National Heart,
Lung, and Blood Institute
Rare Diseases Report FY 2001
Contents
Overview of NLHBI Rare Diseases Research Activities
NHLBI provides leadership for a national program in the causes,
diagnosis, treatment, and prevention of diseases of the heart, blood vessels,
lungs, and blood, and sleep disorders, and in the uses of blood and the
management of blood resources. It conducts and supports, through research in
its own laboratories and through extramural research grants and contracts, an
integrated and coordinated program that includes basic investigations, clinical
trials, epidemiological studies, and demonstration and education projects.
Although the major part of the research supported by
NHLBI addresses common conditions such as hypertension, coronary heart disease,
and chronic obstructive pulmonary disease, a significant amount of research is
devoted to rare diseases in children and adults. NHLBI activities related to
rare disease research in fiscal year (FY) 2001 are described below.
Recent Scientific
Advances in Research on Rare Disease
Heart and Vascular Diseases Program
Abetalipoproteinemia
Abetalipoproteinemia is a recessive disorder characterized by the absence of
apoprotein B-containing lipoproteins from plasma. Fat malabsorption is severe
and triglyceride accumulation occurs. Acanthocytosis, a rare condition in which
the majority of red blood cells have multiple spiny cytoplasmic projections, is
common. Additional symptoms appear to be secondary to defects in the transport
of vitamin E in blood. Projects using genetic, biochemical, and metabolic
approaches to study various aspects of the disease were underway in four grants
in FY 2001. The disorder appears to be related to abnormal processing of
apolipoprotein B (apoB) due to an absence of the microsomal triglyceride
transfer protein (MTP). In FY 2001, studies indicated that MTP is implicated in
both apoB lipoprotein and triglyceride secretion. Cells lacking the ability to
make MTP are unable to assemble and secrete apoB-containing lipoproteins.
However, when MTP production is rectified (through appropriate transfection),
apoB-containing lipoproteins are once more assembled and secreted.
Antiphospholipid Syndrome
(APS)
APS is characterized by the presence of circulating
autoantibodies to certain phospholipids (lipids containing phosphorus). It is
clinically manifested by recurrent blood clotting disorders, a history of fetal
deaths, and autoimmune diseases such as thrombocytopenia. One NHLBI-supported
grant is engaged in efforts to develop more standardized imunoassays that will
reliably detect individual antiphospholipid antibodies and is also
investigating the role of the syndrome in atherogenesis. Circulating antibodies
to oxidized phospholipids, particularly cardiolipin, were found in FY 2001 to
correlate with the presence of isoprostanes, strong biomarkers for
atherogenesis and a means of indicating the extent of atherosclerosis. Genes of
autoantibodies that were cloned on the basis of their ability to bind to
oxidized phospholipids have been discovered to play an important role in
atherogenesis and to confer protection against certain bacterial infections.
Arrhythmogenic Right
Ventricular Dysplasia (ARVD)
ARVD is a family of rare cardiomyopathies that results
in sudden cardiac death and heart rhythm disturbances including fibrillation.
Most forms are believed to be due to the inheritance of autosomal dominant
mutations in genes whose identities remain largely unknown but that clearly
affect myocardial integrity. ARVD is characterized by marked, selective, right
ventricular dilatation, myocardial cell death, and cell replacement with fat
cells and fibrous tissue. Expression in gene carriers is variable, but in those
who display symptoms the outcome is frequently lethal. NHLBI supports work on
ARVD at one of its Specialized Centers of Research (SCOR) in Sudden Cardiac
Death and sponsors a network of three separate groups to investigate causes of
familial forms of ARVD and genotpye-phenotype relationships. In FY 2001 the
SCOR investigators identified a candidate gene product for a Neuroblastoma
apoptosis-related RNA-binding protein that may correspond to a chromosomal
mutation identified earlier as being common to patients with the congenital
form of ARVD. Bartter's Syndrome
Bartter's syndrome, a rare autosomal recessive
disease, typically manifests itself through salt imbalance and low blood
pressure. Research on Bartters syndrome is currently being pursued as a
part of the NHLBI SCOR program in the Molecular Genetics of Hypertension. The
discovery that a mutation in an ATP-sensitive K channel can lead to
Bartters syndrome establishes the genetic heterogeneity of the disease
and demonstrates that this K channel may be an important regulator of blood
pressure, ion balance, and fluid balance.
Beta-Sitosterolemia
Beta-sitosterolemia is a rare inborn error of
metabolism characterized by increased absorption of dietary cholesterol and
plant and shellfish sterols. Patients with beta-sitosterolemia have a markedly
increased risk of premature cardiovascular disease. Effective treatment is not
available at present, although a number of drugs are under development. NHLBI
supports research into beta-sitosterolemia through its intramural Molecular
Diseases Branch and its extramural grant programs. One NHLBI-supported
investigator at the Medical University of South Carolina, who is investigating
the molecular mechanisms of cholesterol absorption and excretion in families
with beta-sitosterolemia, has identified two separate defective genes.
Additional research is identifying specific ABCG sterol transporter protein
mutations in affected families.
Brugada's Syndrome
Brugadas syndrome is a rare inherited disorder
characterized by cardiac electrophysiological abnormalities
specifically, right bundle branch block and ST elevation in the precordial
leads and is associated with a high occurrence of sudden cardiac death.
The condition is currently believed to be similar in cause and potential
treatment to some forms of the long QT syndrome. Both appear to be caused by
mutations at different locations in the SCN5A cardiac muscle sodium ion channel
gene and by resulting aberrations in depolarization and repolarization of these
cells. One NHLBI-supported study demonstrated in FY 2001 that distinct
mutations within a single residue of SCN5A can give rise to either Brugada
syndrome (tyrosine to histidine mutation) or to long QT syndrome (tyrosine to
cysteine mutation) adding evidence for a close relationship between these
disorders. Congenital Heart Disease
Congenital heart disease affects about 8 in 1,000
live-born infants (32,000 per year in the US), making it the most common birth
defect. Abnormal formation of the embryonic heart results in both structural
and functional heart defects. It is an important cause of infant mortality,
pediatric and adult morbidity, and shortened adult life expectancy. About
one-third of affected infants and children require open heart surgery or
interventional cardiac catheterization to repair or ameliorate their defects.
Approximately the same proportion have associated extracardiac anomalies such
as chromosomal abnormalities and syndromes involving other organ systems.
NHLBI has supported research in pediatric
cardiovascular medicine since it first funded heart research grants in 1949.
Researchers supported by NHLBI have been instrumental in developing diagnostic
imaging techniques, including fetal imaging; surgical techniques, including
various operations and refinements in cardiopulmonary bypass; and medical
therapies now used to ensure healthy survival for most affected children. They
have also made significant contributions to the epidemiology of congenital
heart disease and to understanding the molecular and genetic basis of normal
and abnormal heart development.
A key finding from NHLBI-funded researchers this year
was the identification of a new gene, Bop, that is the primary controller in a
cascade of genetic events that lead to the development of heart ventricles in
mouse embryos. This finding may eventually lead to understanding ventricular
malformations in humans. DiGeorge Syndrome
DiGeorge syndrome occurs with an estimated frequency
of 1 in 4,000 live births. It is characterized by many abnormalities, including
cardiac outflow tract anomalies, hypoplasia of the thymus and parathyroid
glands, cleft palate, facial dysmorphogenesis, learning difficulties, and other
neurodevelopmental deficits. It is usually sporadic, but may be inherited, and
is caused by deletion of a segment of chromosome 22. The specific gene that is
abnormal has not been identified. NHLBI supports both human and animal studies
of DiGeorge syndrome through several grants, including two SCORs in Pediatric
Cardiovascular Disease. The finding by NHLBI-funded researchers that mice with
chromosomal deletions similar to those found in humans with DiGeorge syndrome
have deficits in learning and memory could lead to improved treatments for
psycho-developmental abnormalities in affected individuals. Such results
support the need for a comprehensive therapeutic approach to children with
DiGeorge syndrome, such as the team approach developed by a SCOR at the
Childrens Hospital of Philadelphia.
