The RDCRN is designed to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing.
Currently, the RDCRN consists of 20 individual clinical research consortia and a Data Management and Coordinating Center (DMCC). Each consortium focuses on at least three related rare diseases or conditions, participates in multisite studies and actively involves patient advocacy groups as research partners. The DMCC enables uniform high-quality data collection and analysis, and facilitates information sharing across the network. This robust data source helps scientists better understand the common elements of rare diseases so they may apply that knowledge to improving diagnosis and treatment for these conditions.
On Oct. 3, 2019, NIH announced awards to both existing and new RDCRN consortia. Descriptions of the 2019 consortia and DMCC follow:
- Brain Vascular Malformation Consortium: Predictors of Clinical Course
- Brittle Bone Disorders Consortium of the Rare Diseases Clinical Research Network
- Clinical Research in Amyotrophic Lateral Sclerosis and Related Disorders for Therapeutic Development
- Congenital and Perinatal Infections Consortium
- Consortium of Eosinophilic Gastrointestinal Disease Researchers
- Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations
- Dystonia Coalition
- Frontiers in Congenital Disorders of Glycosylation Consortium
- Genetic Disorders of Mucociliary Clearance Consortium
- Global Leukodystrophy Initiative Clinical Trials Network
- Hyperphenylalaninemia Disorders Consortium
- Inherited Neuropathies Consortium
- Lysosomal Disease Network
- Myasthenia Gravis Rare Disease Network (MGNet)
- Nephrotic Syndrome Network
- North American Mitochondrial Disease Consortium
- Porphyrias Consortium
- Primary Immune Deficiency Treatment Consortium
- Urea Cycle Disorders Consortium
- Vasculitis Clinical Research Consortium
- RDCRN Data Management and Coordinating Center
Helen Kim, M.P.H., Ph.D.
University of California, San Francisco
The Brain Vascular Malformation Consortium (BVMC) focuses on three rare brain conditions: familial cerebral cavernous malformation (CCM), Sturge-Weber syndrome (SWS), and hereditary hemorrhagic telangiectasia (HHT). These disorders are poorly understood, are costly to manage, and can cause serious complications such as hemorrhages, seizures, and problems with spinal cord, nerve or brain function. Over the last 10 years, the BVMC made great progress in creating patient registries that led to several important discoveries, including the gene for SWS port-wine stain, the first predictor that stratified hemorrhage risk in HHT patients with brain arteriovenous malformations, and inflammatory genetic modifiers of a novel signaling pathway involved in CCM lesion formation. These scientific discoveries in turn help doctors better diagnose and treat patients. In the next five years, BVMC projects will continue these important lines of work in preparation for clinical trials of treatments for these disorders, working closely with three patient advocacy groups and 24 clinical recruitment centers across North America and Europe.
Brendan Lee, M.D., Ph.D.
Baylor College of Medicine, Houston
Brittle bone disorders (BBDs), also known as osteogenesis imperfecta, include 13 inherited conditions involving bones that break easily. BBDs can cause deformity, chronic pain and lead to premature death. This project’s goal is to form a BBD Rare Disease Clinical Research Consortium composed of 10 medical research sites to better understand and treat BBDs. The consortium aims to explore the genetics of BBDs, observe the natural history of bone fractures in several types of BBDs, test new treatments focused on the skeletal and dental complications, develop new techniques for studying BBD causes and evaluating severity, and optimize a symptom-reporting tool for adults with BBDs. The Osteogenesis Imperfecta Foundation will coordinate junior scientist research training within the consortium.
Clinical Research in Amyotrophic Lateral Sclerosis and Related Disorders for Therapeutic Development
Michael Benatar, MD., Ph.D.
University of Miami Miller School of Medicine, Florida
Amyotrophic lateral sclerosis (ALS) is a fatal disease that involves progressive death of motor nerves in the brain, brainstem and spinal cord. The disease is closely related to disorders such as primary lateral sclerosis, hereditary spastic paraplegia, progressive muscular atrophy and frontotemporal dementia. These diseases have shared genetic causes and underlying biology. They also have in common a lack of effective therapies. The Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium brings together a multidisciplinary group of researchers and a diverse array of patient advocacy groups to bridge the gap between basic scientists and investigators engaged in clinical-translational research. The goals of the CReATe Consortium are to advance understanding of the contribution of genetics to these complex disorders, promote development of biological features (biomarkers) that may enhance therapeutic development efforts, train a new generation of clinical scientists, and engage the public and scientific communities in partnerships that enhance clinical research and therapy development.
