Overview of NIAID Rare Diseases Research Activities

NIAID research activities on rare diseases are classified into four areas: infectious diseases, primary immunodeficiency diseases, autoimmune diseases, and allergic diseases. NIAID's section of this report highlights the Institute's rare diseases advances and activities.

• Infectious diseases include diseases caused by bacteria, parasites, viruses, and fungi. Research on rare infectious diseases is aimed at delineating mechanisms of disease 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 on 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 cells and tissues. NIAID research is focused on the identification of mechanisms of pathogenesis and the development of new approaches to prevention and treatment.
• Allergies are inappropriate or exaggerated reactions of the immune system to substances that cause no symptoms in the majority of people. NIAID research is focused on the development of new approaches for the diagnosis, prevention, and treatment of allergic diseases.

Recent Scientific Advances in Rare Diseases Research

Rare Infectious Diseases

Blastomycosis

Blastomycosis, a systemic fungal infection caused by Blastomyces dermatitidis, is capable of causing disease in both immunocompetent and immunosuppressed hosts. Scientists found a genetically proven virulence determinant of B. dermatitidis, a protein responsible for the ability of invading B. dermatitidis cells to adhere to host cells (WI-1).

Cryptococcosis

Acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis lack or have a greatly diminished inflammatory response, but still develop increased cerebrospinal fluid pressure due to mechanisms other than inflammation. Recent studies have shown that AIDS patients with cryptococcal meningitis experience improved outcome following mechanical drainage to reduce elevated cerebrospinal fluid pressure.

E. coli O157:H7 and associated hemolytic uremic syndrome (HUS)

E. coli O157:H7 is a life-threatening intestinal pathogen most commonly associated with consumption of undercooked beef. Infections in humans can lead to bloody diarrhea and even renal failure in young children and in the elderly. Recent studies indicate that antibiotics should not be used to treat children presenting with bloody diarrhea, as antibiotic use could lead to the release of more bacterial toxins and breakdown of the kidneys, evidenced by bloody urine, and possibly kidney failure from subsequent HUS. Other researchers determined that intiminO157, an E. coli O157:H7 outer membrane protein, causes attachment of the E. coli to intestinal epithelial cells.

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 5 years before the introduction of effective vaccines. New Haemophilus strains constantly emerge through the process of transformation; 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 new cellular targets for the action of new antimicrobial agents.

Hantavirus Pulmonary Syndrome (HPS)

HPS is a newly emerging, rodent-borne viral disease first identified in the 1993 "Four Corners" epidemic in the southwestern United States. It has a case-fatality rate of about 50%. New findings suggest immune plasma from survivors might be a useful approach for treating HPS patients and preventing the development of severe disease in persons who may have been exposed. Researchers have found an association between rapid and high-titered neutralizing antibody at medical presentation and increased survival.

Herpesvirus-associated Neonatal Herpes Simplex Virus (HSV) Infection and Congenital Cytomegalovirus (CMV)

Neonatal HSV infections can present as a local infection of the skin, eyes, mouth, and central nervous system, or as a disseminated infection involving multiple organs. The introduction of antiviral therapy has significantly reduced the mortality rate for neonatal HSV. Acyclovir has been approved for congenital HSV infection. CMV, another herpes-associated virus, causes devastating consequences in congenitally infected children. Most infected infants who survive suffer from profound deafness and/or mental retardation. Scientists completed a phase III trial of ganciclovir for the treatment of congenital CMV infections. Symptomatic babies treated with ganciclovir showed improvement or maintenance of their hearing.

Lyme Disease

Lyme disease, caused by Borrelia burgdorferi, is the most prevalent tick-borne infectious disease in the United States. A new sensitive and specific laboratory test has been devised by researchers to diagnose Lyme disease in vaccinated individuals. Other researchers found that the presence of a soluble CD14 (sCD14) in the blood of patients with early or late Lyme disease may be an indicator of active infection by B . burgdorferi . In Lyme disease, damage resulting from autoimmune reactivity to host tissue may add to the symptoms of infection. Scientists have developed a new method to differentiate between cell surface components of B. burgdorferi and cell surface components of the host that may be involved in the autoimmune reaction.

