Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) supports basic and clinical research on many rare diseases. Although diseases such as type 1 diabetes, type 2 diabetes, and obesity are not rare, there are rare single gene defects that cause these conditions such as Maturity Onset Diabetes of the Young (MODY) and lipodystrophy. In addition, the NIDDK supports research on both common and rare causes of kidney, liver, and GI diseases. The Institute also supports research on genetic metabolic diseases such as cystic fibrosis, lysosomal storage diseases including Krabbe disease and Mucopolysaccharidoses, disorders of amino acid metabolism such as tyrosinemia and maple syrup urine disease, disorders of copper transport including Menkes and Wilson disease, and hematologic diseases such as Cooley’s anemia and sickle cell disease.

Recent Scientific Advances in Rare Diseases Research

Cystic Fibrosis

Cystic fibrosis (CF) is the most common fatal genetic disease in Caucasians, affecting approximately one in 3,000 newborns. Patients are diagnosed in early childhood with symptoms such as failure to thrive. With management of the nutritional problems and infections, the life expectancy for CF has been increased to over 30 years. CF is caused by mutations in the gene encoding the CFTR protein, which resides in the outer surface of cells lining such tissues as the lung and intestine, where it regulates the movement of chloride. The most common mutation of the gene, ΔF508, yields a protein that does not fold properly and is thus degraded before it reaches the cell surface. Researchers have recently tested the effect of a compound called curcumin, purified from the spice turmeric, in a mouse model of CF. When given to mice that are genetically engineered to have the ΔF508 mutation, curcumin treatment enabled the mutant form of the CFTR protein to function effectively, presumably by promoting the correct folding to allow it to reach its normal cellular destination. Indeed, when cells cultured from animals with the ΔF508 mutation were treated with curcumin, the protein was properly routed to the cell surface. Importantly, the amount of curcumin that achieved these promising results in mice is equivalent to a dose that has been well tolerated by humans in previous studies. Therefore, curcumin, which is already known to be safe in people, has the potential to be of value for patients with this devastating illness.


New approaches for treating liver disease are emerging from laboratory studies of hereditary tyrosinemia type I—a rare inherited metabolic disorder associated with severe liver and kidney disease in infants and children. It is caused by a deficiency in an enzyme that breaks down the amino acid tyrosine, resulting in elevated tyrosine levels in the blood (tyrosinemia) and tissue damage. Although a drug for treating this disease was approved in 2002, its long-term efficacy is still in question, and liver transplantation remains the most effective therapy. One way to correct the underlying defect in genetic diseases such as hereditary tyrosinemia would be through transplantation of cells with a functioning copy of the gene for the missing enzyme. In recent years, researchers have explored this possibility in mice that are deficient in the same enzyme that causes hereditary tyrosinemia type I in humans. They found that transplantation of stem cells derived from the bone marrow of healthy adult donor mice into the mice with tyrosinemia resulted in fusion between the healthy and diseased cells, correction of the genetic defect, and repair of the liver. Investigators then wanted to identify which cell type was responsible for this correction. Were stem cells, with their ability to turn into a variety of cell types, required, or could more mature cells—already committed to forming a particular cell type—also work to correct the defect? Researchers addressed this by conducting a series of transplantation experiments using several different types of donor mice that were genetically engineered to produce only certain types of cells that originate in the bone marrow. They found that it was possible to correct the defect in mice with tyrosinemia by using macrophages—a kind of immune cell that develops from cells that form in the bone marrow. These results support the theory that donor stem cells used in prior experiments probably differentiated into macrophages prior to fusing with the recipient’s liver cells. Importantly for potential clinical applications, this study also suggests that, in contrast to bone marrow transplantation, treatment with macrophages could be a less invasive, more efficient type of cell transplantation procedure for genetic liver diseases such as hereditary tyrosinemia. A key benefit of macrophages or their immediate precursor cells is that they could be administered directly into the liver or bloodstream.