Congenital and Perinatal Infections Consortium
David Kimberlin, M.D.
University of Alabama at Birmingham
The Congenital and Perinatal Infections Consortium is focused on reducing the morbidity and mortality of rare viral infections such as congenital cytomegalovirus (CMV) disease, neonatal herpes simplex virus (HSV) infection, and neonatal viral sepsis caused by enteroviruses (EVs) and the related human parechoviruses (HPeVs). These infections have been grouped together because of their pathogenic potential in the neonatal population and the current and future opportunities to intervene meaningfully to improve outcomes. Though antiviral therapeutic agents with activity against each of these viruses already exist (CMV, HSV) or are in development (EV, HPeV), collective consequences include developmental and motor delays, neurologic morbidity, visceral organ damage, hearing and vision loss, respiratory and cardiac complications, septic shock and death. The opportunity to ameliorate disease impact forms a common purpose among the 28 Consortium members. Led by the University of Alabama at Birmingham, these 28 sites have cooperated closely for decades as the Collaborative Antiviral Study Group to investigate the natural history and treatment of rare congenital and perinatal infectious diseases, and will continue to advance their research as an RDCRN member.
Marc E. Rothenberg, M.D., Ph.D.
Cincinnati Children’s Hospital Medical Center
Eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis are disorders in which a type of immune cells (called eosinophils) build up in the digestive tract, causing tissue damage to the esophagus, stomach or colon. These disorders are painful and lifelong, and they make it hard or impossible for people to eat many or all foods. The Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) includes clinical centers in Arkansas, California, Colorado, Illinois, Maryland, Massachusetts, Minnesota, New York, North Carolina, Ohio, Pennsylvania, Switzerland, Texas and Utah. CEGIR’s goals are to collect and store clinical information and biological samples from patients to better understand, diagnose and treat these conditions; develop the best methods to measure symptoms and track patients; develop better treatments; make data available to patients, clinicians, researchers and the public; and engage and cooperate with patient advocacy groups.
Mustafa Sahin, M.D., Ph.D.
Boston Children’s Hospital
Autism spectrum disorder (ASD) affects 1 in 59 children in the United States and is a major public health concern and challenge. The Developmental Synaptopathies Consortium (DSC) aims to explore the underlying causes of autism by focusing on three rare genetic disorders related to ASD. Understanding the pathophysiology of these rare disorders, Tuberous Sclerosis Complex (TSC), PTEN Hamartoma Tumor Syndrome (PHTS) and Phelan-McDermid Syndrome (PMS), will lead to the discovery of therapeutic targets, which is the long-term goal of the DSC. The vast data and deep phenotyping of participants with TSC, PTEN and PMS collected to date will be further expanded in this new cycle of the project to include collection of data into adulthood for each disorder. This will allow for additional understanding of the trajectory of each disease and inform not only the research and clinical community, but also other groups that support and educate people affected by these disorders. Additionally, the electrophysiological investigation of these three related diseases will help in the exploration of translational biomarkers and new therapeutic strategies.
Hyder A. Jinnah, M.D., Ph.D.
Emory University, Atlanta
Dystonia syndromes are disorders that cause uncontrollable, repetitive shaking, turning and twisting of affected body parts. The most common dystonia disorders affect the head and neck, eyelids, vocal cords, hands and forearms, and sometimes the entire body. The overall goal of the Dystonia Coalition is to hasten progress in dystonia research. Specific aims include understanding the natural history of dystonia syndromes, crafting formal diagnostic guidelines for these syndromes, creating a bank of DNA samples for dystonia research, and developing a standardized way to measure the severity of the disorder.
Frontiers in Congenital Disorders of Glycosylation Consortium
Eva Morava-Kozicz, M.D., Ph.D.
Mayo Clinic, Rochester
Congenital disorders of glycosylation (CDG) consist of more than 130 different inborn errors of metabolism at an estimated overall incidence of greater than 1 in 100 000. While they were first genetically defined in the 1990s, there is no data available on natural history, no comprehensive patient registry, no reliable screening tests for many types, and large gaps in clinical trial readiness. In response, a nationwide network of 11 regional centers was established to: define the natural history, validate patient-reported outcomes and share CDG knowledge; develop and validate new biochemical diagnostic techniques and therapeutic biomarkers to increase clinical trial readiness; and evaluate whether dietary treatments restore appropriate glycosylation to improve clinical symptoms and quality of life. As with all RDCRN consortia, patients are key partners in research. The consortium leverages cross-disciplinary, team-based clinical science to address decades of unresolved questions; increase clinical trial readiness; advance and share knowledge, awareness and education on CDG; and, most importantly, to develop treatments and meet currently unmet patient needs.
