Download nephcure in action - Rare Diseases Clinical Research Network

 NEPHCURE IN ACTION The NephCure Foundation’s mission is to support research seeking the cause of Nephrotic Syndrome and FSGS, improve treatment and find a cure. Supported by a Scientific Advisory Board comprised of some of the most knowledgeable experts in NS and FSGS, The NephCure Foundation and friends provide ongoing support for scientists and institutions working to find the cause and cure of these potentially devastating conditions. Through research and collaboration, we are closing the gap between knowledge about these diseases and effective treatments. Background: Healthy kidneys process about 200 quarts of blood a day to sift out about two quarts of waste products and extra water. The actual removal of wastes occurs in about a million tiny units inside the kidneys called nephrons. Within each nephron is a structure called a glomerulus made up of specialized cells that acts as a filtration barrier. Nephrotic syndrome (NS) is a nonspecific disorder in which the kidneys are damaged in some way, causing them to leak large amounts of protein from the blood into the urine. Focal segmental glomerulosclerosis (FSGS) is a specific type of disorder within the NS spectrum that is estimated to cause 10‐15% of cases of that syndrome. Although the exact causes of FSGS are still unclear, research indicates that injury to podocytes, one of the specialized cells in the glomerulus, is a critical failure point. Since podocytes cannot divide to replace lost or damaged cells, End Stage Renal Disease (ESRD) may result. Genetic, cellular and molecular research is often focused on podocytes in order to develop specific, targeted treatment of NS and FSGS. The NephCure Foundation funds activities that include Research, Education and Advocacy
1 Last updated September 28, 2011 THE NEPHCURE FOUNDATION FUNDED RESEARCH PROJECTS The role of microRNAs in progression of FSGS Markus Bitzer, M.D., University of Michigan, Ann Arbor, MI Young Investigator, Project began in 2008 MicroRNAs are small molecules that play an important role in gene expression, regulating the building of proteins to keep them in the right balance. Dr. Bitzer has found that the amounts of some of these microRNAs in kidneys of patients with FSGS are different than in healthy people. Dr. Bitzer is investigating the function of microRNA‐21 and other microRNAs in the kidney to determine how these molecules are expressed and how they might influence the disease. Identifying these mechanisms may lead to the development of new therapies for FSGS using drugs that inhibit microRNAs. Identification of new FSGS gene: Linkage mapping of a large family Elizabeth Brown, M.D., Children’s Hospital Boston, Boston, MA Post‐Doctoral Fellow, Project began in 2008 Genetic mapping is a critical step to understanding how a person inherits the propensity to express certain diseases. In searching for a gene associated with the cause of FSGS, Dr. Brown used genetic data from a large family with a history of FSGS and found mutations in the gene area INF2. This discovery allows researchers to get closer to discovering the cause of the disease. A Drosophila model of diabetic nephropathy Ross Cagan, Ph.D., Mount Sinai School of Medicine, New York, NY Established Investigator, Project began in 2009 Dr. Cagan has developed a model of kidney disease using the Drosophila (fruit fly). The fruit fly has cells in its kidneys that are very similar to podocytes, called nephrocytes. By injuring the nephrocytes, he mimics podocyte injury and searches for ways to then repair it. This model allows for the understanding of how podocytes function as well as for the testing of drugs that can reverse podocyte damage. Functional characterization of human dendrin mutations in the pathogenesis of FSGS Kirk Campbell, M.D., Mount Sinai School of Medicine, New York, NY Young Investigator, Project began in 2009 When podocytes become damaged through diseases such as FSGS, proteinuria develops. With enough podocyte loss, patients can progress to ESRD. Dr. Campbell studies FSGS modeled in the mouse and found that the dendrin gene (DDN) is involved in the regulation of the podocyte. He is examining how DDN mutation can lead to the progression of FSGS, and how it regulates podocyte injury and death. This model may lead to the discovery of new approaches that encourage the repair and/or survival of