NIH Establishes Rare Diseases Clinical Research Network

Rare Diseases Clinical Research Network

On February 27, 2003, ORD in response to the Rare Diseases Act of 2002, P.L. 107-280, released a Request for Applications (RFA) for a Rare Diseases Clinical Research Network together with the National Center for Research Resources (NCRR)/General Clinical Research Consortium (GCRC) Program and in collaboration with other NIH Institutes. ORD, NCRR, and the National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Heart, Lung, and Blood Institute (NHLBI), all components of the NIH, funded eight rare diseases clinical research consortia and one Data and Technology Coordinating Center.

The purpose of the network is to facilitate clinical research in rare diseases through

• Collaborative clinical research in rare diseases, including longitudinal studies of individuals with rare diseases, clinical studies, phase one and two research studies, and/or pilot and demonstration projects to respond to the very differing level of research and to facilitate research that is sorely needed;
• Training of clinical investigators in rare diseases research;
• Clinical data management that incorporates novel approaches and technologies for data management, data mining, and data sharing across rare diseases, data types, and platforms; and
• Access to information for basic and clinical researchers, academic and practicing physicians, patients, and the lay public across the U.S. and abroad. This cooperative program should facilitate many advances including the identification of biomarkers for disease risk, disease severity/activity, and clinical outcome and encourage development of new approaches to prevention, diagnosis, and treatment of many rare diseases beyond those being studied. The easy and free availability of data from the Data and Technology Coordinating Center should also spawn many new research ideas and subsequent applications to NIH Institutes and Centers.

Abstracts of the funded applications follow:

Description from the Grant Application:
We propose to establish a Rare Disease Clinical Research Consortium (RDCRC) at the Children's National Medical Center (CNMC) in Washington, D.C. The RDCRC will draw support from both the Pediatric General Clinical Research Center at CNMC/Georgetown University Medical Center (GUMC) as well as its Mental Retardation and Developmental Disabilities Research Center (MRDDRC). The unifying clinical theme of the RDCRC is the study of urea cycle disorders (UCD). This RDCRC will consist of a network of five academic institutions, each of which has GCRC/MRDDRCs [CNMC/GUMC, Children's Hospital of Philadelphia, Vanderbilt University, Baylor Medical Collage and University of California at Los Angeles]. The proposed RDCRC will comprise a multidisciplinary team of 10 investigators in the following specialties: Genetics, Metabolism, Developmental Pediatrics, Clinical Pharmacology, Neurology, Psychology, Biostatistics, and Neuroimaging. Mark L. Batshaw, M.D., the Director of the CNMC MRDDRC, will serve as Principal Investigator, and Mendel Tuchman, M.D., Director of the PCRC at CNMC, will serve as Co-Director.The primary goals of the RDCRC are to

• Establish a registry and nationwide consortium of regional centers for the diagnosis, treatment and clinical research in UCD;
• Conduct a longitudinal study to determine the natural history of UCD;
• Conduct a clinical trial of an investigational new drug (IND), N-carbamyI-L-glutamate, for treatment of these disorders;
• Conduct a demonstration/pilot project to develop a novel method for measuring in vivo ureagenesis in UCD that will be important for diagnosis and classification of patients and for evaluation of treatment efficacy;
• Train graduate students, pediatric residents, clinical fellows and junior faculty members in the field of inborn errors of metabolism; and
• Develop and maintain UCD website content that will:
  1. include guidelines for health care providers regarding diagnosis and treatment;
  2. provide information to the lay public regarding consultation and treatment at major centers; and
  3. provide links to recent scientific literature for interested investigators.

