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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Institute of Allergy and Infectious Diseases (NIAID)

Overview of NIAID Rare Diseases in Children Research Activities,
FY 2000–FY 2005

NIAID conducts and supports research that strives to understand, treat, and ultimately prevent the myriad of infectious and immunologic diseases that threaten millions of human lives. NIAID programs include a focus on special populations, including children. NIAID has a long history of research support for diseases that are classified as rare in children and has made considerable progress from basic discoveries in microbiology and immunology to the development of diagnostics, therapeutics, and preventive measures such as vaccines. Continued progress in this area of research will have considerable impact on the future health and quality of life for our Nation's children.

NIAID research activities on rare childhood diseases are grouped into the following broad areas: infectious diseases, primary immunodeficiency diseases, autoimmune diseases, and allergic diseases.

  • Infectious diseases include diseases caused by bacteria, parasites, viruses, and fungi. Research on rare childhood infectious diseases is aimed at delineating mechanisms of pathogenesis and developing more effective diagnostic, treatment, and prevention strategies.

  • Primary immunodeficiency diseases are hereditary disorders caused by intrinsic defects in the cells of the immune system and are characterized by unusual susceptibility to infection. NIAID research is focused on the development of technology to make gene transfer an effective and curative therapy, and the identification of gene defects and immunologic abnormalities that lead to defective function.

  • Autoimmune diseases are diseases in which the immune system mistakenly attacks and damages the body's own organs, tissues, and cells. NIAID research is focused on identifying the underlying immune mechanisms that cause or trigger disease onset and on developing interventions to treat autoimmune diseases.

  • Allergies are inappropriate or exaggerated reactions of the immune system to substances that, in the majority of people, cause no symptoms. NIAID research is focused on the development of new approaches to the diagnosis, prevention, and treatment of a wide range of allergic diseases.

Recent Scientific Advances in Rare Childhood Diseases in Children Research

Rare Infectious Diseases

Congenital Cytomegalovirus (CMV)

Consequences of CMV in congenitally infected children can be devastating; most infected infants who survive suffer from profound progressive deafness and/or mental retardation. NIAID's Collaborative Antiviral Study Group (CASG), a multicenter activity supporting the conduct of clinical trials of therapies for viral infections other than HIV, has completed a phase III trial of ganciclovir for the treatment of symptomatic congenital CMV infections. Symptomatic babies treated with intravenous ganciclovir showed improvement in or maintenance of their hearing.

Haemophilus Influenzae Type B (Hib)

Hib was the leading cause of bacterial meningitis and other invasive bacterial disease (meningitis, epiglottitis, septic arthritis, osteomyelitis, and pericarditis) among children younger than five years of age before the introduction of effective vaccines. New haemophilus strains constantly emerge through the process of transformation; that is, strains mutate and acquire new genetic information. Studies have linked the presence of a 26-base-pair sequence to several other known transformation genes. A better understanding of the mechanism of acquisition of new genes by H. influenzae may aid in the development of better strategies for the suppression of antibiotic-resistant strains and the identification of novel cellular targets for the action of new antimicrobial agents.

Streptococcus (Group B)

Group B streptococci (GBS) cause serious illness in newborns, including sepsis, pneumonia, and meningitis. Neurologic sequelae include sight or hearing loss and mental retardation. Infant and maternal GBS infections may be preventable by maternal immunization. A GBS Type II capsular polysaccharide-tetanus toxoid (Type II-TT) vaccine in which GBS capsular polysaccharide was coupled to tetanus toxoid was recently compared to an uncoupled GBS Type II capsular polysaccharide vaccine. The immune response in the recipients of the coupled vaccine was significantly higher than in recipients of the uncoupled vaccine; immune responses to the coupled vaccine were dose-dependent and correlated in vitro with the enhanced uptake of organisms by white blood cells. This study supports the inclusion of capsular polysaccharide Type II coupled to tetanus toxoid in the formulation of a GBS vaccine.

Rare Primary Immunodeficiency Diseases

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS is a disease in which a genetic defect in programmed cell death, or apoptosis, leads to the breakdown of lymphocyte regulation, causing a proliferation of lymphocytes. Recent studies have determined that the risk of becoming ill with ALPS is significantly greater in people who have an abnormality at a specific location of the fas gene (a gene that codes for a protein that triggers lymphocytes to die at the completion of their normal life cycle). Individuals with fas gene mutations are at greater risk for later development of B and T cell lymphomas. Researchers have also identified other mutations involved in ALPS.