damaged podocytes. The Role of Pentraxin‐2 /Serum Amyloid P in preventing glomerulosclerosis and interstitial fibrosis in mouse models of glomerular injury Jeremy Duffield, M.D., Ph.D., University of Washington, Seattle, WA Young Investigator, Project began in 2011 Fibrosis is the irreversible scarring of tissue due to injury or disease that reduces the ability of organs such as the kidney to function properly. The progression of this condition in FSGS cannot be stopped with traditional medications and may lead to ESRD, requiring dialysis or a kidney transplant for survival. Dr. Duffield is testing the efficacy of a compound called Pentraxin‐2 (PTX‐2) in mouse models that express two types of glomerular injury. Preliminary studies have found that PTX‐2 has an antifibrotic effect and may be potentially useful for the treatment and prevention of fibrotic diseases, such as FSGS. 2 Last updated September 28, 2011 The function of calcineurin in podocytes Christian Faul, Ph.D., University of Miami, Miami, FL Young Investigator, Project began in 2009 Calcineurin is a protein that is expressed in all tissues and is inhibited by cyclosporine A (CsA), an immunosuppressant drug sometimes used to treat kidney diseases such as FSGS. Dr. Faul’s research identifies the function of calcineurin in podocytes at the period of transition from early and reversible damage, to late and chronic damage. Examining how signaling happens at this transition could serve as a promising target for drug development. Novel Targets of Rituximab in FSGS Alessia Fornoni, M.D., Ph.D., University of Miami, Miami, FL Bridge Grant, Project began in 2011 Dr. Fornoni demonstrated that rituximab, a specialized drug primarily used for cancer treatment, can help reduce the percentage of patients with post‐transplant recurrence of FSGS to 26 percent, compared with 64 percent for those who did not take the drug. Using kidney biopsies and blood from patients with FSGS, Dr. Fornoni continues to study the mechanism by which rituximab protects podocytes. This may pave the way for the development of a new generation of therapies for recurrent FSGS and for the development of an assay to be used before transplant to identify patients at risk for recurrent FSGS disease. Molecular genetics of Nephrotic Syndrome Rasheed Gbadegesin, M.D. and Michelle Winn, M.D., Duke University Medical Center, Durham, NC Project began in 2008 Dr. Gbadegesin and Dr. Winn collaborate at Duke Center for Human Genetics where they have been examining the genes of more than 100 families in which many members have FSGS. They are sequencing and analyzing genes to find the specific locations or ‘loci’ of a gene or DNA sequence on a chromosome associated with FSGS and the risk factors associated with FSGS disease progression. While the cause of FSGS remains unknown, recent advances in the field of molecular genetics have shown that a defect in genes encoding a component of the kidney filtering mechanism may be responsible for some cases. TRPC1 and TRPC5 channels in glomerular podocytes: Putative role in the pathogenesis of FSGS Anna Greka, M.D., Ph.D., Massachusetts General Hospital, Boston, MA Young Investigator, Project began in 2008 Cells are regulated by signals that direct the movement of substances into and out of the cells through pores, or channels. Channels in the podocytes interact, and a mutation in a gene of one ion channel (TRPC6) is linked to podocyte injury and may play a role in FSGS. Dr. Greka is studying the mechanisms that control these channels to help identify a possible cause of FSGS. Findings may help identify targets for the development of drug therapies. Discovery of urine biomarkers in patients with glomerular disease Michael Janech, Ph.D., Medical University of South Carolina, Charleston, SC Young Investigator, Project began in 2008 Currently, the primary causes of NS (Minimal Change Disease, FSGS, and Membranous Nephropathy) can only be conclusively identified with a kidney biopsy. However, biopsies are not always accurate, especially among patients with FSGS because the disease process is only found in segments of the tissue. Dr. Janech is working to discover urine biomarkers as a non‐invasive method to diagnose kidney diseases. A urine biomarker could also allow for earlier detection and possible prevention. 