing support to six additional researchers. Most ALR investigators are receiving research grants of $500,000 over two years, while several grants are for as much as $1 million for two years. Since its inception in 1999, the Alliance for Lupus Research has become the largest private funder of lupus research in the U.S.
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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 its normal, virus-fighting effects.
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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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Mary K. Crow, MD Hospital for Special Surgery New York, New York |
Summary: Evidence from a number of studies suggests that abnormally high levels of interferon-alpha may contribute to the development of lupus. Interferon-alpha is a protein made by white blood cells, typically in response to viral infections. There are many different forms (subtypes) of interferon-alpha, and each form may have somewhat different effects on the immune system. Dr. Crow is investigating whether specific forms of interferon-alpha are involved in lupus, and whether blocking the actions of these interferon-alpha subtypes can correct immune abnormalities that occur in people with lupus.
What this study means for people with lupus: If scientists can identify specific forms of interferon-alpha that play an important role in lupus, they may be able to develop treatments that target only those forms that contribute to the disease.
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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. 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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Brian L. Kotzin, MD University of Colorado Denver, Colorado |
Summary: This study will attempt to learn more about a gene called Ifi202, which has been identified as an important factor in disease susceptibility in a mouse model of lupus. The activity of the Ifi202 gene is controlled by type I interferons (including interferon-alpha), which are proteins made by white blood cells and thought to play a role in the development of lupus. Using mice that develop a lupus-like disease, Dr. Kotzin is testing whether lupus can be prevented and suppressed by blocking the actions of type I interferons. He is also examining the role of the human version of the Ifi202 gene in lupus.
What this study means for people with lupus: Dr. Kotzin hopes to provide new evidence that type I interferons contribute to the development of lupus, and that the Ifi202 gene is involved. This research may provide the basis for developing more targeted lupus treatments that work by blocking the actions of type I interferons.
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Robert Carter, MD University of Alabama at Birmingham Birmingham, Alabama |
Summary: White blood cells known as B lymphocytes, or B cells, play a central role in the development of lupus and are an important target for new treatments. Dr. Carter and his colleagues have shown that antibodies designed to block the effects of a molecule critical for B-cell survival, known as BLyS (B lymphocyte stimulator), are effective at eliminating B cells. The next phase of Dr. Carter’s research is focusing on the development and testing of antibodies that selectively target certain actions of BLyS and eliminate only those B cells that contribute to lupus, while sparing normal B cells. Normal B cells are a crucial part of the immune system, helping to defend against infection by bacteria and viruses.
What this study means for people with lupus: New approaches that target B cells offer promising new prospects for more effective and targeted treatments for people with lupus. Dr. Carter’s studies are laying the groundwork for more refined therapies that target only disease-causing B cells, preserving the normal B cells that provide immunity against viruses and bacteria. Results emerging from ALR-funded research on BLyS have had a major impact on the activity and interest of the biotechnology industry in this area.
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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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Jeffrey V. Ravetch, MD, PhD The Rockefeller University New York, New York |
Summary: Dr. Ravetch has been studying the effects of a protein called FcgammaRIIB (Fc_RIIB) on the development of lupus in mice. Fc_RIIB proteins are found on the surface of cells and serve as docking sites (receptors) for many other factors that influence the immune system. Dr. Ravetch has shown that mice lacking the Fc_RIIB protein develop a lupus-like illness and that Fc_RIIB helps prevent abnormal immune responses that can lead to lupus-like disease in mice. To find out whether reduced levels of Fc_RIIB are also involved in causing lupus in humans, Dr. Ravetch is comparing the levels of this protein in white blood cells from people with and without lupus, using a novel reagent developed in his laboratory.
What this study means for people with lupus: If a deficiency of Fc_RIIB on cells of the immune system plays a role in the development of lupus in people, as it does in mice, then strategies that correct this deficiency might provide another way of treating 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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Jane Salmon, MD Hospital for Special Surgery New York, New York |
Summary: Recurrent miscarriage (pregnancy loss) is a serious problem for some women with lupus, and in many cases is due to a condition known as antiphospholipid syndrome (APS). In studies that challenged conventional thinking, Dr. Salmon and her colleagues found that a key step leading to pregnancy loss in mice with APS is the activation of “complement”—a group of blood proteins that can cause inflammation and tissue damage. She showed that blocking the activation of one particular complement protein, known as complement component C5, prevents pregnancy loss in a mouse model of APS. In preparation for testing a similar approach in APS patients, Dr. Salmon is doing further studies in mice to learn more details about the mechanisms of tissue damage and pregnancy loss in APS, including the role of C5 and related proteins. She will also search for factors that predict the risk of miscarriage in women with lupus and APS.