Performance Sites:
Children's National Medical Center, Children's Research Institute (CNMC), Washington, D.C.
Georgetown University Medical Center (GUMC), Washington, D.C.
Children's Hospital of Philadelphia (CHOP), Philadelphia, PA
Vanderbilt University (VU), Nashville, TN
Baylor Medical College (BMC), Houston, TX
University of California at Los Angeles (UCLA), Los Angeles, CA

Patient Support Organization:
National Urea Cycle Disorders Foundation (NUCDF)

Description from the Grant Application:
This is an application from an inter-institutional group of investigators with long-standing interest in Rett syndrome, Angelman syndrome (AS), and Prader-Willi syndrome (PWS) to establish a Rare Diseases Clinical Research Consortium (RDCRC) that would be part of the proposed Rare Diseases Clinical Research Network (RDCRN). The consortium will focus on these three disorders with the expectation that they may have near-term potential for meaningful therapy. The specific aims for Rett will be to establish a phenotype/genotype correlation over a broad spectrum of Rett phenotypes, to perform longitudinal studies on a broad sample of individuals with Rett, and to perform a survival study on a broad spectrum of Rett individuals. Clinical trials may be developed based on results of studies of animal models. The specific aims for AS are to conduct a longitudinal assessment of patients with AS according to genotype, to complete the ongoing double-blind, placebo controlled trial of folic acid and betaine in AS, and to develop a follow-on clinical trial for activation of the paternal allele for UBE3A in AS patients. The specific aims for PWS are to conduct longitudinal studies according to genotype, to develop parameters and tools for clinical trials, to test whether autistic features are more frequent in UPD than in deletion cases, and other ideas from collaborators. The aim of a pilot project using comparative genomic hybridization (CGH) on microarrays would be to develop a cytogenetic test that would detect all sizable deletions and duplications of clinical relevance on a single analysis using CGH microarrays. This new methodology would also have the potential to identify new deletion and duplication syndromes. The RDCRC will utilize GCRCs in Houston, Boston, San Diego, Gainesville, and other locations. The consortium is expected to function synergistically with the Mental Retardation Research Center (MRRC) at Baylor. An extensive program is proposed for training new investigators in clinical research on rare diseases. The consortium will have active affiliation with the International Rett Syndrome Association (IRSA), the Angelman Syndrome Foundation (ASF), and the Prader-Willi Syndrome Association (PWSA). It is anticipated that the RDCRC will expand to include other geographic sites for the three diseases to be studied initially, and it is expected that the Center can also expand to include other disorders, such as inborn errors of metabolism amenable to hepatocyte gene therapy, disorders treatable by enzyme replacement therapy, CHARGE association, incontinentia pigmenti, Smith-Magenis syndrome, Xp deletion syndromes, and other chromosomal deletion and duplication syndromes.

Performance Sites:

Baylor College of Medicine, Houston, TX
Greenwood Genetic Center, Greenwood, SC
University of Alabama, Birmingham, AL
University of Florida, Gainesville, FL
Children's Hospital, Boston, MA
Children's Hospital, San Diego, CA
University of California, Irvine (UCI) Medical Center, Orange, CA

Patient Support Organizations:
International Rett Syndrome Association (IRSA)
Angelman Syndrome Foundation (ASF)
Prader-Willi Syndrome Association (USA), (PWSAUSA)

Description from the Grant Application:
This application proposes to investigate three rare neurological channelopathies: periodic paralysis, non-dystrophic myotonic disorders, and episodic ataxia. The research plan will exploit the strengths of seven collaborating centers to link molecular scientists studying these disorders with clinical investigators with established expertise in the development of new treatments for neurological disease. It will extend a prototype NIH training program in experimental therapeutics to train a cadre of patient-oriented-researchers committed to rare disorders. Study investigators have strong links with the patient advocacy organizations focused on these rare disorders: The Periodic Paralysis Association, the National Ataxia Foundation and the Muscular Dystrophy Association. A particular strength of the collaborating institutions is an established nationwide infrastructure, including GCRCs and a biostatistician, for the implementation of multicenter clinical trials that will facilitate investigation of the efficacy of putative new treatments for rare diseases.

Currently-funded studies of the pathophysiology of the three specific target diseases will provide resources for molecular characterization of subjects and make it possible to:

1. Begin the characterization of the phenotype/natural history of each;
2. Devise outcome measures for treatment trials;
3. Assess quality of life -- all in preparation for pilot clinical trials of novel treatments.