3 Last updated September 28, 2011 Interactions of slit diaphragm protein Fat1 with conventional kinesin, microtubules, and the actin cytoskeleton Duncan Johnstone, M.D., Ph.D., University of Michigan, Ann Arbor, MI Young Investigator, Project began in 2008 Complex cells such as podocytes have cytoskeletons that maintain cell structure and aid in the transport of substances into and out of the cell. The cytoskeleton is made up of a network of proteins that include Fat1, kinesin and microtubules. Mutations can lead to the rearrangement of the podocyte actin cytoskeleton, which disrupt transport and can lead to renal disease. Dr. Johnstone studies how the abnormal interaction of these proteins may cause the abnormalities that result in FSGS. The dual role of beta‐catenin in podocytes Hideki Kato, M.D., Ph.D., Albert Einstein College of Medicine, Bronx, NY Post‐Doctoral Fellow, project began in 2009 As noted above, research indicates that injury to podocytes plays a pivotal role in FSGS disease. Previous studies from Dr. Kato’s laboratory demonstrated that the protein beta‐catenin is important in maintaining the structure of the glomerulus, and Dr. Kato examined the molecular mechanism that activates beta‐catenin to impact the development of proteinuria and glomerular disease. The Role of myosin 1e‐synaptopodin interaction in podocyte functions Mira Krendel, Ph.D., SUNY Upstate Medical University, Syracuse, NY Young Investigator, Project began in 2009 Complex cells such as podocytes have cytoskeletons that maintain cell structure. Dr. Krendel has found that mutations in myosin 1e, a protein in the cytoskeleton of the podocyte, result in severe defects in the glomerulus. Additionally, myosin 1e interacts with synaptopodin, an important regulator of podocytes. Dr. Krendel hypothesizes that this interaction is involved in regulating podocytes and is examining the mechanism that causes myosin 1e loss and resulting podocyte dysfunction and NS. In addition to examining this interaction at the molecular level, Dr. Krendel is testing the role of myosin 1e and synaptopodin interaction in renal functions in a mouse model. NephCure Foundation Nephrotic Syndrome Biobank Project – (now a part of NEPTUNE, see below) Matthias Kretzler, M.D., University of Michigan, Ann Arbor, MI Alicia M. Neu, M.D., Johns Hopkins University School of Medicine, Baltimore, MD Laura Barisoni, M.D., New York University School of Medicine, New York, NY Project began in 2008 Drs. Kretzler, Neu and Barisoni created a NS “Biobank” that enables the procurement and storage of biological samples such as kidney biopsy, urine and blood samples as well as the medical histories from patients with NS. The Biobank facilitates the examination of NS at the genetic, cellular and molecular levels. Results will be used to develop a system of markers to subdivide different forms of FSGS, which will provide finer details about prognosis, responsiveness to various drugs and failure of some patients to respond to treatment. Towards personalized molecular medicine of Nephrotic Syndrome: Transcriptional network analysis to predict treatment response of FSGS Sebastian Martini, M.D., University of Michigan, Ann Arbor, MI Post‐Doctoral Fellow, Project began in 2009 Minimal change disease (MCD), FSGS, and membranous nephropathy (MN) are the primary glomerular diseases associated with NS. The progression of FSGS is often unpredictable, and can be difficult to treat thus leading to ESRD. Dr. Martini is identifying the regulatory pathways, or transcriptional networks, that these diseases might have in common, as well as FSGS‐specific biomarker ‘signatures’. Identifying what biomarkers differentiate FSGS from the other diseases may potentially be applied to slow disease progression. 4 Last updated September 28, 2011 Cell and molecular biological analysis of synaptopodin Peter Mundel, M.D., Massachusetts General Hospital, Boston, MA Bridge Grant, Project began in 2011 Podocytes form part of the final barrier in kidneys that prevents spillage of large amounts of protein from the blood into the urine (a condition called proteinuria found in patients with NS and FSGS). Determining the mechanisms for maintaining structural and functional integrity of these cells is of critical importance in understanding how to sustain normal glomerular filtration. Previous studies demonstrated that a protein called synaptopodin plays a role in stabilizes the kidney filter. Dr. Mundel is testing how the activation of an enzyme in podocytes (tyrosine kinase Src) changes podocyte cells by degrading synaptopodin leading to proteinuria. His research will provide a better understanding of the biological mechanism underlying the dynamic re‐