Pertussis

Bordetella pertussis is the primary etiologic agent of pertussis or whooping cough. Before immunization, pertussis was widespread, with high morbidity and mortality in infants and young children. Exposure of the host to B. pertussis results in an increased production of chemicals by human respiratory epithelial cells that cause white blood cells to be attracted to the area, increased expression of mucin (mucus), altered mucus consistency, and respiratory cilia paralysis. After effecting these changes, the organism binds to mucus. Damage to host tissue ensues due to a toxin produced by B. pertussis . Toxin secretion can be altered by agents that alter membranes. These discoveries may lead to new strategies for the treatment of whooping cough.

Acute Rheumatic Fever (ARF)

ARF is a disease characterized by inflammatory lesions involving primarily the heart, joints, subcutaneous tissues, and central nervous system. Cases of ARF follow a group A streptococcal upper respiratory tract infection, although the exact mechanisms mediating the development of disease remain speculative. A baboon model has been developed to study the molecular events necessary for group A streptococci (GAS) to colonize the throat and to examine aspects of the immune response to GAS in the throat that may be involved in the development of acute rheumatic fever.

GAS Invasive Disease

GAS can cause invasive disease such as necrotizing fasciitis (flesh-eating bacteria) and streptococcal toxic shock syndrome. Recently, the crystal three-dimensional structure of streptococcal pyrogenic exotoxin (SpeB), a major virulence factor of GAS, has been determined. The three-dimensional structure will provide information that will be useful for the design of inhibitors with therapeutic potential and vaccine candidates for prevention of severe invasive disease.

Group B Streptococci (GBS)

GBS cause serious illness in newborns, including sepsis, pneumonia, and meningitis. 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 that in the recipients of uncoupled vaccine. This study supports the inclusion of capsular polysaccharide type II coupled to tetanus toxoid in the formulation of a multivalent 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 (blood cells critical to immune function). 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 development of B and T cell lymphomas. Researchers have also identified other mutations involving ALPS.

B Cell Immunodeficiencies

Patients with B cell immunodeficiencies have recurrent, potentially life-threatening infections due to a lack of mature B cells (which produce antibodies). In an immunodeficient patient, researchers identified a novel mutation in B cell linker protein (BLNK), which serves as a "molecular scaffold," bringing together enzymes and their target molecules in the B cell. Mice with the BLNK mutation were also immunodeficient.

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. 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 a fully immunologically matched sibling. In another clinical trial, investigators demonstrated functional correction of the genetic defect for an 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.

Job Syndrome

Job syndrome, also known as hyperimmunoglobulin E recurrent infection syndrome (HIE), is a rare inherited disease characterized by recurrent bacterial infections of the ears and elevated levels of the antibody immunoglobulin E. Investigators have linked a genetic defect in HIE patients to chromosome 4.

Severe Combined Immunodeficiency (SCID)

SCID is a rare congenital syndrome response. Some children with SCID have lived for years in germ-free rooms or "bubbles" necessitated 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, making them highly susceptible to recurrent infections. XHIM is 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 synthetic CD40 ligand protein. A second form of XHIM 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.

Wiskott-Aldrich Syndrome (WAS)

WAS is an inherited blood cell disorder caused by mutation in the WAS protein (WASP). WAS is characterized by low levels of platelets (cells important for blood clotting), immune deficiency caused by insufficient number and function of lymphocytes (blood cells critical to normal immune functioning), and eczema. Researchers have determined that the level of mutated WASP in platelets and lymphocytes correlates with disease severity.

Rare Autoimmune Diseases

Systemic Lupus Erythematosus (SLE)

SLE is an autoimmune disease characterized by the production of antibodies against proteins in nuclei of the body's own cells. Antibodies form complexes with nuclear proteins and become trapped in the kidneys, leading to inflammatory kidney disease. Scientists showed that C-reactive protein (CRP) promotes clearance of nuclear proteins and may help prevent lupus-related inflammatory kidney disease. In contrast, estrogen has been found to enhance the production of antibodies against the body's own cells in lupus in animal models.