Polycystic Kidney Disease

Polycystic kidney disease (PKD) and other inherited cystic kidney diseases frequently cause kidney failure and death; some rare forms of PKD primarily affect children. There are no effective treatments. One characteristic common to several of these disorders is an elevated level of cyclic adenosine monophosphate (cAMP) in the kidneys. Within cells, cAMP transmits messages that affect their growth and function; abnormally high levels of cAMP in certain kidney cells are thought to contribute to cyst formation. Researchers treated animal models of the two predominant forms of human PKD and another cystic kidney disease using a chemical, OPC31260, which lowers cAMP production in the kidneys. The treatment halted disease progression, and in some cases resulted in improvement. OPC31260 and similar compounds are currently undergoing testing in human clinical trials for treatment of other diseases and so far appear to be safe. Thus, drugs of this class are promising candidates for phase I clinical trials to treat patients with PKD.


Mucopolysaccharidoses (MPS) are a group of disorders that result from a defect in enzymes needed to degrade mucopolysaccharides. These undegraded molecules become trapped and accumulate in the lysosomes of the cell, causing cell death. The incidence of this group of diseases is about 1 in 22,500 births. Aldurazyme, an enzyme replacement therapy (ERT) for MPSI, which is given intravenously every week, was introduced last year. Replacement of a missing enzyme can result in an immune reaction to this protein, which may be foreign to some patients with null mutations. In order to prevent a strong antibody response to this protein, a tolerization regimen has been developed in the dog model of MPSI. This regimen consisted of a 60-day course of cyclosporine A and azathiprine with low-dose infusions of the enzyme. The dogs tolerated the enzyme for up to 6 months following the treatment. This promising approach, which may be applicable to other disorders using ERT, needs to be tested in humans.

Krabbe Disease

Krabbe disease, also called globoid cell leukodystrophy, is a genetic lysosomal storage disease that occurs in approximately 1 in 200,000 births. This disease usually manifests in the first year of life, resulting in neuronal degeneration and eventually death. However, impressive results have been reported in patients who receive a cord blood transplant prior to the initiation of symptoms. In order to identify at-risk infants prior to the appearance of symptoms, a high-throughput screening test is needed for Krabbe disease. NIDDK-supported investigators have developed a newborn screening test for Krabbe disease using tandem mass spectrometry that can be performed on a dried blood spot. This technology paves the way for including newborn screening for Krabbe disease in newborn screening programs to allow early diagnosis so that a life-saving cord blood transplantation can be performed.

Crohn’s Disease

Crohn’s disease (CD) is a chronic, currently incurable digestive disease, most commonly affecting either the colon or the portion of the small intestine nearest to it, the ileum. Symptoms frequently include abdominal pain, nausea, vomiting, weight loss, and diarrhea, which is occasionally bloody. The precise causes of CD are unknown, but bacteria in the gut are thought to contribute. There may also be a genetic component: the disease not only runs in families but Americans and Europeans with the disease also frequently have particular variants of a gene called card15, which is expressed in immune cells and is believed to have a role in innate immunity to bacteria. In a new study, researchers found that the card15 gene is expressed at high levels in so-called Paneth cells, which lie at the base of invaginations in the small intestine. The Paneth cells secrete anti-microbial compounds, probably playing an important role in controlling gut bacteria. Thus, card15 and Paneth cells represent an apparent link between the genetic and bacterial risk factors for the illness and are a promising target for development of therapeutics.

Hirschsprung Disease

Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by absence of the enteric neurons in the distal gut. One of the primary genes involved in HSCR is the G protein-coupled endothelin receptor B gene (EDNRB). Expression of this gene is required for migration of the cells forming the enteric nervous system into the colon. To better understand the expression of this gene, NIDDK-funded investigators studied the regulatory region of this gene. They identified a region that modulates the expression of this gene through the binding of the neural crest transcription factor, SOX10. Engineered mice with a deletion or mutation of these sites did not express EDNRB and developed megacolon. These studies may explain the interaction among the genes that cause HSCR. In addition, understanding the function of this regulatory region could explain spatiotemporal regulation of gene expression.

Rare Diseases Research Initiatives

In September 2004, the NIDDK and NIH Office of Rare Diseases jointly funded the Rare Liver Diseases Consortium to expand studies in children with serious cholestatic liver diseases, including Alagille syndrome, progressive familial intrahepatic cholestasis, alpha-1-antitrypsin deficiency-associated disease, the mitochondrial hepatopathies, and inborn errors of bile acid metabolism. These disorders have serious, if not fatal, consequences and severely affect normal growth and development. The Consortium will develop a longitudinal hypothesis-driven database study of these diseases and collect biosamples in the NIDDK Central Repository to facilitate future studies.