Chronic Granulomatous Disease (CGD)

CGD is an inherited genetic disorder characterized by a failure of white blood cells called neutrophils to make oxygen compounds that kill bacteria and fungi. The disorder leaves individuals vulnerable to life-threatening infections and inflammatory growths, or granulomas, which can damage the lungs, liver, and other organs. Scientists recently reported a promising therapeutic approach for individuals with CGD. Patients with CGD underwent a preparative regimen that causes intense immunosuppression without destroying the bone marrow, followed by the transplant of immunologically matched sibling stem cells; this approach provided a cure for a subset of CGD patients with fully immunologically matched siblings. In another clinical trial, investigators demonstrated functional correction of the genetic defect for the X-linked form of CGD in three of five patients treated with multiple infusions of gene corrected cells.

Familial Hemophagocytic Lymphohistiocytosis (FHL)

FHL is a rare genetic disorder caused by mutations in at least three genes that results in uncontrolled activation of the immune system, leading to death in early infancy or childhood. Researchers demonstrated that a protein called perforin, part of the cell-destroying apparatus in killer T cells, is missing or inactive in FHL patients. These results may prove beneficial in the development of better diagnostic approaches and new therapies for this disease and new approaches to control undesired T cell responses in autoimmune diseases, transplantation, allergy, and asthma.

Job's Syndrome

Job's syndrome, also known as hyperimmunoglobulin E recurrent infection syndrome (HIE), is a rare inherited disease characterized by recurrent bacterial infections of the ears, sinuses, lungs, or skin and elevated levels of the antibody immunoglobulin E. Patients may also have scoliosis, weak bones and recurrent bone fractures, strokes or other brain disorders, severe itching, and skin inflammation. Scientists have linked a genetic defect in HIE patients to chromosome 4. Finding the gene or genes involved in HIE will be critical for the development of better strategies for HIE, especially gene therapy.

Severe Combined Immunodeficiency Disorder (SCID)

SCID is a rare congenital syndrome characterized by little if any immune response. Some children with SCID have lived for years in germ-free rooms and "bubbles" required by their unusual susceptibility to infectious agents that can be life-threatening.

A study that may prove critical to the development of a treatment for SCID involves improving the function of the thymus by stem cell transplantation. Scientists studied 83 SCID patients who had undergone bone marrow transplantation to receive stem cells over an 18-year period. T cells that developed in each patient were identified, characterized, and followed over time with molecular and cellular markers. The number of T cells reconstituted in the thymus peaked to near normal levels 1-2 years after transplantation, with continued thymic function for up to 14 years.

X-linked Hyper-IgM Syndrome (XHIM)

Individuals with XHIM lack, or have only trace amounts of, several functional classes of antibodies, or immunoglobulins (IgG, IgA, IgE), but have normal or elevated levels of the antibody IgM, causing them to be highly susceptible to recurrent infections. The majority of cases of this disease are caused by a defect in the T cell surface molecule, CD40 ligand, which binds to the B cell receptor CD40. Scientists are studying the treatment of patients with XHIM with a human-made CD40 ligand protein.

A second form of XHIM associated with ectodermal dysplasia (the abnormal development of specific tissues including, among other structures, the skin, hair, nails, sweat glands, and teeth) may be caused by a mutation in both CD40 and a cell-signaling pathway. Patients with this mutation do not produce IL-12 (which is important in eliciting an immune response to intracellular organisms) upon signaling via CD40.

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

FY 2000 and FY 2001 Research Activities

NIAID supports a wide range of research activities in rare childhood diseases, including clinical trials. Because many clinical trials are ongoing and dependent on accrual, the termination date of funding is not always well-defined.

Rare Infectious Diseases

  • NIAID supports the Collaborative Antiviral Study Group (CASG), a multicenter activity supporting conduct of clinical trials of therapies for viral infections other than HIV. The CASG:

      - Conducts Phase III studies evaluating the use of oral acyclovir following the standard-of-care treatment with intravenous acyclovir to limit the recurrence of neonatal herpes virus infections limited to the skin, eye and mouth, or central nervous system. (FY 1997 to present)

      - Conducts a clinical evaluation of treatment of neonatal enteroviral sepsis with pleconaril (VP63843). (FY 1999 to present)

  • NIAID is supporting phase I/II trials for three different candidate vaccines for CMV: a glycoprotein subunit, engineered live recombinant viruses, and a prime-boost strategy using a glycoprotein delivered both as a subunit and in an avian poxvirus vector. (FY 1999 to present)

  • NIAID is the sponsor of a phase I safety and immunogenicity trial at Baylor College utilizing a GBS type III polysaccharide-tetanus toxoid conjugate vaccine in third-trimester pregnant women. As a part of the maternal immunization program, this vaccine had previously been shown to be safe and well-tolerated in clinical trials in postpartum women and women of childbearing age. A trial with pregnant women is in progress. (FY 1999 to present)