Rare Diseases Research Initiatives

FY 2000-Funded Activities in Infectious Diseases

• NIAID's Mycoses Study Group (MSG) supported four clinical trials examining antifungal therapy for the opportunistic and endemic mycoses.
• NIAID supported genome sequencing of etiologic agents of rare diseases, including: Rickettsia typhi (etiologic agent of typhus), Burkholderia mallei (etiologic agent of glanders), Brucella suis (etiologic agent of brucellosis) , Bacillus anthracis (etiologic agent of anthrax), Coxiella burnetti (etiologic agent of Q fever), Cryptococcus neoforman s (etiologic agent of cryptococcosis), E. coli 0157:H7 (etiologic agent of gastritis and HUS), Ehrlichia phagocytophila (etiologic agent of ehrlichiosis), Haemophilus ducreyi (etiologic agent of chancroid), Treponema pallidum (etiologic agent of syphilis), and Streptococcus pyogenes (etiologic agent of group A streptococci invasive disease) .
• NIAID supported studies on: the identification and characterization of genes that influence virulence in B. anthracis (etiologic agent of anthrax), factors that determine host sensitivity or resistance to anthrax lethal factor, genetic factors involved in the expression of virulence of Yersinia pestis (etiologic agent of plague), and new animal models to assess the virulence of Rickettsiae (etiologic agent of Rocky Mountain spotted fever and other spotted fevers).
• NIAID collaborated with the NIH Fogarty International Center (FIC) to support the "International Training and Research on Emerging Infectious Diseases" program to address research training needs related to emerging and re-emerging infectious diseases in developing countries.
• The viral hepatitis program funded a grant for hepatitis A and three grants for hepatitis D.
• NIAID is supporting phase I/II trials for three different candidate vaccines for human CMV. These include 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 (Vaccine and Treatment Evaluation Unit).
• The Collaborative Antiviral Study Group (CASG) conducted 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 of the skin, eyes, mouth, or central nervous system, and conducted a phase III study evaluating long-term therapy of herpes simplex encephalitis with oral valacyclovir.
• NIAID supported 46 grants and contracts on Lyme disease. Grants also were awarded to support research on other vector-borne bacterial infections. These grants support research on: animal models of disease, microbial physiology, mechanisms of pathogenesis and host immunity, vectors and disease transmission, therapeutic approaches, and test development.
• A study titled "Study and Treatment of Post Lyme Disease" was completed.
• NIAID supported a phase I clinical trial to evaluate a broadly effective GAS vaccine at the University of Maryland's Center for Vaccine Development.
• NIAID was the sponsor of a phase I safety and immunogenicity trial utilizing a GBS type II polysaccharide-tetanus toxoid conjugate vaccine in pregnant women.
• NIAID continues to support research on the epidemiology and basic biology of GBS disease, along with GBS vaccine research and clinical trials of GBS conjugate vaccines through a 5-year multidisciplinary contract awarded in late 1997.
• In collaboration with Los Alamos National Laboratories, NIAID has established a relational database (STD GEN) for pathogens that cause sexually transmitted diseases. The genomic sequence of HSV1 was incorporated in FY 2000.
• NIAID supported the maintenance of the "World Reference Center for Arboviruses" and has ongoing contracts to screen possible antiviral compounds for activity against West Nile virus.
• NIAID participated in the development and support of programs such as The Global Alliance for Vaccines and Immunization (GAVI) in an effort to protect health and save lives through the widespread use of safe vaccines.

FY 2000 Newly Issued Initiatives in Infectious Diseases

• Bacteriology and Mycology Study Group (BAMSG) (RFP-AI-01-11): to establish a collaborative group with expertise to construct and conduct clinical studies addressing serious fungal and resistant bacterial diseases.
• Animal Models of Human Viral Infections for Experimental Therapies (RFP-AI-01-003): to evaluate experimental therapies for potential clinical efficacy and toxicity in animal models of clinically important, emerging, and rare human infections.
• Preparedness Against Illegitimate Use of Bacterial Pathogens (RFA-AI-00-004): to support the study of virulence determinants, host resistance/susceptibility factors, novel therapeutics, and novel or improved candidate vaccines against bacterial pathogens involved in biological warfare, many of which cause rare diseases.
• Challenge Grants: Joint Ventures in Biomedicine and Biotechnology (RFA-AI-00-010): to promote joint ventures between NIH and the biotechnology, pharmaceutical, and medical device industries through one-on-one matching of federal dollars by qualified organizations.