Doxorubicin Cardiomyopathy
The generic drug, doxorubicin (brand name, Adriamycin)
is a potent, broad-spectrum antitumor agent effective in treating a variety of
cancers including solid tumors and leukemia. Unfortunately, its clinical use is
limited by dose-dependent cardiac side effects that lead to degenerative
cardiomyopathy, congestive heart failure, and death. In addition, some adult
patients treated with the drug when they were children are now developing
dilated cardiomyopathy. Endocardial biopsies from patients undergoing
doxorubicin therapy reveal a disruption of myofibrils, impairment of
microtubule assembly, and a swelling of the endoplasmic reticulum. Doxorubicin
cardiotoxicity is also characterized by a dose-dependent decline in
mitochondrial oxidative phosphorylation and a decrease in high-energy phosphate
pools.
Several NHLBI-supported investigators have reported
research advances in the past year. One has demonstrated that cardiac tissue
from doxorubicin-treated rats expresses an increased tolerance for withstanding
short periods of oxygen deprivation. This observation is providing novel
insights into the molecular regulation of compensatory responses that may
underlie the adaptation phenomenon that has been widely described
for other types of cardiac challenge. The same investigator has observed a
potential cardioprotective effect against doxorubicin-induced mitochondrial
cardiomyopathy by carvedilol, a non-selective beta-blocker with alpha-1
blocking (vasodilating) and anti-oxidant properties. This promising result
provides exciting opportunities for supporting clinical trials of carvedilol as
protection against the debilitating side-effects of doxorubicin. This is
particularly relevant in that the class of drugs known as beta-adrenergic
receptor antagonists, of which carvedilol is one, are currently widely
prescribed as safe and effective prophylactic measures for treating many other
cardiovascular disorders, including congestive heart failure. Adding
doxorubicin-induced cardiomyopathy to the list of indications for carvedilol
may prove to be a highly effective means of reducing the incidence and/or
severity for cardiac failure that limits the clinical success currently
achievable with doxorubicin.
Another investigator is examining explicit pathways
through which reactive oxygen species are involved in doxorubicin-induced
cardiomyopathy. She has discovered a marked inhibition of activity of the
myocardial membrane-associated enzyme phospholipase A2 by clinically relevant
concentrations of doxorubicin. This novel observation suggests new means of
doxorubicin action and has significant implications for elucidating the
mechanisms underlying doxorubicin cardiotoxicity and pharmacological
interventions to prevent it. Dysbetalipoproteinemia
Dysbetalipoproteinemia is a rare disorder with a
strong heritable component characterized by the presence of beta-migrating very
low-density lipoprotein (VLDL). The disorder leads to the formation of
characteristic yellow skin plaque (xanthomas) and predisposes to early ischemic
heart disease and peripheral vascular disease. Research into the genetics and
biochemical events underlying the etiology and pathophysiology of the disease
is underway in two NHLBI-supported grants. A mutant form of apoprotein E
(apo-E2) has been identified as the primary molecular defect in
dysbetalipoproteinemia. Animal models synthesizing apo-E variants are being
created to facilitate basic research. In FY 2001, animals expressing human
apo-E2 were found to have significant increases in the apo-E2 content of VLDL
and intermediate-density lipoproteins (IDL). High levels of apo-E2 are
accompanied by higher levels of total cholesterol and plasma triglycerides.
Familial
Hypercholesterolemia (FH)
FH is an inherited autosomal dominant trait
characterized by elevated concentrations of low-density lipoproteins (LDL).
Cholesterol derived from LDL is deposited in arteries and causes heart attacks
and xanthoma lesions on tendons and skin. The defect in FH is a mutation in the
gene specifying the receptor for plasma LDL. The receptors facilitate removal
of LDL and, when deficient or absent, the rate of LDL removal is low, resulting
in an elevated LDL level. The homozygous form of FH is rare (one in a million),
but people who have it are highly prone to premature coronary heart disease.
Several NHLBI grants support studies on the biochemistry, genetics, and
potential treatment of the disease. A major program project supports research
on various aspects of regulating LDL receptors and cholesterol levels in the
blood. Genetically-manipulated animal models have been created specifically to
study FH. Regulation of LDL receptor activity and other lipoprotein receptors
involved in disease progression is being elucidated. Development of apheresis
methods for removing excess LDL from plasma is progressing, and testing of a
combination of pharmacological agents is being planned.
Familial Hypertrophic Cardiomyopathy
(FHCM)
FHCM is associated with myofibrillar disarray in the
heart muscle that in turn leads to fibrosis and hypertrophy (enlargement of the
heart). Although patients may remain asymptomatic for some time, eventually
shortness of breath, palpitations, and heart failure emerge, and sudden death
ensues. Some die during childhood whereas others survive to their sixth or
seventh decade. FHCM is associated with mutations in more than one protein,
suggesting a heterogeneous group of disorders. During the past decade,
scientists made significant progress in uncovering the genes associated with
FHCM. It is known, for instance, that FHCM can be caused by many different
mutations in the contractile proteins that comprise the heart wall. However,
understanding of who will die suddenly or whether certain factors, such as high
blood pressure or extreme stress, will trigger sudden death remains elusive.
NHLBI supports research on the genetic basis and mechanisms involved through
several investigator-initiated grants and in two SCORs in Heart Failure.
One SCOR program has demonstrated that simvastatin
reverses cardiac hypertrophy and fibrosis in a rabbit model, and losartan
reverses fibrosis in a mouse model. This is the first time that any drug has
been shown effectiveness in an animal model of FHCM. Additionally, these
investigators have preliminary findings that spironolactone is equally
effective as a treatment, indicating that angiotensin II is involved in
fibrosis and hypertrophy formation. An investigator in the second SCOR program
has observed that the immunosuppressive drug, cyclosporin A, dramatically
exacerbates the hypertrophic response in his mouse model of FHCM and that the
calcium channel blocker, diltiazem, prevents this cyclosporin A-mediated
response. He is currently assessing the effects of calcium channel blockers on
the course of FHCM in mice. Familial Hypobetalipoproteinemia (FHBL)
FHBL is an apparently autosomal dominant disorder of lipid metabolism
characterized by very low levels of apoprotein B-containing lipoprotein
cholesterol. One NHLBI-supported project is using genetic, biochemical, and
metabolic approaches to study various aspects of the disease. In FY 2001,
information gained from newly-identified families with FHBL enabled researchers
to markedly narrow down the chromosome region containing the responsible genes.
The most promising of the 60 genes in this narrower region are now being
sequenced. Also, eight families have been identified that may have a new form
of FHBL, since they have a susceptibility region near, but not in, the apoB
gene on chromosome 2.
Infectious Myocarditis
Infectious myocarditis, which affects both children
and adults, is an inflammation of the heart muscle that sometimes leads to
progressive heart failure and the need for heart transplantation. NHLBI
supports both human and animal studies of the disease. The infectious agent,
Coxsackievirus B3 (CB3), is believed to be involved in many clinical cases of
human myocarditis. One NHLBI-supported investigator is studying both
susceptible and resistant strains of CB3 to determine the role of natural
killer cells and cytokines components of the innate immune system
in the pathology of myocarditis. The presence of certain cytokines in mice
indicates that a Th1 immune response is taking place. In male mice, this
response appears to be related to increased disease. Another investigator is
looking at the pathogenesis of acute rheumatic fever (ARF), a consequence of
group A streptococcal bacteria. Here, too, evidence supports a role for a Th1
response in the pathogenesis of the disease. Reovirus-induced myocarditis in
mice provides an outstanding tool to investigate non-immune mediated
myocarditis. The reovirus (reo is an acronym for respiratory enteric
orphan) is a naturally occurring virus that is believed to cause mild
infections of the upper respiratory and gastrointestinal tract of humans.
Studies have shown that viral RNA synthesis in cardiac myocytes is a
determinant of reovirus-induced myocarditis. Furthermore, genetic analysis of
reoviruses that cause myocarditis has implicated several specific viral genes.