Stephanie Davis, M.D. – The University of North Carolina at Chapel Hill
Thomas Ferkol, M.D. – Washington University in St. Louis
Consisting of eight clinical research sites across North America, the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) has focused on several inherited and acquired disorders that lead to respiratory diseases that produce thick discharges from infected tissues. During the past 15 years, the consortium has made numerous advances that profoundly changed clinical practice, particularly in primary ciliary dyskinesia, a rare disease characterized by chronic sinopulmonary infections, middle ear involvement, laterality defects, and infertility. Novel insights into the genetics of primary ciliary dyskinesia have allowed consortium investigators to define clinical features, revolutionize diagnostics, and uncover genotype-phenotype relationships. Recently, the consortium has expanded its focus to include primary immunodeficiencies, a heterogeneous group of disorders that often share clinical features with primary ciliary dyskinesia. The overarching goal of this multidisciplinary effort is to define the genetic bases, pathophysiology and clinical manifestations; expand diagnostic capabilities, and identify therapeutic targets and trial endpoints in these rare, chronic respiratory diseases, ultimately improving outcomes for affected individuals.
Global Leukodystrophy Initiative Clinical Trials Network
Adeline L. Vanderver, M.D. – Children's Hospital of Philadelphia
S. Ali Fatemi, M.D., M.B.A. – Kennedy Krieger Institute
Florian S. Eichler, M.D. – Massachusetts General Hospital
Leukodystrophies are a complex, often progressive group of disorders affecting the white matter of the brain due to the loss or absence of myelin, the lipid membrane that insulates axons in the central nervous system. Despite advances in the diagnosis of these disorders, they remain widely under-recognized, with unmet gaps in clinical care and curative therapeutics. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) is a consortium of scientists, industry stakeholders, and patient advocacy leaders working together to promote advances in the diagnosis and treatment of leukodystrophies. Specifically, it seeks to create a robust research infrastructure that will allow for collection and analysis of longitudinal natural history data, development of novel clinical outcome assessments, and identification of surrogate biomarkers — ultimately paving the way for transformative therapeutic trials across the leukodystrophies. In parallel to these approaches, the GLIA-CTN will work closely with a diverse group of stakeholders to promote disease awareness and education, promote education and awareness — including newborn screening and early diagnosis — and establish clinical guidelines to support the short- and long-term care of individuals living with leukodystrophies.
Hyperphenylalaninemia Disorders Consortium
Cary Harding, M.D.
Oregon Health & Science University, Portland
The Hyperphenylalaninemia Disorders Consortium studies the health, neurologic, cognitive, neuropsychiatric, patient-reported and quality-of-life outcomes in individuals with chronic elevations of the amino acid phenylalanine in blood (hyperphenylalaninemia). Elevated blood phenylalanine is typically detected at birth in the United States through newborn screening and is caused by inherited disorders affecting the metabolism of phenylalanine. The most common disorder is phenylketonuria (PKU) but the consortium also studies other rarer disorders of phenylalanine metabolism, including defects in biopterin synthesis or recycling, or deficiency of the chaperone protein DNAJC12. The consortium, which partners with a patient advocacy group, the National PKU Alliance (NPKUA), provides informational and educational resources to patients, their families, their providers and the public regarding these rare disorders and trains the next generation of rare disease researchers and practitioners. The consortium has formed a clinical trial network with the facile ability to evaluate emerging novel assessment methods or therapies for these diseases. Its goals are to assess the longitudinal outcomes of this patient population and to refine and improve current and future therapies for these disorders in phenylalanine metabolism.
Michael E. Shy, M.D.
University of Iowa, Iowa City
Charcot-Marie-Tooth disease (CMT) are genetic neuropathies, or disorders of the peripheral nervous system. The Inherited Neuropathies Consortium (INC) is a network of researchers working to find the best treatments for CMT. Over the past few years, the INC has carried out studies; identified multiple genetic causes of CMT; begun testing possible markers for CMT; enrolled thousands of patients in its studies; trained young scientists in CMT research; and created a website that provides information about CMT to patients, families and researchers. INC’s future goals include conducting further natural history studies to enable clinical trials; continuing the search for biological features (biomarkers) of disease; continuing to identify novel genetic causes and modifiers of CMT; and maintaining and updating its website to continue providing information to patients, their families, doctors and researchers.
Chester B. Whitley, M.D., Ph.D.