  • NIAID continues to support research on the epidemiology of GBS disease, basic biology of GBS, GBS vaccine research, and clinical trials of GBS conjugate vaccines through a multidisciplinary contract awarded to Brigham and Women's Hospital. (FY 1997 through FY 2002)

  • NIAID will be the investigational new drug (IND) sponsor for a safety and immunogenicity clinical trial to evaluate a GBS Type V capsular polysaccharide-tetanus toxoid conjugate vaccine in healthy women. The IND has been submitted to the U.S. Food and Drug Administration (FDA), and the clinical trial is expected to begin in 2001. (FY 2001 through undetermined time since research activity is a clinical trial)

  • NIAID is supporting a study in three rural Alaskan villages to investigate the epidemiology of Hib carriage and transmission in Alaskan Native infants and to evaluate risk factors and immunologic parameters associated with carriage. An intervention study will be initiated in hopes of demonstrating the feasibility of at least one approach to Hib elimination in this high-risk population. (FY 2000 through FY 2002)

  • NIAID participates with other national research agencies in support of The Global Alliance for Vaccines and Immunization (GAVI). GAVI was established in 1999 to replace the Children's Vaccine Initiative. The mission of GAVI is to protect health and save lives through the widespread use of safe vaccines, in the belief that every child, regardless of place of birth or socioeconomic status, should be protected against vaccine-preventable disease. (Activity is a consortium.)

Rare Primary Immunodeficiency Diseases

  • NIAID, through a contract to the Immune Deficiency Foundation (IDF), established and maintains a registry of clinical information on U.S. residents affected by primary immunodeficiency diseases. For each disease, the registry collects information on incidence, clinical phenotypes and phenotype/genotype correlations, and natural course of the disease, including complications, effects of therapy, causes of death, and prognosis. (FY 1998 through FY 2002)

  • NIAID, NCI, and NICHD co-funded a research project involving the use of a new screening device that specifically targets minority populations to determine if the occurrence of primary immunodeficiency diseases in large urban Hispanic and African American populations is under-diagnosed. (FY 2000 through FY 2002)

Rare Autoimmune Diseases

  • NIAID chairs the Autoimmune Disease Coordinating Committee to increase collaboration and facilitate the development of coordinated research in autoimmune diseases among the many NIH Institutes, other Federal agencies, and private groups. (Funding years not applicable)

  • Through the Clinical Trials Network for Stem Cell Transplantation for Autoimmune Diseases established in FY 2000, NIAID is sponsoring clinical trials to assess the safety and efficacy of hematopoietic stem cell transplantation for treating severe autoimmune diseases, along with integrated studies of underlying mechanisms. (FY 2000 through FY 2004)

  • NIAID continues to support research projects awarded in FY 1999 in response to several new trans-NIH initiatives in autoimmunity, including: Environment/Infection/Gene Interaction in Autoimmunity (FY 1999 through FY 2001); Target Organ Damage in Autoimmune Diseases (FY 1999 through FY 2003); and Pilot Trials on Innovative Therapies for Rheumatic and Skin Diseases (FY 1999 through FY 2003).

  • NIAID issued an RFA to establish the Cooperative Study Group for Autoimmune Disease Prevention, a collaborative network of investigators focused on the development of interventions to prevent autoimmune diseases. NIDDK, NICHD, NIDCR, NIAMS, ORWH, and the Juvenile Diabetes Research Foundation International are co-sponsoring this RFA. (FY 2001 through FY 2005. Funding after the first year will depend on progress in first year and availability of funds.)

Rare Allergic Diseases

  • In FY 2001, NIAID will recompete its long-standing Asthma and Allergic Diseases Research Centers (AARDCs) program. With co-funding from NIEHS, this program will support basic and clinical research on the mechanisms, diagnosis, treatment, and prevention of asthma and allergic diseases, with a major emphasis on human studies. (FY 2001 through FY 2005)

Broadly Relevant Rare Disease Activities

  • Through the Immune Tolerance Network, an international consortium of more than 70 basic and clinical investigators from 40 institutions in 9 countries, NIAID supports clinical trials and assay development for promising tolerance induction strategies for the treatment of multiple immune-mediated disorders, including allergic and autoimmune diseases. (FY 1999 through FY 2005)

  • In FY 2000, NIAID investigators entered into three Cooperative Research and Development Agreements (CRADAs) related to rare childhood diseases. CRADAs funded the production and evaluation of human anti-herpes simplex virus monoclonal antibody as a therapeutic agent for treatment of neonatal HSV (FY 1997 to FY 2002); a stem cell gene therapy system for CGD (FY 1993 to FY 2001); and the adoptive transfer of T cell clones for treatment of immunologically mediated and infectious disease (FY 1993 through FY 2001).