Klippel-Trenaunay-Weber Syndrome (KTWS)
KTWS is a very rare vascular deformation disease
involving capillary, lymphatic, and venous channels. It usually manifests as
cutaneous port-wine capillary malformations, varicose veins, and enlargement of
soft tissues and bone in one limb. KTWS symptoms are usually present at birth,
with 75 percent of patients having symptoms before the age of 10. A molecular
approach to characterizing the genes that contribute to KTWS is being taken in
an NHLBI-supported grant at the Cleveland Clinic Foundation. The investigator
proposes that KTWS pathogenesis involves the disruption of key genes for
vascular morphogenesis during embryonic development. He has characterized a KTS
translocation involving chromosomes 5 and 11 and identified a novel vascular
gene as the strong candidate gene for KTWS.
Long QT Syndrome (LQTS)
LQTS is characterized clinically by a prolonged QT
segment on an electrocardiograph and is associated with syncope, ventricular
arrhythmias, and sudden cardiac death. This family of related diseases is
believed to be caused by alterations in the cardiac cell action potential
induced by mutations in at least six cardiac ion channel genes. NHLBI currently
supports research on LQTS through a SCOR on Sudden Cardiac Death and through
numerous individual grants that address the various molecular, clinical, and
genetic bases of the condition. One NHLBI-supported study identified in FY 2001
mutations in the genes encoding the beta adrenergic receptors that may be
associated with acquired LQTS, thus indicating a possible role for non-channel
proteins in contributing to the development of arrhythmias and sudden
death. Niemann-Pick Type
C Disease (NPC)
NPC is an autosomal recessive, lipid-storage disorder
that is usually characterized by excessive accumulation of cholesterol in the
liver, spleen, and other vital organs. Patients have cardiovascular disease,
enlargement of the liver and spleen (hepatosplenomegaly), and severe
progressive neurological dysfunction. Biochemical analyses of NPC cells suggest
an impairment in the intracellular transport of cholesterol to post-lysosomal
destinations. The gene deficiency in Niemann-Pick disease types A and B has
been identified as sphingomyelinase. The gene deficiency in types C and D has
been identified as the NPC-1 protein, but few clues regarding its potential
function(s) have been derived. Two NHLBI grants and a subproject in a SCOR
program support research to study the regulation of intracellular cholesterol
movement that leads to cholesterol accumulation in NPC disease.
The accumulation of cholesterol in NPC results from an
imbalance in the flow of cholesterol among membrane compartments.
Characterization of a putative cholesterol sensor in the plasma membrane that
affects cholesterol trafficking into or out of cells is underway. The gene
deficiency in NPC that encodes a cholesterol-binding protein has been
identified. These new data will help fill a major gap in current understanding
of cholesterol transport in the cell. Building on our knowledge of how
cholesterol gets into lysosomes and what happens after lipid reaches the
endoplasmic reticulum (ER), researchers now face the challenge of elucidating
how cholesterol gets out of the lysosomes and into the ER. Smith-Lemli-Opitz Syndrome
(SLOS)
SLOS is an inherited autosomal recessive disorder
caused by a defect in the enzyme that catalyzes the last step in cholesterol
biosynthesis. As a result, endogenous cholesterol synthesis is inadequate to
meet biological demands for functions such as membrane structure and bile acid
synthesis, and the precursor 7-dehydrocholesterol and its derivatives
accumulate. Newborns with SLOS have a distinctive facial dysmorphism; suffer
from multiple congenital anomalies including cleft palate, congenital heart
disease, genitourinary abnormalities, and malformed limbs; and exhibit severe
developmental delays, digestive difficulties, and behavioral problems. The
syndrome is thought to account for many previously unexplained cases of mental
retardation. During FY 2001 NHLBI supported two investigator-initiated grants
whose research foci are relevant to SLOS. One is conducting basic studies in
sterol balance and lipid metabolism on 50 infants with SLOS. The study is also
investigating the effectiveness of cholesterol-supplemented baby formula in
ameliorating some of the behavioral and digestive symptoms of SLOS, and the
effectiveness of simvastatin therapy in lowering the plasma concentrations of
toxic forms of abnormal cholesterol precursor compounds. Intermediate
evaluation of progress indicates that infants tolerate the treatments well. The
second grant, which ended in FY 2001, focused on basic analytical chemistry
aspects of SLOS in the hope of developing an improved diagnostic test.
Diagnostic and screening tests for SLOS are based on the presence of abnormally
high levels of certain compounds from the sterol biosynthesis pathway that
build up due to a lack of needed enzymes. Improved chemistry methods developed
with support from this grant have led to improved separation of these compounds
and more accurate determination of their concentrations in blood and other
biological fluids, such as amniotic fluid.
Tangier Disease
Tangier disease is a rare syndrome characterized by a
deficiency of high-density lipoprotein (HDL), mild hypertriglyceridemia,
neurologic abnormalities, and massive cholesterol ester deposits in various
tissues, such as the tonsils. The disease is inherited as an autosomal
co-dominant trait and appears due to hypercatabolism rather than a defect in
HDL synthesis. A member of the ATP-binding cassette (ABC) transporter family,
human ABCA1, located on chromosome 9 has been identified as the defective gene.
ABCA1 is conceived as the gatekeeper for eliminating excess cholesterol from
tissues and therefore key in determining the amount of cholesterol accumulating
in the artery wall. Research on the cell biology and biochemistry of the human
ABCA1 and its role in the disease is underway in two NHLBI-supported studies.
In FY 2001, these studies found that unsaturated fatty acids reduce macrophage
ABCA1 content by enhancing its degradation rate. Also, ABCA1 was shown to be
responsible for the transport of a-tocopherol from cells.
The NHLBI intramural Molecular Disease Branch also has
been actively studying Tangier disease for a number of years and announced five
major findings in FY 2001:
(1) The complete genomic sequence and the regulatory
elements modulating gene expression have been determined for the ABCA1
transporter,
(2) ABCA1 transgenic mice have been developed to
study the mechanisms involved in the removal of excess cholesterol from cells,
(3) the ABCA1 transporter has been shown to recycle
from the cell surface to a late endocytic compartment establishing a new
pathway for the transport of intracellular cholesterol to the cell membrane for
removal by HDL,
(4) the specific plasma apolipoproteins in HDL which
act as acceptors for cholesterol removed from cells mediated by the ABCA1
transporter have been identified and the molecular structural requirements to
function as cholesterol acceptors have been elucidated, and
(5) Overexpression of the ABCA1 transporter in mice
results in a marked decrease in diet induced atherosclerosis indicating that
the development of drugs to upregulate the expression of the ABCA1 transporter
may be a new approach to the treatment of cardiovascular disease.
Lung Diseases Program
Advanced Sleep Phase Syndrome
(ASPS)
ASPS is a rare, genetically-based sleep disorder
characterized by an early evening onset of sleep, normal sleep duration, and
spontaneous early awakening. NHLBI supports basic research to elucidate the
neural pathways through which the biological clock mechanism regulates sleep;
clinical research to elucidate genetic risk factors; and applied research on
the role of the biological clock in disturbed sleep and alertness of shift
workers, school-age children, and drowsy drivers.
Alpha-1 Antitrypsin (AAT) Deficiency
AAT deficiency is an inherited deficiency of a
circulating proteinase inhibitor that is manufactured primarily in the liver.
Deficiency states (circulating serum AAT levels below 0.6 mg/ml) are associated
with emphysema, presumably from inadequate protection against enzymatic
destruction by neutrophil elastase. Fifteen percent of the AAT-deficient
population also develop liver disease. NHLBI funds a variety of clinical and
basic research on AAT deficiency, including studies of the molecular mechanisms
that impair secretion of AAT, methods of gene therapy delivery, and how to
increase the availability of defective, but partially active, AAT.
NHLBI-supported investigators are defining the abnormalities and degradation
pathways of the AAT protein, characterizing the inflammation that leads to
disease in various AAT deficiency states, and evaluating the possibility of
treating the disease with drugs that would enhance the release of partially
active mutant protein from liver cells. A genetics study of families is seeking
to identify other genes that may modify the nature and severity of the disease
as expressed in different individuals. In addition to research that
specifically focuses on AAT, NHLBI supports related studies addressing the
general causation of emphysema; the function, synthesis, secretion, and
interaction of the enzymes that are inhibited by AAT; animal models of other
enzyme inhibitor deficiencies; gene regulation; gene therapy; cellular
signaling, injury, and repair; and protein processing. Asbestosis
Asbestosis, an occupational lung disease, is the
interstitial pneumonitis and fibrosis caused by exposure to asbestos fibers.