FY 2000-Funded Activities in Immune-mediated Diseases

• NIAID, through a contract with 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, natural course of the disease (including complications), effects of therapy, causes of death, and prognosis.
• NIAID, NCI, and the National Institute of Child Health and Human Development (NICHD) co-funded a research project involving the use of a new screening device to determine if the occurrence of primary immunodeficiency diseases in large urban Hispanic and African American populations is underdiagnosed.
• NIAID supported clinical trials and test development for promising tolerance induction strategies for the treatment of multiple immune-mediated disorders through the Immune Tolerance Network, an international consortium of more than 70 basic and clinical investigators from 40 institutions in 9 countries.
• NIAID chairs the Autoimmune Disease Coordinating Committee, an effort to increase collaboration and to facilitate the development of coordinated research in autoimmune diseases among the many NIH Institutes, other Federal agencies, and private groups.
• 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, through the Clinical Trials Network for Stem Cell Transplantation for Autoimmune Diseases, established in FY 2000.
• NIAID continued to support research projects awarded in FY 1999 in response to several trans-NIH initiatives in autoimmunity, including: Environment/Infection/Gene Interaction in Autoimmunity, Target Organ Damage in Autoimmune Diseases, Pilot Trials on Innovative Therapies for Rheumatic and Skin Diseases, and Registries for Neonatal Lupus and Juvenile Rheumatoid Arthritis.

FY 2000 Newly Issued Initiatives in Immune-mediated Diseases

• Asthma and Allergic Diseases Research Centers (RFA-AI-00-012): to support a multidisciplinary research program focused on studies of immunologic and other mechanisms underlying human asthma and allergic diseases.
• Innovative Grant on Immune Tolerance (RFA-AI-00-006): to support novel work on the molecular mechanisms and applications of antigen-specific immune tolerance, which is the selective and long-term inactivation of the immune responses.
• Hyperaccelerated Award—Mechanisms in Immunomodulation Trials (RFA-AI-00-005): to support mechanistic research studies in clinical trials of interventions that enhance immune function for immune system-mediated diseases.
• Cooperative Study Group for Autoimmune Disease Prevention (RFA-AI-00-016): to support a collaborative network of investigators focused on the development of interventions to prevent autoimmune diseases.

FY 2000 Cooperative Research and Development Agreements (CRADAs)

In FY 2000, NIAID investigators entered into six CRADAs related to rare diseases. CRADAs funded the production and evaluation of human antiherpes simplex virus monoclonal antibody as a therapeutic tool for treatment of neonatal HSV, stem cell gene therapy systems for CGD, the adoptive transfer of T-cell clones for treatment of immunologically mediated and infectious diseases, the development of a hepatitis A vaccine, and an acellular pertussis vaccine clinical trial.

Rare Disease-Related Program Workshops, Symposia, and Meetings

• In an effort to stimulate research and research collaborations on rare diseases, NIAID and the Office of Rare Diseases (ORD) co-sponsored the workshop, "Protocol Development for Autologous Stem Cell Transplantation (SCT) in Pediatric Rheumatic Disease."
• NIAID, in collaboration with other NIH Institutes, the Jeffery Modell Foundation, and the IDF, sponsored a March 2000 symposium titled, "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.
• The June 2000 NIH Lyme Disease Coordinating Committee meeting of focused on several NIH-supported clinical studies on Lyme disease.
• The NIAID-industry "Summit on Development of Infectious Disease Therapeutics" was held September 26-27, 2000. Issues of NIAID and industry collaboration in the development of therapeutics for addressing public health priorities in infectious disease were discussed.