The focus of investigation is on:

1. Andersen-Tawil syndrome, a periodic paralysis with associated life-threatening cardiac arrythmias for which no treatment has been identified;
2. The non-dystrophic myotonias caused by sodium and chloride channel mutations for which there is no established treatment and there have been no well-designed clinical trials;
3. The episodic ataxias EA1 and EA2 for which treatment is not yet defined.

Both cellular model systems and animal models, funded separately, are/or soon will be available for each of these disorders and can provide preclinical data necessary for proposed phase one and two trials of novel treatments. These three disorders are prototypes for the development of treatment strategies for more than 50 other rare neurological channelopathies. They may also offer a window for understanding more common disorders likely to be caused by CNS channel mutations/dysfunction such as migraine and epilepsy.

Performance Sites:
Brigham and Women's Hospital, Boston, MA
National Institute of neurological Diseases and Stroke, NIH
University of California, Los Angeles, CA
University of California, San Francisco, CA
University of Kansas Medical Center, Kansas City, KS
University of Rochester School of medicine, Rochester, NY
University of Texas Southwestern Medical Center at Dallas, TX

Patient Support Organizations:

Description from the Grant Application:
Idiopathic bone marrow failure states and cytopenias (IBMFS&C;) are rare disorders characterized by hematopoietic progenitor or stem cell failure resulting in deficient production of one, or all, blood cell lineages. Immune pathophysiology is a unifying factor in many cases of all these diseases. Prior collaborative trials have led to the improvement of effective medical therapy for aplastic anemia (AA), but ongoing multicenter studies are required to advance further the outcome for AA and especially the other bone IBMFS for which few useful treatment options exist. The IBMFS&C; Rare Disease Clinical Research Consortium (RDCRC) at The Cleveland Clinic Foundation (CCF) Cancer Center, will encompass a consortium of several specialized centers, patient advocacy group, and data and a collaboration with a data technology coordinating center (DTCC), the IBMFS&C; RDCRC will focus on AA, paroxysmal nocturnal hemoglobinuria, single-lineage cytopenias including large granular lymphocyte leukemia and pure red cell aplasia, and various myelodysplastic syndromes. This proposal presents a multi targeted approach to improving the medical therapy for IBMFS&C; that includes:

• Implementing treatment algorithms for each IBMFS that define standards of care.
• Systematically evaluating novel laboratory assays that may improve the diagnostic accuracy or understanding of pathophysiologic mechanisms.
• Enrolling patients into a longitudinal follow-up study to correlate new and established diagnostic variables with outcome.
• Comparing medical and transplant approaches for each relevant disorder.
• Developing experimental treatment protocols for disease subsets currently without good treatment options or without a standard treatment approach.
• Training of postdoctoral fellows to develop clinical trials and translational research projects for the IBMFS&C.;
• Educating community physicians in the diagnosis and management of the IBMFS&C;, and
• Improving outreach, education and referral resources for patients and physicians, in collaboration with the Aplastic Anemia & MDS International Foundation (AAMDSIF).

Performance Sites:
The Cleveland Clinic Foundation, Cleveland, OH
UCLA Department of Hematology and Oncology, Los Angeles, CA
The Penn State Cancer Institute, Milton S. Hershey Medical Center, Hershey, PA
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Aplastic Anemia and Myelodysplasia International Foundation, Annapolis, MD

Patient Support Organization:
Aplastic Anemia and MDS (Myelodysplasia Syndromes)International Foundation, Inc.
Paroxysmal Nocturnal Hemoglobinuria (PNH) Support Group

Description from the Grant Application:

• Develop a clinical data repository in collaboration with other Rare Disease Clinical Research Consortia and the Rare Disease Data and Technology Coordinating Center.
  
• Build a vasculitis clinical specimen bank for storage of serum, plasma, DNA and tissue samples linked to the clinical data repository.
  
• Enact a national recruitment program in cooperation with various vasculitis patient advocacy groups.
  