New research findings have improved understanding of the role of genetic
susceptibility in lung injury from asbestos. Following asbestos exposure, lung
fibroblasts are activated to grow and produce connective tissue. Certain inbred
mice, the 129 mouse strain, do not develop asbestos-induced fibrogenesis,
whereas other inbred strains do. Studies using growth factors suggest that the
fiber deposition in the lungs of 129 mice is due to an intrinsic difference in
the ability of the lung fibroblasts to respond to growth factors. In mice it
was also demonstrated that excess levels of transforming growth factor-beta
(TGF-beta) can induce fibrogenesis in the lungs of fibrogenic-resistant mice,
thus providing a clue as to how individual growth factors may contribute to the
development of fibroproliferative lung disease.
Bronchopulmonary Dysplasia (BPD)
BPD is a chronic lung disease characterized by
disordered lung growth, specifically, changes in cell size and shape and a
reduction in the number of alveolar structures available for gas exchange. It
affects at least 10,000 very-low-birth-weight infants each year and is
associated with neonatal intensive care costs as high as $60,000 per patient.
The incidence of BPD has increased in recent years due to the increased
survival of smaller premature infants. The NHLBI Collaborative Program for
Research in BPD provides a well-characterized primate model for a
multi-disciplinary exploration of the etiology of the disease. NHLBI also
supports two clinical trials on the role of nitric oxide in preventing and
treating chronic lung disease in premature infants. A safety and dosage Phase
II clinical trial for intratracheal instillation of the anti-inflammatory
uteroglobin, CC10, in premature infants is nearing completion. In FY 2001,
reduction of ventilatory injury with Nasal Continuous Positive Airway Pressure
(nCPAP) was demonstrated in the pre-term baboon model of BPD; histologic
examination revealed thin saccular walls with minimal fibro-proliferation and
improvements in internal alveolar surface area. In addition, the NHLBI
intramural research program developed new technologies for the prevention of
nosocomial pneumonia and ventilator-induced injury that may reduce patient
morbidity and mortality in the intensive care unit.
Churg-Strauss
Syndrome
Churg-Strauss syndrome is a rare disorder that was
first reported in the 1950s. It is characterized by the formation and
accumulation of an abnormally large number of certain white blood cells
(eosinophils), inflammation of blood vessels (angiitis or vasculitis), and
inflammatory nodular lesions (granulomatosis). Onset typically occurs between
15 to 70 years of age, and the disease affects both males and females. Patients
with the syndrome are often affected by asthma. Churg-Strauss syndrome can be
severely debilitating, and even fatal if untreated, but patients usually
respond well to corticosteroid treatment. Over 90 cases of Churg-Strauss
Syndrome have been reported in less than 2 years by physicians who had switched
asthma patients from corticosteroid therapy to anti-leukotriene therapy. It is
unclear whether the increased reports of Churg-Strauss are the result of an
untoward effect of the anti-leukotriene therapy or a primary eosinophilic
disease that had been clinically recognized and treated as asthma but was
uncovered as Churg-Strauss once the corticosteroid therapy was
withdrawn. NHLBI does not currently support research specifically investigating
Churg-Strauss syndrome, however, it does support numerous
investigator-initiated grants studying the basic mechanisms of asthma,
including examination of the role of eosinophils. NHLBI also supports clinical
studies of severe asthma and of medications used in asthma management, such as
anti-leukotriene therapy. An NIH workshop report on the relationship of asthma
therapy and Churg-Strauss syndrome was published in the Journal of Allergy
and Clinical Immunology in FY 2001. Congenital Central Hypoventilation Syndrome
(CCHS)
CCHS, also known as Ondine's Curse, is a
rare disorder characterized by normal breathing while awake but shallow
breathing during sleep that is not effective in moving fresh air into the
lungs. NHLBI supports a basic research program to elucidate the anatomical and
physiological organization responsible for neural rhythm generation and
translation into breathing. Research is focused on improving our understanding
of how breathing is regulated and the conditions under which reflexive
generation of respiratory rhythm is abolished. Identification of the neuronal
pathways producing respiratory rhythm and pattern are prerequisite for a full
understanding of a variety of respiratory sleep disorders such as CCHS. Recent
findings obtained from overnight sleep studies indicate that CCHS is associated
with a diminished sensitivity to levels of carbon dioxide in blood during
non-rapid eye movement (non-REM) sleep. During REM sleep, other neural drives
to breathe appear to supervene to enable adequate ventilation. Genetic and
pathological studies of CCHS patients may enable identification of the genes or
areas of the central nervous system involved in the syndrome and the
abnormalities in ventilation. Congenital Diaphragmatic Hernia (CDH)
CDH is a developmental disorder that occurs once in
every 2,400 births. Often CDH occurs in isolated fashion, i.e., not associated
with other life-threatening anomalies or chromosomal aberrations. Affected
neonates usually die soon after birth because lung tissue compressed by the
herniated viscera is inadequately developed, and hypoplasia of the pulmonary
vascular bed leads to pulmonary hypertension or persistent fetal circulation
syndrome. For infants who survive this disease, the cost of postnatal care can
exceed $100,000. In June 1999, NHLBI awarded a grant for an
investigator-initiated clinical trial to test the efficacy of an in
utero surgical technique to correct lung hypoplasia as compared to
post-natal care in a group of human fetuses at 24-28 weeks gestation in whom
the most severe form of congenital diaphragmatic hernia had been identified.
Because the group assigned to post-natal care had an approximate mortality of
30 percent, rather than the expected 80 percent, it was concluded that a much
larger sample size would be required. The investigators were unable to arrange
for the necessary multi-site collaborations, so enrollment had to be terminated
in July 2001. The patients already enrolled in the trial continue to be
followed. Cystic
Fibrosis (CF)
CF is a multi-system disease characterized by
defective transport of chloride and sodium across the cell membrane. It is the
nations number one genetic cause of death among children and young
adults. More than 25,000 Americans have CF, with an incidence of about 1 in
3,300 among Caucasians. Ninety percent of persons with CF die from pulmonary
complications. The responsible gene, the CF transmembrane conductance regulator
(CFTR), was identified in 1989. More than 800 mutations and DNA sequence
variations identified in the CFTR gene contribute to the highly variable
presentation and course of the disease. NHLBI supports a vigorous program of
basic, clinical, and behavioral research focused on the etiology,
pathophysiology, and treatment of the pulmonary manifestations of CF. The NHLBI
Program in Gene Therapy for Cystic Fibrosis and Other Heart, Lung, and Blood
Diseases is focused on overcoming the many barriers to gene therapy for CF,
such as vector entry, persistence of expression, selective targeting to
appropriate organ or cell, toxicity of the vector, and host immune response.
The program also evaluates potential new pharmacologic therapies. An example of
a promising therapeutic strategy being investigated for CF is the screening of
compounds that upregulate the chaperone proteins that maintain CFTR
in its proper shape to function correctly.
Lack of understanding of the pathogenesis of CF
airways disease reflects, in part, ignorance of the physiology of the airway
surface liquids (ASL) that are vital for gas exchange and lung defense in the
normal lung. A major scientific advance over the past year has provided
definitive evidence for the importance of low ASL volume in the pathogenesis of
CF airway epithelial disease, contributing to thickened mucus
generated by ASL volume depletion and greater adherence of mucins to the
surfaces of the CF airways. Based on these findings, studies are underway to
develop therapeutic approaches to normalize ASL volume in CF. In addition, the
NHLBI intramural program reported in FY 2001 that diagnostic approaches based
on immunological detection of the Pseudomonas aeruginosa type III
secretory apparatus and its associated cytotoxins provide evidence for early
colonization and/or infection in children with CF.