The NIDDK has undertaken a review of its Centers Program. The major recommendation was to encourage more translational research to be conducted in our disease-specific Centers. To accomplish this, NIDDK has put out RFAs for two new types of Centers: PKD Research and Translation Core Centers, DK-04-012, and CF Research and Translation Core Centers, DK-04-008. NIDDK expects to fund two new Centers from each RFA in 2005. In addition, the NIDDK reissued RFAs for two existing Centers programs that support rare disease research: Centers for PKD Research, DK-04-011, and Centers of Excellence in Molecular Hematology, DK-04-15. NIDDK expects to fund two PKD Centers and three Hematology Centers in 2005.

In partnership with NCI and NIAID, NIDDK issued PA-04-068, “Development of Assays for High Throughput Drug Screening.” The purpose of this PA is to encourage the use of high-throughput small molecule screening in both research and drug discovery programs by funding the development of innovative assays that may be adapted for automated screening. The assays would aim to identify new tools for basic research and promising new avenues for therapeutics development. One specific bullet calls for research involving mutant proteins responsible for inborn errors of metabolism, cancer, or other rare diseases. Assays developed under this PA will be eligible for consideration by the NIH Molecular Library Screening Centers that are being developed as a component of the NIH Roadmap. The first applications submitted to this PA are expected to be funded in 2005.

Rare Disease-specific Conferences

On November 20–21, 2003, the NIDDK and the Oxalosis and Hyperoxaluria Foundation co-sponsored a meeting on Oxalosis and Hyperoxaluria in Annapolis, MD. The chairs of the organizing Committee were Dawn Milliner, M.D., Mayo Clinic, and Gill Rumsby, Ph.D., University College London along with Craig Langman, MD, Children's Memorial Hospital Chicago on behalf of the Oxalosis and Hyperoxaluria Foundation. Marva Moxey-Mims, MD, and Rebekah S. Rasooly, Ph.D., of NIDDK served as co-organizers. A total of 23 lectures were given by senior and junior investigators in sessions titled Enzyme Form and Function, Oxalate and the Cell, Diagnosis of Primary Hyperoxaluria, and Toward Rational Therapeutics. In addition, a patient and the parents of a pediatric patient made presentations. Approximately 50 investigators, clinicians, and trainees from the United States, Canada, Europe, and Japan attended the workshop. The workshop featured much new research that was unpublished. Several especially noteworthy reports were of the promise of molecular chaperones for therapeutics by Jeff Kelly, Scripps, and Chris Danpure, University College London; and basic research and preliminary clinical studies using Oxalobacter as a treatment by Marguerite Hatch, University of Florida, and Bernd Hoppe, University Children's Hospital Cologne, Germany. In addition, Dawn Milliner, Mayo Clinic, and Gill Rumsby, University College London, presented unpublished data about the challenges of physiological and genetic diagnosis and led a discussion aimed at evolving a consensus algorithm for publication. Finally, John Lieske and Dawn Milliner of the Mayo Clinic presented the new Web-based NIDDK-funded International Registry of Hereditary Calcium Urolithiasis. The meeting provided a much-needed forum for exchanging new research on primary hyperoxaluria and for developing a consensus among international experts about diagnosis and treatment of the disease. At the adjournment of the workshop, participants agreed to meet again in 2004 in Rochester, Minnesota.

On May 4 and 5, 2004, NIDDK, ORD and the Oxalosis and Hyperoxaluria Foundation sponsored a workshop titled, “Protein Misfolding and Misprocessing in Disease.” Allen Spiegel (Director, NIDDK) and Steve Groft (Director, ORD) introduced the meeting, noting that the primary objective was to stimulate research that will translate basic cell biology, biochemistry, and biophysics findings about protein structure and assembly into potential therapies for monogenic and other misfolding and misprocessing disorders. In his introduction, Brett Rosen (Oxalosis and Hyperoxaluria Foundation) highlighted the human value of this research in providing hope for patients suffering from these diseases and for their families. The meeting was well attended, with 209 participants. The audience included clinicians, clinical researchers, and basic scientists at all career levels from academic institutions, the NIH, and the private sector. Twenty-one of the MDs who attended received CME credit. In all, there were 31 scientific talks, 4 of which were selected from abstracts submitted by junior investigators. Twenty-nine posters were presented at an active and crowded poster session. Rare diseases specifically covered in presentations: cystic fibrosis, nephrogenic diabetes insipidus; collegen diseases, including osteogenesis imperfecta; primary hyperoxaluria; Gitelman’s syndrome; alpha-1-anti-trypsin deficiency; congenital hyperinsulinism; Wolfram syndrome; Gaucher disease; polycystic kidney disease; familial amyloidosis; familial amyloid polyneuropathy; congenital nephrotic syndrome; Fabry disease; GM1 gangliosidosis; and Tay-Sachs disease. Following the meeting, NIDDK staff met with investigators to develop future initiatives to support the development of therapeutics based on correcting protein misfolding.