organization of the podocyte in normal and proteinuric kidneys and, in the long term, enable the development of therapies that protect podocytes. Molecular genetics of inherited FSGS Martin Pollak, M.D., Beth Israel Hospital, Boston, MA Bridge Grant, Project began in 2008 Dr. Pollak’s laboratory studies the genetic basis of NS and FSGS. He is conducting mutational analyses of genes known to cause FSGS. By comparing the genes between family members affected with a disease and those who are unaffected, in collaboration with Dr. Elizabeth Brown, they have discovered multiple mutations in the gene INF2, which are expressed in the podocyte. MGH Glomerular Center Dynamin Project Jochen Reiser, M.D., Ph.D., at the University of Miami Medical School, Miami, FL Sanja Sever, Ph.D., at Massachusetts General Hospital, Boston, MA Project began in 2008 By discovering how healthy podocyte structure is maintained, treatment can be developed to protect podocyte structure and function. Dr. Reiser and Dr. Sever have uncovered how the protein dynamin regulates the healthy structure of the podocyte. Specifically, they have found that some forms of the enzyme cathepsin (CatL) have a positive role and another form can lead to destruction of the podocyte, causing proteinuria. Experiments focus on developing dynamin drug therapies to block the process that destroys the podocyte leading to FSGS. The role of protein hic‐5 in the induction of proteinuria Michelle Rheault, M.D., University of Minnesota, Minneapolis, MN Post‐Doctoral Fellow, Project began in 2008 Podocytes sit on top of the glomerular filter membrane, which separates the blood from the urine. Signaling between receptors and proteins define healthy cellular shape, regulation, and adhesion. Abnormal cell signaling of the podocytes can result in loss of proteins in the urine (proteinuria). Dr. Rheault is examining how the signaling of protein hic‐5 mediates the adhesion of podocytes and the mechanism by which hic‐5 causes proteinuria. Findings may allow for discoveries of what contributes to podocyte dysfunction and proteinuria. Post‐transcriptional regulation of gene expression in Glomerular Disease Valerie Anne Schumacher, Ph.D., Children’s Hospital Boston, Boston, MA Young Investigator, funded in part by the “Cure for Cole” fund Project began in 2009 DNA contains the genetic code or instructions needed to build proteins that help make up cells. mRNA translates the DNA into protein, and each protein has a different function. Most of the inherited forms of NS are caused by mutations in genes that produce proteins critical in podocyte structure. Dr. Schumacher’s research aims to clarify how mutations in the protein WT1 found in the podocyte and how the mechanism of mRNA result in steroid resistant NS that rapidly progresses to FSGS and eventually ESRD. She is studying the 5 Last updated September 28, 2011 generative capability of podocytes to be able to prevent podocyte damage and promote podocyte repair in patients with steroid‐resistant NS. The role of GTPase dynamin in foot process effacement Sanja Sever, Ph.D., Massachusetts General Hospital, Boston, MA Established Investigator, Project began in 2009 Podocytes form foot processes, extending into the glomerular filtration barrier. Most forms of NS are characterized by reduction of these extensions and their reorganization, called podocyte ‘foot process effacement’. Dr. Sever’s research focuses on the mechanism that leads to podocyte foot process effacement or reorganization. Additionally, Dr. Sever has found that GTPase dynamin regulates podocytes, and she is examining the molecular mechanism by which dynamin regulates the foot process effacement in order to find new pathways that drugs can target. Parietal Epithelial Cells, a Regenerative Cell Population Bart Smeets, Ph.D., Aachen Medical Clinic, Aachen, Germany Post‐Doctoral Fellow, Project began in 2008 Loss of podocytes can cause leakage of proteins into the urine (proteinuria) and they cannot divide and replace themselves. Dr. Smeets has found that parietal epithelial cells (PECs) next to the podocyte can change into podocytes and possibly replace them. Dr. Smeets is studying how these parietal cells regenerate and if they can differentiate and