Idiopathic Pulmonary Fibrosis
(IPF)
IPF is a rare chronic lung disease of unknown cause
affecting between 3 and 30 individuals per 100,000 population. Individuals with
IPF develop abnormal, excessive scarring in the lungs that can cause
progressive shortness of breath and coughing. Currently available treatments,
most commonly with corticosteroids in combination with other potent drugs, and
less commonly with lung transplantation, do little to prevent a relatively
rapid death in most patients. NHLBI-supported research on IPF is examining the
molecular and cellular events that trigger the inflammation of alveoli seen in
the early stages of the disease and that influence progression to the
irreversible, fibrotic end stage. Three NHLBI intramural observational clinical
research protocols focusing on the natural history and pathogenesis of the
disease are open for enrollment of subjects with familial and non-familial
forms of IPF. The protocols have established collaborations with extramural
sites and are working with the Pulmonary Fibrosis Association and other
patient-support organizations to recruit patients. In FY 2001 NHLBI intramural
scientists found that aberrant transcriptional control in alveolar macrophages
may be a contributing factor in the pathogenesis of IPF.
Lymphangioleiomyomatosis (LAM)
LAM is a rare lung disease that affects women, usually
during their reproductive years. Symptoms develop as the result of
proliferation of atypical, non-malignant smooth muscle cells in the lungs.
Diagnosis is usually made by lung biopsy. Common symptoms include shortness of
breath, cough, and sometimes coughing up blood. Patients often develop
spontaneous pneumothorax or chylous pleural effusion (collapse of the lung or
collection of milky looking fluid around the lung). The clinical course of LAM
is quite variable, but is usually slowly progressive, eventually resulting in
death from respiratory failure. Although no treatment has been proven effective
in halting or reversing LAM, lung transplantation is a valuable treatment for
patients with end-stage lung disease. Some patients with tuberous sclerosis
complex (TSC), a genetically transmitted disease, develop lung lesions
identical to those seen in LAM. In some cases, the clinical distinction between
TSC and LAM may be difficult.
NHLBI supports research on LAM in both its intramural
and extramural programs. As part of the intramural program, the Institute has
established a research laboratory at the NIH Clinical Center to learn more
about the cause and progression of LAM at the clinical, cellular, and molecular
levels. Researchers are determining the characteristics of the unusual smooth
muscle cells that damage the lungs of LAM patients. An important aspect of the
research is learning how growth is regulated in these cells.
The NHLBI extramural program supports a national LAM
Patient Registry that is coordinated by the Cleveland Clinic Foundation. The
Office of Research on Womens Health co-funds the registry with NHLBI. The
LAM Registry began enrolling patients in the summer of 1998. Enrollment closed
in September 2001 with 253 LAM patients recruited. The Registry is helping to
manage the collection and distribution of LAM tissue for current LAM projects,
as well as serving as a repository of LAM tissue for future research.
During FY 2001 additional progress was made in
understanding the genetic mechanisms leading to smooth muscle proliferation in
LAM and the relationship between LAM and TSC. Previously it was reported that
mutations in the TSC2 gene can cause pulmonary LAM. More recently it was shown
that in an individual patient the same types of mutations occur in cells taken
from LAM lesions in the lungs and in cells taken from kidney tumors, known as
angiomyolipomas. This suggests that the cells in the lung and the kidney have a
common genetic origin. This discovery may lead to new diagnostic and
therapeutic strategies for women with LAM. Also in FY 2001, the NHLBI
intramural program reported that data from its ongoing study of the natural
history of LAM have established clinical, pathological, physiological, and
genetic criteria that define disease severity and progression.
Narcolepsy
Narcolepsy is a disabling sleep disorder affecting
over 100,000 people in the US. It is characterized by excessive daytime
sleepiness and rapid onset of deep (REM) sleep. Other symptoms involve
abnormalities of dreaming sleep, such as dream-like hallucinations and
transient periods of physical weakness or paralysis (cataplexy). Through
programs such as the SCOR in Neurobiology of Sleep and Sleep Apnea, NHLBI
supports research on the regulation of sleep and wakefulness, the regulation of
muscle tone during sleep, and the genetic basis of narcolepsy in humans and
animals. One new study finds that low cerebrospinal fluid levels of hypocretin,
a neurochemical messenger linking sleep with the regulation of muscle tone, are
highly specific to narcolepsy and could potentially have utility as a
diagnostic procedure. Another study has determined that hypocretin is an
excitatory chemical in brain regions regulating sleep.
Persistent Pulmonary Hypertension of the
Newborn (PPHN)
PPHN affects approximately 1 in 1,250 live born term
infants. Due to inappropriate muscularization of fetal pulmonary vessels, the
lung arteries of affected newborns fail to dilate after birth to allow for
normal blood flow through the lung. Such infants are poorly oxygenated and
require costly and prolonged medical care including: intubation of the airway,
inhalation of 100 percent oxygen, mechanical ventilation, and, often,
heart/lung bypass (extracorporeal membrane oxygenation). One NHLBI SCOR on the
Pathobiology of Lung Development is focused on the unique vascular response of
the neonate to injurious stimuli with a view toward identifying the basic
molecular mechanisms involved in the development of the vasculature. Such
research may provide information for the treatment of hypertensive pulmonary
disorders such as PPHN. Enrollment began in late1999 for a clinical study that
will address maternal risk factors such as cigarette smoking and antenatal
exposure to the non-steroidal anti-inflammatory drugs, aspirin and ibuprofen.
Experimental evidence consistently suggests that maternal exposure to these
agents plays a role in the etiology of the disorder. Buccal cell specimens are
being collected and stored for future genetic analyses should a relationship be
demonstrated.
Inhaled nitric oxide (NO) is an experimental therapy
that offers promise for less invasive treatment of PPHN. Recent studies point
to a critical role for endogenous NO as a modulator of levels of vasoactive
mediators whose levels determine pulmonary vascular tone and reactivity. There
are three known isoforms of NO synthase (NOS) in mammals and all are
developmentally regulated in the fetal lung. Recent work with a premature
baboon model of BPD has demonstrated a decline in two NO isoforms, nNOS and
eNOS, during the genesis of chronic lung disease. Other investigators report a
bi-phasic release of NO in response to shear stress during development. These
findings suggest that NO plays an important role during lung development.
Primary Ciliary
Dyskinesia (PCD) PCD, also known as Kartegeners
syndrome or immobile ciliary syndrome, is an inherited disease characterized by
defects in the cilia lining the respiratory tract. The result is impaired
ciliary function, reduced or absent mucous clearance, and susceptibility to
chronic, recurrent respiratory infections, including sinusitis, bronchitis,
pneumonia, and otitis media. The disease typically affects children ages 0 to
18, but the defect associated with it has a variable clinical impact on disease
progression in adults as well. Many patients experience hearing loss, male
infertility is common, and situs inversus (having organs on the opposite side
from usual) occurs in approximately 50 percent of PCD patients. Clinical
progression of the disease is variable with lung transplantation required in
severe cases. For most patients, aggressive measures to enhance clearance of
mucus, prevent respiratory infections, and treat bacterial superinfections are
recommended. Although the true incidence of the disease is unknown, it is
estimated to be 1 in 32,000 or higher. Recent results of NHLBI-supported
studies are providing new insight into the identification of the genetic basis
of PCD. As part of an overall effort to gather sufficient numbers of patients
for phenotypic and genetic studies, an international database containing
detailed pedigrees, natural history information, and clinical and physiologic
data of well-characterized PCD patients and family members is being assembled.
A selected cohort of patients with defects in the outer dynein arm (ODA) of
cilia, the most common form of PCD, were chosen for initial genetic studies.
Identification of six to ten genes for the vast majority of common PCD patients
who have ODA defects could lead to genetic diagnostic testing, enabling more
definitive identification and earlier diagnosis of PCD patients.
Primary Pulmonary
Hypertension (PPH)
PPH is a rare, progressive lung disorder characterized
by a sustained elevation of pulmonary artery pressure. It is associated with
structural changes in the small pulmonary arteries and arterioles resulting in
resistance to blood flow. The process eventually leads to an enlarged,
overworked right ventricle that is unable to pump enough blood to the lungs
resulting in heart failure and death, usually within 3-5 years of initial
diagnosis. Estimates of the incidence of PPH range from 1 to 2 per million,
with women being predominantly affected. Approximately 6-10 percent of cases
are familial PPH, a form inherited as an autosomal dominant trait. NHLBI
supports basic research on the cellular and molecular events underlying the
pathogenesis of PPH. The dominant themes of this research are: (a) isolation
and characterization of a familial PPH gene, (b) better understanding of the
structural aspects of the disease that cause proliferative and obliterative
changes in the vasculature, (c) identification of genetic factors that affect
functional and structural changes in the vasculature, (d) development of
preclinical markers, and (e) identification and evaluation of more effective
treatments.