University of Minnesota, Minneapolis
Lysosomal disorders (LD) are a group of approximately 70 inherited metabolic conditions resulting from defects in lysosomal function; usually deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. Collectively, LD are not especially rare; estimates suggest that approximately 1 in 5,000 newborns will be affected with one identified LD. Individually however, each disorder occurs with a much lower frequency. Although each LD results from a unique gene mutation, at the biochemical level they share a common characteristic — the inability to clear metabolic substrate from the lysosome. Presenting symptoms vary widely among the disorders and are modified by age of onset and severity (To date, approximately a dozen LD have therapeutic options, but apart from one LD (MPS I), LD therapies have not been particularly effective in those LD conditions with neurologic dysfunction. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. The overarching thematic goals of the LDN are: clinical trial readiness, newborn screening, long-term outcomes, and global reach. The LDN will advance these goals through clinical investigation via longitudinal studies focused on elucidation of disease pathology. Continuing educational efforts of the LDN focus on training new fellows interested in a career in the LD field.
Myasthenia Gravis Rare Disease Network (MGNet)
Henry J. Kaminski, M.D.
The George Washington University, Washington, D.C.
Myasthenia gravis (MG) is an autoimmune disease that blocks the signal from nerve to muscle, producing weakness. The nature of the disease can range from isolated severe vision problems, like drooping eyelids or double vision, to profound general weakness leading to breathing muscle failure. Although the cause of MG is not known, the disease appears to vary based on the types of antibodies injuring the muscle, age, sex, and abnormalities of the thymus gland, which an is important part of the immune system. The Myasthenia Gravis Rare Disease Network (MGNet) serves as a centralized, international consortium for physicians, scientists, and patient advocacy groups as well as industry partners to develop resources and implement ideas to enhance discovery, treatment, and advocacy for the patient community. The immediate goals of MGNet are to further define how patients respond to conventional treatments over time, evaluate a novel drug for therapy of some forms of MG, find biological markers of the disease (biomarkers), and encourage new scientists to focus research on MG.
Matthias Kretzler, M.D.
University of Michigan, Ann Arbor
Focal and Segmental Glomerulosclerosis, Minimal Change Disease and Membranous Nephropathy, presenting as Nephrotic Syndrome (NS), are a group of rare renal diseases that may cause serious complications and end-stage kidney disease, generating significant individual, societal and economic burdens. The Nephrotic Syndrome Study Network (NEPTUNE) brings together physician scientists at 26 sites in the United States and Canada, along with patient advocacy groups to advance research on these diseases. Already, NEPTUNE has established a rich translational and clinical research infrastructure for more than 750 rigorously phenotyped study participants with detailed clinical, histological, genetic, transcriptomic and proteomic data sets. Using a systems biology, NEPTUNE applies a precision medicine approach to define NS in molecular terms, identifies novel therapeutic targets and is testing strategies to match patients to their right treatments tested in ongoing clinical trials.
Michio Hirano, M.D.
Columbia University, New York
Mitochondrial diseases affect approximately 1 in every 5,000 people. These diseases can cause muscle weakness, difficulty thinking, seizures, hearing and vision loss, digestive problems, learning disabilities, and organ failure. The North American Mitochondrial Disease Consortium (NAMDC) is a network of clinicians and researchers at 17 different clinical sites working to better understand mitochondrial diseases, improve diagnosis and explore treatments. In the past eight years, NAMDC has established a biorepository for tissue samples, a large registry and follow-up study with more than 1,500 patients, a website to educate and recruit patients, and studies to define the natural history of mitochondrial diseases. NAMDC also has initiated research studies that focus on several subtypes of mitochondrial diseases as well as a training program to educate the next generation of researchers. During the next few years, NAMDC will expand its clinical registry study and biorepository, perform advanced molecular diagnostic testing, conduct natural history and treatment studies, and continue training future clinician-scientists.
Robert J. Desnick, Ph.D., M.D.
Icahn School of Medicine at Mount Sinai, New York
The porphyrias are a group of rare, inherited disorders, each caused by a deficiency with one of eight enzymes necessary to produce heme, an important component of hemoglobin and other proteins. The porphyrias are classified as either acute hepatic (liver) or cutaneous (skin); the former is characterized generally by acute attacks of severe abdominal pain accompanied by nausea, vomiting and other symptoms, whereas the latter mainly includes blistering or burning in response to sun exposure. The rarity of these diseases has limited understanding of how they naturally progress and what other factors influence symptoms. The Porphyrias Consortium (PC) brings together experts at six main academic institutions, seven satellite sites, the American Porphyria Foundation, and biopharmaceutical companies interested in improving diagnosis and treatment for these diseases. The PC aims to continue studying the characteristics and genetics of the porphyrias; promote development of new biomarkers to track the progression of these diseases; develop and test new treatments; and train the next generation of porphyria clinicians and researchers.