On May 8–10, 2004, NIDDK, NHBLI, and the Office of Rare Diseases provided support for the meeting titled “ Workshop on Bioiron in Thalassemia, Sickle Cell Disease, and Hemochromatosis,” sponsored by the Center for BioIron at CHORI, Oakland, CA, through 1R13 DK065630-01. The workshop was attended by more than 30 registrants, with additional students and postdoctoral fellows from various California Bay Area universities and medical schools. The principal organizer of the workshop was Elizabeth C. Theil, Ph.D., an internationally recognized expert on the mechanisms of iron transport and iron overload. The purpose of the workshop was to enhance translational research in bioiron, including iron overload with hypertransfusion and malabsorption as the iron source, and to provide opportunities for collaborative research interactions for junior scientists in groups already engaged in basic/clinical research. The location was selected to take advantage of established foci of unusual strength in clinical and basic research and training in bioiron related to hemochromatosis or sickle cell disease and thalassemia and to begin to rectify underdeveloped potential to share common information on iron. Topics ranged from the interactions of liver iron and hepatitis C and mechanisms of iron chelation in iron overload to organ dysfunction in iron-overloaded patients with thalassemia. Participants engaged in a summary session where topics of future research interest were discussed, based on unresolved issues identified in the workshop. Staff members of the NIDDK and NHLBI were present during this discussion. Following the workshop, these staff members met to identify priority areas that might be addressed in future initiatives.

On June 20–22, 2004, NIDDK, NICHD, and ORD provided support for the Ninth International Workshop on Multiple Endocrine Neoplasias. The total registration at the meeting was 196 and there were 65 posters. Three keynote talks covered broad issues. Symposium 1 covered molecular biology of pituitary tumors with an emphasis on mechanisms of tumorigenesis. Symposium 2 covered thyroid tumors with a focus on long-term follow-ups of surgery indicating prevention and cure of medullary thyroid cancer in men2. Working groups met to discuss patient issues, tyrosine kinase inhibitor drugs, and organization of a pheochromocytoma consortium. The workshop abstracts have been published in the Journal of Internal Medicine 255:696–730, 2004.

In 2003, the NIDDK and NIBIB funded four grants in response to RFA DK-03-007, Noninvasive Measurements of Iron by Magnetic Resonance Imaging. A meeting of these grantees was held in September 2004, and considerable progress has been made in developing each of these projects. The diagnosis and management of patients with iron overload, including those with Cooley’s anemia, would be improved greatly if physicians had ready access to a noninvasive, safe, and accurate way to measure body iron levels. It was apparent from the reports at the meeting that MRI technology has potential as a technology to measure body iron. Reasonably high quality images of stored iron have been obtained and, even at this stage, have begun in some cases to be useful clinically. A second meeting is planned for 2005.

Activities with Rare Diseases Patient Advocacy Groups

The Cooley’s Anemia Foundation, NIDDK, NHLBI, CDC, and HRSA participated in the first inter-agency meeting focused on thalassemia held on September 17, 2004. The purpose was to learn about the activities in the different agencies to enhance integration and communication. One of the recommendations from this first interagency meeting is to establish a Thalassemia Working Group within the government for greater communication and cooperation.

On April 22, 2004, NIDDK and the Oxalosis and Hyperoxaluria Foundation held a Calcium Oxalate Stone Disease Taskforce Meeting in Bethesda, MD. The purpose was to formulate a research agenda for hereditary calcium oxalate stone disease, emphasizing translational research that will bring promising discoveries from the laboratory to a clinical research setting. Numerous recommendations emerged from this meeting for enhancement of research on improved diagnostics, epidemiology, pharmacologic treatment, microbial therapies, and gene therapy as well as strengthening of training for investigators in this area.


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Last Reviewed: July 22, 2005