• Utilize the extensive resources of the General Clinical Research Centers at each Primary Consortium Site

Aim 2, Conduct a series of related longitudinal studies of novel biomarkers of vasculitis disease activity. Utilizing the consortium Clinical Data Repository and Clinical Specimen Bank and in coordination with biostatistical support from the Data and Technology Coordinating Center, the Consortium Biomarkers Project will use several promising techniques to develop new markers of disease activity including:

• Proteomics
• Molecular Markers of Oxidative Stress and Inflammation.
• Additionally, this program will be established in a fashion that would easily allow for testing of future novel biomarkers by investigators both within and beyond the consortium.

Aim 3, Utilize the consortium and patient base to conduct Phase I and II clinical trials within the proposed grant period and create the infrastructure to greatly facilitate the design and performance of other future trials.

Aim 4, Establish the Vasculitis Clinical Investigator Fellowship as a core mission on the consortium to provide a mechanism to support, train, and mentor fellows interested in establishing academic careers focused on vasculitis research. This aim will address the pressing need in academic medicine for the training and retaining of patient oriented clinical investigators.

Aim 5, Build and contribute to an electronic website resource with substantive content for clinicians, researchers, and patients.

Performance Sites:
Boston University Medical Center, Boston, MA
Cleveland Clinic Foundation, Cleveland, OH
Johns Hopkins University, Baltimore, MD
Mayo Clinic, Rochester, MN

Secondary Sites:
National Cancer Institute, NCI/FDA Clinical Proteomics Program, Bethesda, MD
University Health Network, Mount Sinai Hospital, Toronto University, ON, Canada
Rheumaklinik Bad Bramstedt, Germany
Assistance Hôpitaux Publique De Paris, Hôpital Avicenne, Paris, France
University of Alabama at Birmingham, AL
New York Bone & Joint Beth Israel Medical Center, New York, NY

Patient Support Organizations:

Description from the Grant Application:
A consortium of investigators, institutions, and patient support groups will constitute a Rare Disease Clinical Research Consortium focused on a diverse group of disorders characterized by defects in steroidogenesis. We will study the longitudinal history of these rare disorders and determine the outcome of treatment on height, fertility and gender. Long-standing informal collaboration between investigators at Mount Sinai School of Medicine, Rockefeller University, Columbia University, the University of Texas Southwestern Medical Center, the University of Québec, Hospital Debrosses (Lyons), and the Hospital das Clínicas da FMUSP (São Paulo) will facilitate the creation of a productive cooperative research network that draws on the extensive experience of each investigator. Clinical Research Centers at Mount Sinai, Rockefeller, and the University of Texas Southwestern Medical Center will participate. Each investigator in the consortium has followed a large group of patients with a specific genetic defect affecting steroid synthesis over many years, encompassing the natural history of these diseases from prenatal life to death. Creation of a storage and management database will constitute a scaffold for ongoing research, enabling the preservation and use of this large body of clinical data assembled by experts in each disorder. Moreover, design of templates for a standardized clinical description of these disorders will permit prospective studies which can offer open enrollment to affected individuals or individuals at risk. Our research group includes the investigators who have identified the molecular genetic defect for each disorder, where known, and who maintain laboratories dedicated to the identification of new mutations. The combination of clinical and molecular genetic information will raise the standard of medical care and may permit development of novel treatments based on detailed knowledge of the natural history and molecular genetic basis of these disorders. Important elements of our plan are to

1. Establish the clinical research consortium which pools data from our sites in cooperation with the DTCC and analyzes this data,
2. Educate young investigators in the management and clinical research of steroid disorders, and
3. Strengthen our connections with patient support groups to enable individuals affected or at risk to have new kinds of input and access to optimal medical care.