Jennifer M. Puck, M.D. - University of California, San Francisco
Donald B. Kohn, M.D. - University of California, Los Angeles
The Primary Immune Deficiency Treatment Consortium (PIDTC) was established in 2009 to study and define optimal treatments for rare genetic disorders of the immune system, collectively known as primary immunodeficiency diseases. The PIDTC includes 44 immunology and transplantation centers throughout the United States and Canada as well as six patient advocacy groups. In its first nine years, the PIDTC has studied clinical features and outcomes following hematopoietic cell transplantation (HCT), gene therapy (GT) and enzyme replacement therapy (ERT) for patients with severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Primary immunoregulatory disorders (PIRD) were recently added for the current funding cycle. All these diseases were chosen because they are life-threatening and difficult to treat, often requiring HCT for survival. Because no single center follows enough affected individuals to encompass the full spectrum of these disorders, the consortium has been essential to define their natural history and perform robust statistical assessments to address the impact of patient-related variables, such as genotypes and infections, as well as treatment-related variables on clinical outcomes. PIDTC contributions to understanding pathogenesis and defining which treatments produce optimal survival and quality of life have been published in over 100 papers to date. Looking forward to the next five years, the PIDTC will strengthen its infrastructure for multicenter clinical trials so as to apply new knowledge about these primary immunodeficiencies to achieve advances in care, with the goal of improving the lives of people living with these rare medical conditions.
Andrea L. Gropman, M.D., FAAP, FACMG
Children's National Medical Center, Washington D.C
Urea cycle disorders (UCDs) are rare but devastating genetic conditions. Fifteen years ago, the Urea Cycle Disorders Consortium (UCDC) became one of the first members of the RDCRN. Since then, UCDC has flourished into an international network of 16 academic centers in the United States, Canada and Europe that provide state-of-the-art care and conduct cutting-edge clinical research. During the next five years, the consortium will focus research on three major studies as well as pilot studies on innovative diagnostics and therapies. The three major protocols include a long-term natural history study of patients with UCDs that has been active since 2006; a project investigating sub-clinical seizures in neonates with hyperammonemia and its impact on the development of epilepsy, neurodevelopment and affect brain function and biochemistry; and an MRI study of liver fibrosis as a complication of UCDs. The consortium also continues to train the next generation of rare diseases researchers, provide education on UCDs to health care professionals and the public in partnership with the National Urea Cycle Disorders Foundation, and work with the pharmaceutical/biotechnology industry to develop and test novel medications and treatments to help improve the lives of those affected by UCDs.
Peter A. Merkel, M.D., M.P.H.
University of Pennsylvania, Philadelphia
Vasculitis refers to a group of rare diseases that involve inflammation of blood vessels, which disrupts blood flow and often causes damage to the body’s organs. The cause of most forms of vasculitis remains unknown, and treatments involve the use of strong medications that can have serious side effects. The Vasculitis Clinical Research Consortium (VCRC) is an international, multicenter clinical research infrastructure for the study of vasculitis. Established in 2003, the various projects of the VCRC have included >100 academic medical centers around the world dedicated to the study of vasculitis. The VCRC focuses on conducting clinical trials of new therapies for vasculitis, studying the genetics of these diseases, discovering new blood tests to help monitor and understand these diseases, conducting online research, and training young scientists in the study of vasculitis. The VCRC will continue its efforts to better understand and treat vasculitis by conducting new clinical trials and expanding and utilizing the VCRC Clinical Data Repository, the VCRC Biospecimen Repository, and the VCRC Tissue Repository. All these activities involve a strong partnership with patients and advocacy groups.
Eileen King, Ph.D. and Maurizio Macaluso, M.D., DrPH, FACE
Cincinnati Children’s Hospital Medical Center
The Data Management and Coordinating Center (DMCC) will serve as the centralized source for data storage and sharing among the RDCRN’s 20 research consortia. The DMCC also will serve as a learning center to help scientists across the network share best practices about conducting rare disease research. Its work will include stepped-up efforts to help the many families involved with rare disease advocacy groups become even more involved and informed about the network and its findings. The center’s goals include: providing clinical research and data management and coordinating support to individual research consortia; coordinating activities across the network and further advancing the network as the prominent critical rare diseases resource; and serving as the major conduit of research information from the network to the scientific community, including regulatory agencies, the pharmaceutical industry, physicians, patients, and families.