replace the podocytes. If therapy can be developed to replace abnormal podocytes with healthy ones, then normal function could be restored. Clinical study of oral galactose and novel therapies for resistant FSGS clinical testing Howard Trachtman, M.D., Cohen Children’s Medical Center, New Hyde Park, NY Project began in 2008 To date there is no common effective treatment or cure for FSGS. Most commonly, patients are treated with prolonged use of steroid regimens with many side effects. There is a pressing need to find and develop treatments for FSGS patients with reduced side effects. Initial studies show that galactose, a sugar given orally, may lower the level of a circulating factor that increases the permeability of the glomerulus and is found in the blood of patients with FSGS. In an ongoing clinical trial funded by The NephCure Foundation and the Pediatric Kidney Foundation along with an award from the NIH, Dr. Trachtman and his colleagues are evaluating the benefits of adding galactose or another drug called Humira® to the standard FSGS therapy to determine if these less toxic compounds can be used successfully to reduce the recurrence of FSGS. Presently, the clinical trial has been approved for 16 sites around the USA. OTHER NEPHCURE AND DONOR ADVISED GRANTS The Nephrotic Syndrome Study Network (NEPTUNE) NephCure has joined the National Institutes of Health’s Office of Rare Diseases Research (ORDR) and 19 universities in developing a multidisciplinary research and education platform aimed at studying the primary causes of Nephrotic Syndrome ‐ FSGS, Minimal Change Disease and Membranous Nephropathy. This $10.25 million, five year project ($6.25 million provided by ORDR, $2 million from NephCure and $2 million in‐kind from the University of Michigan) will fund the consortium to: 1.
2.
3.
4.
5.
Establish an infrastructure to efficiently conduct clinical and translational research in NS Identify biomarkers (used for the diagnosis of disease) and potential therapeutic targets for NS Conduct clinical studies in NS Implement a program to train scientists with M.D./Ph.D. degrees in conducting research in kidney disease Develop multimedia educational resources on NS for laypersons and physicians
6 Last updated September 28, 2011 6. Develop a secured repository of clinical data and biospecimens of NS patients for sharing among researchers thus stimulating research into these diseases internationally Endowed University Chair The Robert C. Kelsch Collegiate Chair in Pediatric Nephrology at the University of Michigan was endowed with major support from a NephCure Founder. The Head of the Section of Pediatric Nephrology at Michigan traditionally holds the Chair. All proceeds from the Chair’s endowment are earmarked for basic research into the molecular mechanisms of FSGS and Minimal Change. Dr. Sebastian Martini’s research is currently funded by the Endowed Chair. NEPHCURE PARTNERSHIP GRANTS The Kidney Foundation of Canada (KFOC) NephCure and The KFOC will co‐fund grants for two Canadian citizens or qualified researchers employed by a Canadian institution whose research is relevant to:  Understanding the cause, mechanism and treatment of primary forms of FSGS  Investigations of the mechanisms of normal glomerular biology or pathobiology that can be applied commonly to all forms of glomerular disease; these investigations will be applicable to identifying treatments of minimal change disease and primary FSGS American Society of Nephrology (ASN) The NephCure Foundation and the American Society of Nephrology (ASN) are in discussions to jointly fund a new Career Development Grant to foster the independent careers of junior faculty whose research focuses on topics relevant to FSFG and other diseases that result in nephrotic syndrome. NEPHCURE ADVOCATES Advocacy in Action Following several meetings between NephCure officials with federal officials at the NIDDK a “Funding Opportunity Announcement,” was created entitled, Exploratory Basic Research in Glomerular Disease (PA‐O6‐228), a first step in funding new research into glomerular disease. The intent of which is to invite applications from investigators with diverse scientific interests, who wish to apply their expertise into basic research to enhance the understanding of the pathogenesis of the various forms, primary or secondary, of Glomerular Disease. This program was recently renewed. Additionally, in 2003, NephCure was