Performance Sites:
Mount Sinai School of Medicine, New York, NY
Rockefeller University, New York, NY
Laval University, Quèbec, Canada
University of Texas Southwestern Medical Center at Dallas, TX
Hospital Debrosses Lyon, France
Hospital das Clinicas da FMUSP, São Paulo, Brazil
Columbia University College of Physicians & Surgeons, New York State Psychiatric Institute, New York, NY

Patient Support Organization:
CARES (Congenital Adrenal Hyperplasia Research, Education, & Support), Foundation, Inc.
National Adrenal Diseases Foundation (NADF)
Androgen Insensitivity Support Group (AISSG)
The Magic Foundation

Description from the Grant Application:
We seek to establish a research consortium that will facilitate clinical research in rare lung diseases by

1. Promoting collaboration among centers already focused to clinical research on rare lung diseases,
2. Attracting & training highly qualified investigators,
3. Collecting clinical data from geographically distributed patients into a large, centralized database, and
4. Making the accumulated clinical data available to those affected or possibly affected by a rare lung disease, their clinicians, clinical and basic investigators, and the general public.

Performance Sites:
Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH
Cleveland Clinic Foundation, Cleveland, OH
Oregon Health & Sciences University, Portland, OR
International Medical Center of Japan, Tokyo, Japan
Harvard University and Brigham and Women's Hospital, Boston, MA
Medical University of South Carolina, Charleston, SC
National Heart, Lung, and Blood Institute, Bethesda, MD
National Jewish Medical and Research Center (NJMRC), Denver, CO
Royal Melbourne Hospital, Melbourne, Australia
University of Florida Medical Center, Gainesville, FL
University of Texas Health Center, Tyler, TX

Patient Support Organizations:
Alpha-1 Foundation
The LAM Foundation
Pulmonary Fibrosis Foundation

Description from the Grant Application:

Rare disorders that are associated with an increased thrombotic risk include the antiphospholipid antibody syndromes (APS), heparin-induced thrombocytopenia (HIT), combined thrombophilic states, paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, and the catastrophic ‘thrombotic storm'. These disorders frequently exhibit more "aggressive" clinical phenotypes, affecting arterial, venous, and/or microvascular beds. Diagnostic and/or therapeutic limitations exist for each of these disorders, and prospective studies are needed to more clearly define the syndromes and develop better therapies. This multi-institutional academic consortium focuses on rare thrombotic disorders, and will

• Genetic analysis of familial APS, familial APS/autoimmune syndromes, and patients with catastrophic ‘thromobotic storm.'
• Identify risk factors for thrombosis in patients with antiphospholipid antibodies and HIT.
• Define the natural history of patients with elevated heparin-platelet factor 4 antibodies after bypass.
• Emerging opportunities from ongoing studies will be identified that promote new research directions, projects, and translational activities that foster links between the consortium and industry.

Performance Sites:

Patient Support Organizations:

Description from the Grant Application:
The project director will establish a Rare Diseases Clinical Research Center (RDCRC) at The University of North Carolina (UNC) and an associated consortium with three other geographically dispersed sites to study rare diseases of the airways. These four sites in the consortium will collaborate in diagnostic, genetic, and other studies in patients with genetic impairments in mucociliary clearance, specifically primary ciliary dyskinesia (PCD), variant forms of Cystic Fibrosis (CF), and pseudohypoaldosteronism (PHD). Patients with these unusual disorders with increased morbidity and mortality often have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. The two central hypotheses are that

1. A broad-based systematic approach to the diagnostic evaluation of these patients will yield more precise diagnostic criteria and better diagnostic techniques, including genetic testing; and

2. Systematic evaluation of specific cohorts of these patients with state-of-the-art methodologies and rigorous cross-sectional and longitudinal study designs will provide better understanding of clinical pathogenesis of these disorders. In a five-year longitudinal study of 300 patients with PCD, we will use innovative techniques, including measurement of PFTs and HRCTs of the chest in infants, to define early onset and progression of pulmonary disease in PCD. Moreover, 10 additional geographically dispersed sites will serve as PCD Clinical Centers, to assist in the follow-up care of PCD patients in the longitudinal study. This collaborative effort will improve care by defining clinical practice guidelines, especially for PCD. The pilot projects in PCD are designed to develop better diagnostic tools, biomarkers and screening tests, to characterize the respiratory pathobiology, and evaluate novel therapeutic agents. The existing training program in rare airway diseases will be extended to established and young investigators at UNC, and to investigators at other sites. The consortium will work with the Data and Technology Coordinating Center to coordinate and expand current Web sites to provide information to the lay public, patients, and medical professionals for education, referral, and recruitment of study subjects.