FY 2002 Planned Research Activities

In FY 2002, NIAID plans to fund the following initiatives:

  • "Evaluation of Control Measures Against Diseases Other than AIDS," to address programmatic priorities in vaccine development, with a focus on candidate vaccines in general populations, including children. The evaluation of GBS vaccines is anticipated.

  • "Prevention of Group B Streptococcal (GBS) Disease," to support preclinical and clinical studies of vaccine candidates for the prevention of GBS disease.

  • "Partnerships for Novel Therapeutics and Vector Control Strategies in Infectious Diseases," to encourage private-sector involvement in research and development on novel treatments for human infectious diseases of high public health impact in areas that are currently not a high priority or that may be too financially risky.

  • "Expanded Phase II and IV Vaccine Trials in Humans," for the clinical evaluation of new and improved vaccine candidates in various populations, including children.

  • "Pathogen Functional Genomics Resource Center," to address the need for additional resources and facilities for functional analysis of pathogen genomes, including genomes of pathogens that cause rare childhood infectious diseases.

  • Expansion of the primary immunodeficiency registry to include patients with additional genetically determined immunodeficiency diseases.

  • Through NIAID's Vaccine and Treatment Evaluation Units, a study is planned to determine whether the unique immunologic effects of the H. influenzae Type B (Hib) polyribosylribitol phosphate Neisseria meningitidis outer membrane protein (PRP-OMP) conjugate vaccine causes a deficit in the immune response to Hib among very low birth-weight premature infants.

FY 2003 Through FY 2005 Research Plans

NIAID has an annual planning process to develop and select initiatives that solicit research applications in specific areas, including rare childhood diseases. Because planning for initiatives begins two years in advance of the award year, there are no currently approved initiatives for FY 2003 through FY 2005. However, projects are expected to be initiated as part of the regular structured planning process. NIAID will continue to stimulate and support research that may lead to more effective and accepted prophylactic and therapeutic approaches for the prevention and control of rare infectious and immunologic childhood diseases.

FY 2000 and FY 2001 Meetings Related to Rare Diseases in Children

  • The NIAID-industry "Summit on Development of Infectious Disease Therapeutics" was held September 26-27, 2000. Issues of collaboration between NIAID and industry for the development of therapeutics for addressing public health priorities in infectious disease were discussed.

  • In March 2000, NIAID, in collaboration with other NIH Institutes, the Jeffrey Modell Foundation, and the IDF, sponsored a symposium entitled, "Advances in the Diagnosis and Treatment of Primary Immunodeficiency Diseases: Risk of Cancer," focusing on advances in biomedical research that led to new insights into the diagnosis and treatment of primary immunodeficiency diseases and on the etiology of cancer in primary immunodeficient patients.

  • At the 2001 American Academy of Asthma, Allergy, and Immunology Annual Meeting, NIAID sponsored a symposium entitled, "Re-thinking Immunotherapy for the Twenty-First Century: Bench to Bedside," focusing on immunotherapy for asthma and allergic diseases.

  • NIAID, with the CDC National Program Office, organized a "Workshop on Cytomegalovirus (CMV) Vaccine Development," October 25-27, 2000.

Planned Meetings Related to Rare Diseases in Children

In an effort to stimulate research and research collaborations on rare diseases, including rare childhood diseases, NIAID and ORD will co-sponsor the following four meetings in FY 2001:

  • "Gene Therapy: A Promising Treatment for Primary Immunodeficiency Disease," to explore the need for clinical trials and data collection strategies for primary immunodeficiency diseases and to assess the value of gene therapy for the treatment of primary immunodeficiency diseases.

  • "Bare Lymphocyte Syndrome (BLS) and Gene Expression of Class II Major Histocompatability Complex (MHC)," to review and update the state of science, examine opportunities for collaboration, and explore the implications of the regulation of MHC gene expression for BLS and other immunological diseases.

  • "The Innate Immune System and Its Involvement in Autoimmune Diseases," to identify gaps in knowledge regarding the role of the innate immune system in etiology, pathology, and treatment of autoimmune diseases.

  • "Animal Models of Autoimmune Disease: Current Models vs. Advanced Technology," to explore the strengths and weaknesses of each animal model, and determine if other models can and need to be developed to efficiently translate animal studies to humans.

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Last Reviewed: February 2, 2005
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