What this study means for people with lupus: Dr. Salmon’s research will provide a clearer, more detailed understanding of the causes of recurrent miscarriage in lupus and APS. This work, which has opened the door to human studies, may pave the way toward new, more targeted and more effective treatments for preventing recurrent miscarriage and other pregnancy complications associated with lupus and with APS.
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Joseph M. Ahearn, MD University of Pittsburg Pittsburgh, Pennsylvania |
Summary: The typical course of lupus includes periods of active disease, called flares, and periods of wellness, or remission. Lupus flares can lead to irreversible organ damage, so it is important to detect flares early and begin appropriate treatment. However, the laboratory tests that doctors use to monitor disease activity in people with lupus are not always accurate. Dr. Ahearn is doing studies to show that a simple, rapid, and inexpensive test that he has developed is more accurate for diagnosing lupus and monitoring disease activity than currently available laboratory tests. The new test measures inflammation-causing proteins known as complement on the surface of red blood cells (erythrocytes).
What this study means for people with lupus: This study may lead to earlier and more accurate detection of disease flares, enabling speedier treatment and reducing the frequency of unnecessary treatments. The work may also provide better ways for measuring responses to new therapies being tested in clinical trials for people with lupus.
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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—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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Jacques F. Banchereau, PhD Baylor Institute for Immunology Research Dallas, Texas |
Summary: Previous studies led by Dr. Banchereau provide strong evidence that interferon-alpha contributes to immune system abnormalities in children and adolescents with lupus. Research also suggests that interferon-alpha plays an important role in the development of lupus in adults. Dr. Banchereau and his colleagues are producing human and mouse antibodies that target interferon-alpha and block its effects on immune cells. They will identify the antibody that is most effective at “neutralizing” interferon-alpha and test the effects of this antibody in a mouse/human model of lupus created by transplanting immune cells from lupus patients into mice.
What this study means for people with lupus: Lupus in children is a particularly aggressive disease, and better, more specific, treatments with fewer side effects are urgently needed. Laboratory-produced antibodies that block the effects of interferon-alpha may provide more specific and effective therapy for lupus in both young people and adults.
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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 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. This 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: Recent studies in both mice and people with lupus suggest that immune system defects are associated with specific changes in the normal patterns of gene activity. Increasing or decreasing the activity of individual genes in different cell types is one of the main ways by which the body regulates the many processes that keep it alive and healthy. Using mice that develop a disease similar to human lupus, Dr. Mishra is investigating the possibility that abnormal patterns of gene activity in lupus are due to an imbalance in biochemical factors (called histone deacetylases) that cells use to switch genes on and off. Dr. Mishra will also determine whether a drug that targets these gene-regulating factors can prevent the progression of lupus-like disease in mice.
What this study means for people with lupus: If factors that regulate gene activity are involved in the development of lupus, then compounds that target these factors, including a drug already in clinical trials for treating human cancer, may provide the basis for new, more specific treatments.
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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 long-term 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 atorvostatin 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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Derry C. Roopenian, PhD The Jackson Laboratory Bar Harbor, Maine |
Summary: A hallmark of lupus is an overabundance of antibodies—in particular, abnormal antibodies that react against the body’s own healthy cells and tissues and cause much of the tissue damage typical of this disease. Dr. Roopenian has shown that a protein called FcRn is responsible for maintaining the high levels of antibodies necessary to cause lupus, and thus may be a promising target for new treatments. Dr. Roopenian is studying the extent to which mice genetically deficient in FcRn are protected from lupus, to verify that FcRn is a priority target for new treatments. He also plans to develop treatments that stop FcRn from maintaining too many antibodies and take steps to ensure that these treatments will be useful for clinical studies in people with lupus.
What this study means for people with lupus: This research may lead to the development and human testing of new, more specific treatments for lupus that target FcRn. Because FcRn has a very specialized effect on the immune system, treatments that target this molecule should have fewer undesirable side effects than current treatments.
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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 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.
Target Identification in Lupus 2003
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