In November 2001, the FDA approved a new drug,
Bosentan (Tracleer) for the treatment of PPH. Bosentan is the first oral
treatment approved for PPH, and is also the first in a new class of drugs,
known as endothelin receptor anatagonists, to be available commercially.
Endothelin, a potent vasoconstrictor that also stimulates growth of vascular
cells, is present in high concentrations in the bloodstream of patients with
PPH. Results of a small (32 patient) double-blind, placebo-controlled study
suggest that Bosentan, which acts by blocking endothelin receptors, increases
exercise capacity and improves heart function in patients with pulmonary
hypertension. Future trials should help clinicians better define the place of
this new class of agents in the therapy of pulmonary hypertension. Larger
studies will be needed to address important issues such as improvement in
survival and their potential use in severely ill patients who are receiving
prostacyclin therapy. Other recent work suggests that levels of circulating
endothelin may serve as prognostic markers for patients with PPH and as a tool
for the selection of patients who may benefit from treatment with endothelin
receptor antagonists.
Multiple agents represent another approach beginning
to be applied to the treatment of PPH. Investigators are exploring, for
example, the use of an oral phosphodiesterase inhibitor (sildenafil) as a
therapeutic adjunct to inhaled iloprost. In very preliminary studies,
sildenafil caused a long-lasting reduction in pulmonary artery pressure and
pulmonary vascular resistance, with a further additional improvement after
iloprost inhalation. Similarly, a small pilot study of iloprost inhalation
combined with epoprostenol treatment in patients who had adverse effects during
treatment with epoprostenol showed that the combination therapy significantly
reduced pulmonary artery pressure and improved cardiac index and other
indicators of cardiopulmonary function. These findings suggest that combined
therapies may be useful in improving treatment of PPH.
The discovery last year of a genetic cause of PPH has
opened up a host of opportunities for research into the etiology and
pathogenesis of PPH. New findings this year suggest that there is considerable
heterogeneity in mutations of a gene (BMPR2) that is associated with PPH.
Additional factors, either genetic and/or environmental, may be required for
development of the clinical phenotype. Other PPH genes remain to be identified
since approximately half of the PPH families have BMPR2 mutations. Data suggest
that many cases of apparently sporadic PPH may in fact be familial, as failure
to detect familial PPH is complicated by incomplete expression within families,
skipped generations, and insufficient family pedigrees.
Recent findings on the pathogenesis of PPH indicate
that endothelial cells within plexiform lesions of patients with PPH have
genetic alterations associated with genetic (microsatellite) instability and
abnormal growth and gene expression similar to that seen in neoplasia. Other
studies suggest that the disorganized growth of endothelial cells in plexiform
lesions from PPH patients involves disordered angiogenesis thus allowing for
the expansion of endothelial cells. Pulmonary smooth muscle cells from patients
with PPH have recently been reported to show abnormal responses to cell growth
signaling pathways, and a recently published study from researchers in France
is providing evidence for a link between abnormal expression of a serotonin
transport protein and abnormal proliferation of vascular smooth muscle in PPH
patients. Sarcoidosis
Sarcoidosis is a disease involving organ systems
throughout the body, in which normal tissue is invaded by pockets of
inflammatory cells called granuloma. Most sarcoidosis patients have granuloma
in their lungs. The disease can exist in a mild form that spontaneously
disappears or in a severe form that results in a life-long condition. Estimates
of the number of Americans afflicted range from 13,000 to 134,000, and between
2,600 and 27,000 new cases appear each year. As many as 5 percent of
individuals with pulmonary sarcoidosis die of causes directly related to the
disease. The morbidity associated with the disease can be severe and result in
significant loss of function and decrease in quality of life. The causes of
sarcoidosis are presently unknown, but disease development is thought to
involve the victim's immune system. NHLBI supports laboratory-based research to
investigate granuloma formation and to obtain a better understanding of
initiating events, the disease process, and the contribution of susceptibility
genes.
A multi-center NHLBI study conducted from 1996 to 1999
found that sarcoidosis patients were almost five times more likely than
controls to report a sibling or parent with a history of sarcoidosis. White
sarcoidosis cases were much more likely to have an affected relative than were
African-American cases. However, the investigators found that even for family
members (siblings and parents) the risk of sarcoidosis is small, about one
percent, and therefore concluded that increased surveillance is probably not
warranted. They also found that sarcoidosis appears to increase the risk of
depression.
Blood Diseases and Resources Programs
Aplastic Anemia (AA)
and Paroxysmal Nocturnal Hemoglobinuria (PNH)
AA is a form of bone marrow failure in which
hematopoietic cells are replaced by fat, resulting in low blood counts. In PNH,
a clone derived from a single hematopoietic stem cell expands, leading to
marrow failure, red blood cell destruction, and venous thrombosis. The NHLBI
intramural Hematology Branch has a large clinical and laboratory program
devoted to bone marrow failure syndromes, including AA and PNH. Bench studies
include immunology, cell biology, virology, and molecular biology approaches to
the failure to produce blood cells. Clinical studies include therapeutic
interventions to reduce autoimmunity in patients with AA. In FY 2001 the branch
established an animal model of immune-mediated AA, showing the pivotal role of
type 1 cytokines in causing severe marrow cell destruction. In addition, it
completed analysis of its large trial of immunosuppression in severe AA and
found that early robust improvement in blood counts is highly predictive of
long-term survival without malignant evolution.
Cooley's Anemia
Cooleys anemia (also called beta-thalassemia,
thalassemia major, or Mediterranean anemia) is a genetic blood disease that
results in an inadequate production of hemoglobin. Individuals affected with
Cooley's anemia require frequent and lifelong blood transfusions. Because the
body has no natural means to eliminate iron, the iron contained in transfused
red blood cells builds up over many years and eventually becomes toxic to
tissues and organ systems. In addition, many affected children acquire other
diseases such as hepatitis through years of transfusion exposure.
NHLBIs extramural research efforts related to
Cooleys anemia include (a) identification of mutations in the globin gene
cluster that lead to the disorder, (b) elucidation of the mechanisms and
therapeutic approaches associated with naturally occurring mutations that
result in elevated levels of fetal hemoglobin (Hb F) in adult red blood cells,
(c) iron chelation, (d) clinically-useful therapies and drugs, including gene
therapy, (e) efficient identification and targeting of hematopoietic stem
cells, (f) how ex vivo manipulation of stem cells alters their biologic
properties, and (g) improved vectors for use in gene transfer efforts. The
Institutes strategic approach also includes a clinical research network
to test new therapies and a program of sibling donor cord blood banking and
transplantation for hemoglobinopathy families.
FY 2001 witnessed a number of important scientific
advances for Cooleys anemia. New methods of transfusion therapy are being
developed to improve adherence with deferoxamine regimens for patients
receiving chronic transfusions. Less toxic methods of stem cell transplantation
are being developed that may be useful for patients with thalassemia. For
example, the NHLBI intramural program is working on a vaccine to prevent
cytomegalovirus reactivation after stem cell transplantation using a CMV pp65
protein canarypox construct. Finally, several compounds that increase Hb F
values have been described. They are hydroxyurea, which is a compound in
routine use in sickle cell disease, a number of butyrate-based compounds, and
5-azacytidine. Creutzfeldt-Jakob Disease (CJD)
CJD is a slowly degenerative, invariably fatal, rare
disease of the central nervous system, characterized by motor dysfunction,
progressive dementia, and vacuolar degeneration of the brain. The disease has
been associated with a transmissible agent. A protease-resistant protein or
prion is the hallmark of the transmissible spongiform encephalophaties (TSE)
family of diseases to which CJD belongs. Classical CJD occurs worldwide at a
rate of 1-2 cases per million per year. The lack of a rapid, sensitive, and
specific test for TSE infectivity has slowed progress in the study and control
of CJD and other prion diseases. The development of assay systems to detect
prion diseases is a high priority in public heath. It could form the basis of a
blood/tissue donor screening test, and provide a diagnostic test for
neurologists; there is currently no way of detecting the disease in its
pre-clinical stage. These assays could also be useful in testing for TSE in
animals, especially domestic animals used for human consumption. In FY 2001,
NHLBI-supported investigators reported that mouse skeletal muscle can propagate
prions and accumulate substantial titers of them. Because significant dietary
exposure to prions might occur through the consumption of meat, even if it is
largely free of neural and lymphatic tissue, a comprehensive effort to map the
distribution of prions in the muscle of infected livestock is needed.