a major advocate for the recently completed FSGS Clinical Trial, a five‐year $15 million National Institutes of Health program studying the effect of various treatments on FSGS patients. NEPHCURE SUPPORTED PHYSICIAN AND RESEARCHER CONFERENCES American Society of Nephrology – www.asn‐online.org ASN Kidney Week 2011 will be held in Philadelphia, PA November 8‐11. NephCure uses this opportunity to promote NephCure funded research projects and to meet with clinicians and scientists from around the world. American Society of Pediatric Nephrology – www.aspneph.com NephCure provides support for the annual conference of the ASPN because so many NS and FSGS patients are young. ASPN officials conduct programs dealing specifically with NS and FSGS. International Pediatric Nephrology Association – www.ipna‐online.org IPNA presents up‐to‐date reviews of advances in pediatric nephrology including new advances in translational medical research. IPNA hosts sessions that bring researchers from around the world to discuss the latest and most 7 Last updated September 28, 2011 intriguing research and treatment for Nephrotic Syndrome and FSGS. The IPNA International Conference is held every two years. In 2010, along with IPNA leadership, NephCure organized a special session titled “FOCUS on FOCAL” with over two dozen participating nephrologists and researches. Midwest Pediatric Nephrology Consortium – www.mwpnc.org NephCure provides support for the Midwest Pediatric Nephrology Consortium, whose mission is to advance the care of children with renal, dialysis and transplant kidney disorders through the promotion of collaboration of research and education by those in the field of pediatric nephrology throughout the Midwest. The next meeting is in October 2011. The Podocyte Conference ‐ www.podocytebristol.org.uk Researchers from a variety of scientific disciplines and from around the world meet to promote interactions and new collaborations and to investigate emerging directions in podocyte and glomerular biology research. NephCure was the lead sponsor at the 2010 Conference in Bristol, UK and is organizing the conference scheduled for April 2012 in Miami, FL. NEPHCURE EDUCATES PATIENTS AND FAMILIES Lunch and Learn Seminars ‐ http://www.nephcure.org/nephcure‐lunch‐learn.htm NephCure funds and organizes patient education seminars around the country. These seminars are free to participants and provide the opportunity to learn about renal biology, disease pathology and pediatric and adult treatment options from both clinicians and researchers in the field of nephrology. Other healthcare professionals including social workers, dietitians and renal nurses offer insight, pertinent information and participate in group discussions. Web Based Updates on Important NS/FSGS Research ‐ http://www.nephcure.org/articles‐literature.htm Both the scientific community and the lay public are clamoring for more information on these diseases, and NephCure staff receives frequent calls from families wanting to know, “What’s the latest in science?” NephCure scouts the scientific literature and provides quarterly reports that are posted on our webs site. NEPHCURE IS HERE FOR PATIENTS AND FAMILIES NephCure is a team of families and friends dealing with FSGS and NS. We organize team meetings and events
throughout the United States. NephCure is also growing internationally. Research has no boundaries, and NephCure
works with partners and institutions in several countries.
“The NephCure Foundation has been amazing in filling a huge need for educating patients and their families and
also funding research in this area. Kidney disease hasn’t traditionally received the attention that it should.
NephCure’s work is a tremendous step in increasing awareness, providing a resource for families and in pushing
research forward.”
Martin Pollak, M.D. Associate Professor of Medicine, Harvard Medical School and Chief of Nephrology, Beth Israel Deaconess
Medical Center, Boston, MA
“The NephCure Foundation is an excellent example of positive advocacy‐group action, interaction and leveraging of resources with the National Institutes of Health.” Marva Moxey‐Mims, M.D., Director, Pediatric Nephrology and Renal Centers Programs, The National Institutes of Health, Washington, D.C. For more information or to get involved contact [email protected] or 1‐866‐NEPHCURE Visit our website at www.nephcure.org 8 Last updated September 28, 2011