Patient Support Organization:
Primary Ciliary Dyskinesia (PCD) Foundation
Cystic Fibrosis Foundation (CFF)

Description from the Grant Application:
The Principal and Co-Investigators propose the development of a coordinated and integrated rare liver diseases clinical research consortium. The consortium will include sites at the Children’s Hospital in Denver and five clinical sites within the United States, each with investigators who have extensive clinical experience, patient populations, and research programs for these disorders, and each with a General Clinical Research Center (GCRC). The consortium will focus on investigations of 5 genetic causes of intrahepatic cholestasis. These disorders have serious if not fatal consequences (without liver transplantation) and severely affect the children’s normal growth and development. The five related disorders are a-1-antitrypsin deficiency, Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis and metabolism defects, and mitochondrial hepatopathies.

The consortium will develop a longitudinal hypothesis-driven database study of these diseases. During this study, serum, DNA, and liver tissue will be obtained from all patients and stored for future studies. The consortium will also include

• 3 biological core facilities to ensure the highest quality analysis of genetic information, liver histopathology, and bile acid biochemistry for subjects enrolled in this study;
• an administrative core;
• a pilot/demonstration project program to encourage innovative scientific investigation;
• a training program in order to attract new investigators to the study of rare liver diseases; and
• development of electronic internet-based clinical, educational, histologic, and research resources for these diseases.

Performance Site:
The Children’s Hospital Denver, Denver, CO
Children’s Hospital of Philadelphia, Philadelphia, PA
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
King’s College, London, England
Mount Sinai School of Medicine, New York, NY
University of California/San Francisco, San Francisco, CA
University of Colorado Health Sciences Center, Denver, CO

Patient Support Organizations:
American Liver Foundation
The Alagille Syndrome Alliance
Alpha-1 Foundation
Children’s Liver Association for Support Services (CLASS)
United Mitochondrial Disease Foundation (UMDF)

Description from the Grant Application:
This proposal seeks support to establish a Data and Technology Coordinating Center (DTCC) for the Rare Diseases Clinical Research Network. The DTCC will play an active role in the development of the Network. It will facilitate research in the design of clinical protocols and the data management and analysis necessary to support them. Working with the Rare Diseases Clinical Research Consortia, the DTCC will make available a coordinated clinical data management system for the collection, storage and analysis of data from multiple diseases and multiple clinical sites. The data management system will be a secure web-based system that includes the capability to capture and integrate many different forms of data (clinical, imaging, genetics, pathology, etc.), and the scalability to serve as a national clinical information network. Among its features will be a user-friendly system for recruitment and referral, tools for cross-disease data mining, data sharing, and a public portal to relevant data resources. This application applies novel approaches to and technologies for data management and training, includes the use of web-based video streaming and also seeks to conduct research and development of new approaches to distributed computing, federated databases, and data mining.

Performance Site:
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

In FY 2002, the ORD provided one-time supplementary awards to 44 existing intramural and extramural Institute and Center research grants. The purpose of these supplements was to generate pilot and demonstration projects as well as research training foci on rare diseases and planning grants for a subsequent Request for Applications (RFA) for rare diseases research. The supplemental grants ranged from research on prion disease to scleroderma, to congenital heart block, to the molecular basis for neuronal migration, elctrocorticographic studies of human cortical function, and the study of marrow stromal cells for lysosomal disease CNS defects.

For more information, please contact:

Giovanna M. Spinella, M.D.
CDR, US Public Health Service
Director, Extramural Research Program
Office of Rare Diseases, OD, NIH
6100 Executive Blvd. Rm. 3B01-MSC 7518
Bethesda, MD 20892-7518
Telephone: 301 402-4336
Fax: 301 480-9655
E-mail: ord@od.nih.gov