Furthermore, muscle may provide a readily biopsied tissue that can be used to
diagnose prion disease in asymptomatic animals and even humans.
Fanconi Anemia
(FA)
FA is an autosomal recessive bone marrow failure
syndrome characterized by a decrease in blood cells and platelets
(pancytopenia), developmental defects, and cancer susceptibility. Many FA
patients can be identified at birth because of congenital anomalies, although
approximately 25 percent do not have birth defects. FA is a clinically
heterogeneous disorder; it can currently be divided into at least eight
different complementation groups designated A through G. Delineation of the
interrelationship of the FA proteins and their functions through localization
and functional studies is a high priority research area for NHLBI. In addition,
NHLBI supports research that focuses on identifying and cloning the remaining
FA genes, developing protocols for efficient identification and targeting of
hematopoietic stem cells, obtaining information on how ex vivo
manipulation of stem cells alters their biologic properties, producing improved
vectors, and exploring the utility of cord blood banking. Two FA genes, FAC and
FAA, that account for an estimated 75 percent of all FA patients world wide,
have been cloned. The cellular localization of the functional complex and the
role of the complex in DNA repair and prevention of mutagenesis have been
exciting developments over the past year. Recent transplantation protocols
using Fludarabine have provided new hope that stem cell transplantation may be
a therapeutic option for patients with FA.
Graft versus Host Disease (GvHD)
Acute GvHD is a condition that typically occurs within
3 months after allogeneic hematopoietic stem cell transplantation. Donor T
cells react against foreign tissue antigens in the recipient. GvHD
is characterized by skin rash, liver dysfunction, vomiting, and diarrhea. Acute
GvHD often precedes development of chronic GvHD, which may require years of
treatment with immunosuppressive drugs. NHLBI supports basic and clinical
research grants focused on understanding the pathophysiology of GvHD,
especially in unrelated transplants. The NHLBI program emphasizes understanding
of the roles of both major and minor histocompatibility antigens in disease
pathogenesis, development of tolerance, function of donor T cells in allogeneic
hosts, and mechanisms of GvHD prevention including depletion of donor T cells
from the graft. Current studies attack the problem of GvHD from several
directions: the variables that affect its induction and severity; the effector
mechanisms; and whether GvHD can be suppressed while other necessary immune
responses are maintained. The program supports two multi-center clinical
studies: the Unrelated-Donor Marrow Transplant Trial of T-cell Depletion and
the Cord Blood Banking and Transplantation Study. The Blood and Marrow Clinical
Transplant Network was funded in FY 2001 to conduct Phase III trials including
studies of GvHD. To date, older or sicker patients have been excluded from
allogeneic hematopoietic cell transplantation (HCT) because of toxicities from
the treatment regimen. Recently, investigators have developed a less toxic
regimen, based on the use of postgrafting immunosuppression to control graft
rejection and GvHD, that has dramatically reduced the acute toxicities of
allografting. Now HCT with the induction of potent graft-versus-tumor effects
can be performed in previously ineligible patients, largely in an outpatient
setting. Finally, the NHLBI intramural research program in FY 2001 described
how the alloimmune environment reshapes the immune response of the donor after
stem cell transplantation by identifying innate T cell responses to known and
putative tumor specific antigens.
Hemophilia
Hemophilia is a hereditary bleeding disorder that
results from a deficiency in either blood coagulation factor VIII or factor IX.
There are about 20,000 hemophiliacs in the US, all of whom are dependent on
lifelong treatment to control periodic bleeding episodes. NHLBI supports a
broad spectrum of activities on blood coagulation and its disorders. Research
on hemophilia includes viral and non-viral approaches for gene therapy,
mechanisms of antibody inhibitor formation, modification of factors for
improved therapeutics, safety of plasma derived products, and blood product
associated infections. In addition, basic genetic, molecular biology, and
protein biochemistry studies of factors VIII and IX are supported to improve
understanding of the mechanisms of action and regulation of these critical
coagulation proteins. One program project studies multiple approaches to
developing gene-based therapies for hemophilia A and B, and another studies new
therapies that can be used in the presence of inhibitory antibodies.
Gene therapy studies by NHLBI-supported scientists have shown sustained
expression of factor IX in mice and hemophilic dogs after administration of
adeno-associated viral (AAV) vector expressing factor IX. Based on pre-clinical
safety and efficacy data, a clinical study for intrahepatic delivery of AAV
vector expressing factor IX was initiated in August 2001. Studies by
NHLBI-supported investigators have improved understanding of the immune
response to factor VIII that leads to the formation of inhibitory antibodies.
Studies in a hemophilia mouse model demonstrated in FY 2001 that long-term
immune tolerance to factor VIII could be induced after early blockade of the
interaction between the antibodies CD40 and CD40L. In addition, the structure
of a region of factor VIII bound to an inhibitory antibody was determined that
could be useful in efforts to develop less antigenic factor VIII products.
Immune Thrombocytopenic
Purpura (ITP)
ITP is an autoimmune disease manifested by production
of antibodies that react with specific proteins on the surface of platelets.
The reaction results in rapid clearance or destruction of platelets
(thrombocytopenia) and clinically-significant bleeding. The underlying cause is
unknown, but the disease is associated with other autoimmune disorders.
Although ITP may occur at any age, acute (temporary) thrombocytopenic purpura
is most commonly seen in young children. About 85 percent of affected children
recover within 1 year and experience no recurrence. Thrombocytopenic purpura is
considered chronic when it lasts more than 6 months. Its onset may occur at any
age. Adults more often have the chronic disorder and females are affected two
to three times more often than males. Most adult patients respond at least
transiently to standard therapies including steroids and splenectomy, but a
majority eventually relapse and some develop very severe chronic refractory
ITP.
Part of the NHLBI research program on thrombosis and
hemostasis is directed toward understanding the biology of platelet production
from megakaryocytes, the function of the growth factor thrombopoietin (TPO),
and the structure and function of platelet surface glycoprotein antigens.
Studies on TPO have not borne out the initial promise of this therapeutic
strategy. While mice with the TPO gene knocked out maintained a
basal level of circulating platelets and did not bleed, a number of human
subjects with thrombocytopenia who received TPO developed antibodies to the
protein and their clinical conditions worsened. The investigators concluded
that TPO is an amplification factor, but it may not be essential for
megakaryocytopoiesis and platelet production. On the other hand, migration of
the bone marrow megakaryocytes to a more permissible environment for platelet
production could be a critical factor. In another development, a monoclonal
antibody, rituximab, directed to B-lymphocytes for the treatment of cancer, was
found in initial studies to be beneficial for patients with ITP.
Lymphedema
Lymphedema is an accumulation of lymphatic fluid in
interstitial tissue that causes swelling, most often in the arm(s) and/or
leg(s), and occasionally in other parts of the body. Lymphedema can develop
when lymphatic vessels are missing or impaired (primary or congenital), or when
lymph vessels are damaged or lymph nodes removed (secondary). When the
impairment becomes so great that the lymphatic fluid exceeds the lymphatic
transport capacity, an abnormal amount of protein-rich fluid collects in the
tissues of affected areas. Left untreated, this stagnant, protein-rich fluid
not only causes tissue channels to increase in size and number, but also
reduces oxygen availability in the transport system, interferes with wound
healing, and provides a culture medium for bacteria that can result in a
lymphangitis infection. The incidence of primary lymphedema has been estimated
to be between 1 in 6,000 and 1 in 300 live births, so it may be a rare disease,
or it may be a more common disease which predisposes to the secondary type and
is under recognized. NHLBI investigator-initiated projects are seeking to
identify the developmental, molecular, and cellular defects that contribute to
lymphedema and are seeking to design effective therapeutic interventions to
treat both primary and secondary lymphedemas. In December 2000, NHLBI issued a
Program Announcement (PA) inviting applications to study the pathogenesis and
treatment of lymphedema. Sickle Cell Disease (SCD)
SCD is an inherited blood disorder that is most common
among people whose ancestors come from Africa, the Middle East, the
Mediterranean basin, or India. SCD is the most common genetic blood disorder in
the U.S., affecting approximately 1 in 500 African-American newborns and 1 in
1,000 Hispanic newborns. It occurs when an infant inherits the gene for the
sickle hemoglobin from both parents or the gene for sickle hemoglobin from one
parent and the gene for another abnormal hemoglobin from the other parent. In
patients with the disease, the hemoglobin molecules in the red blood cells
(RBCs) which carry oxygen throughout the body tend to damage the RBC walls,
causing them to stick to blood vessel walls. This leads to the painful sickle
cell episodes that are the hallmark of the disease. Chronic end-organ damage
occurs to the brain, lungs, kidneys, spleen, and liver, and leads to premature
death, with the median age at death for severely affected individuals occurring
between 42 and 48 years.
NHLBIs current sickle cell disease portfolio
includes research on the following topics: (a) development of methods for gene
transfer and gene replacement in the hematopoietic stem cell; (b)
characterization of interactions between sickle cells and the vascular
endothelium; (c) improved understanding of hemoglobin gene switching to allow
increased production of fetal hemoglobin; (d) a Phase III clinical trial of
hydroxyurea in children with sickle cell anemia to determine if hydroxyurea can
prevent the onset of chronic end organ damage; (e) an epidemiologic study of
the incidence of parvovirus B19 seroconversion in children with sickle cell
disease; (f) an epidemiologic study of the adult patients who participated in
the Multicenter Study of Hydroxyurea Trial; (g) a study of non-myeloablative
preparative regimens for bone marrow transplantation leading to mixed chimerism
as curative therapy for severely affected SCD patients; and (h) a study of
sibling cord blood banking and transplantation of cord blood derived stem cells
to cure severely affected sickle cell disease patients. In addition, the NHLBI
Intramural program continued an ongoing seroconversion study of B19 parvovirus
in sickle cell anemia patients in preparation for a recombinant vaccine trial
of baculovirus-engineered empty capsids.
Progress in SCD research in FY 2001 was highlighted by
a report of a gene therapy cure of the transgenic mouse model of sickle cell
disease. Investigators at the Massachusetts Institute of Technology and the
Albert Einstein College of Medicine announced the insertion of a beta
hemoglobin A gene variant into hematopoietic stem cells in two transgenic SCD
mouse models (Berkeley and SAD). The animals were able to produce the corrected
hemoglobin cells for up to 10 months with associated correction of hematologic
parameters, splenomegaly, and prevention of urine concentrating defect. This
experiment paves the way for additional animal studies and ultimately human
clinical trials to find a safe way to neutralize the abnormal blood producing
gene before the introduction of gene-therapy-treated blood producing cells.
Systemic Lupus
Erythematosus (SLE)
SLE or lupus is an autoimmune disorder in
which the body produces antibodies that harm its own cells and tissues. Typical
symptoms of SLE are fatigue, arthritis, fever, skin rashes, and kidney
problems. Lupus affects more women than men. Patients with SLE have a higher
incidence of thrombosis and spontaneous loss of pregnancy. Its cause is unknown
and there is no known cure, but the symptoms can be controlled with appropriate
treatment and most patients can lead an active life. As part of its broad
program of research in hemostasis and thrombosis, NHLBI is supporting studies
on the development of diagnostic tests in pregnant women with SLE. Recent
studies suggest that circulating antibodies in lupus patients compete with a
protein, annexin V, that forms an anti-thrombotic shield in the placenta. The
result is that procoagulant phospholipids remain exposed, cause thrombosis in
the vessels of the placenta, and lead to fetal loss.
Thrombotic Thrombocytopenic Purpura
(TTP)
TTP is a potentially fatal disease characterized by
low blood platelet levels and widespread platelet thrombi in arterioles and
capillaries. Both endothelial cell damage and intravascular platelet
aggregation have been suggested in the pathogenesis of TTP. Microscopic
examination of thrombi has revealed the presence of abundant von Willebrand
factor (vWf), a plasma protein. An interaction between vWf and the platelet
surface glycoprotein complex I (GP I) is believed to be essential for the
formation of a thrombus. vWf is synthesized as large polymers and is then
cleaved into smaller units by a plasma protease. NHLBI grantees have confirmed
the presence of inhibitory antibodies to this enzyme in the plasma of some
patients with TTP. Inhibition of the enzyme results in large multimers of vWf
in plasma that can spontaneously aggregate platelets. The NHLBI grantees
succeeded in isolating a new metalloprotease, the ADAMTS 13 degradative enzyme
inhibitor, and established that mutations in the gene that expresses ADAMTS 13
are the genetic basis of familial TTP. Efforts are being made to produce
recombinant ADAMTS 13. Rare Disease
Research Initiatives
Ongoing Initiatives
Adult Hydroxyurea Patient Follow-up Study (aka:
Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients'
Follow-up) Beryllium-Induced Diseases Cellular and
Molecular Mechanisms of Primary Pulmonary Hypertension Chronic
Fatigue Syndrome: Pathophysiology and Treatment Clinical Research on
Cooley's Anemia Comprehensive Sickle Cell Centers
Creutzfeldt-Jakob Disease Assay Methods Development Developmental
Processes in Differential Expression of Globin Genes
Environment/Infection/Gene Interactions in Autoimmune Disease
Genomic Applications for Heart, Lung, and Blood Research
Homocyst(e)inemia and Atherosclerosis Human Umbilical Cord Blood
Stem and Progenitor Cells: Collection, Storage, and Transplantation
Immunogenetics of Inhibitor Formation in Hemophilia Mitochondrial
DNA Mutations in Heart, Lung, and Blood Diseases Molecular Biology
and Genetics of Sleep and Sleep Disorders Programs of Excellence in
Gene Therapy Retinoid Treatment in Emphysema: Feasibility
Studies SCOR in Hematopoietic Stem Cell Biology SCOR in
Neurobiology of Sleep and Sleep Apnea, Airway Biology and Pathogenesis of
Cystic Fibrosis, and Acute Lung Injury SCOR in Pathobiology of
Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and
Molecular Mechanisms of Asthma SCOR in Pediatric Cardiovascular
Disease Stem Cell Transplantation to Establish Allochimerism
Strategies to Augment Alveolization Thalassemia (Cooley's
Anemia) Clinical Research Network Thrombocytopenia: Pathogenesis and
Treatment Tuberculosis Academic Award Vascular and
Hematopoietic Development and Disease
Initiatives Started in 2001 Blood and Marrow Transplant
Clinical Research Network
A new RFA, initiated by NHLBI and cosponsored by NCI,
organizes a network to accelerate research on the management of hematopoietic
stem cell transplantation, standardize existing treatments, and evaluate new
ones. The network of 14 interactive clinical centers and a data coordinating
center provides a coordinated, flexible mechanism over a maximum period of 10
years to accept ideas and build consensus from the transplant community;
develop protocols; expeditiously perform multi-center Phase II and Phase III
clinical trials; provide information to physicians, scientists, and the public;
and, in turn, improve stem cell transplantation therapy for diseases such as
leukemia, sickle cell disease, thalassemia, and Fanconi anemia.
Genetic Aspects of
Tuberculosis in the Lung
A new RFA, initiated by NHLBI and cosponsored by
NIAID, stimulates research on the genetic aspects of tuberculosis in the lung,
exploiting advances in molecular biology and genomics research. Special
attention is paid to the interaction between host and microbial genes and to
the identification of genes or families of genes that determine virulence or
latency, or that determine reactivation of disease or resistance to
antituberculous drugs. Of particular interest are studies using new
biotechnologies such as microarrays, molecular beacon technology, or
differential signature-tagged mutagenesis (DSTM), and studies involving
innovative collaborations with computational biologists to identify genes that
mediate the pathogenesis of tuberculosis and elucidate the responsible
mechanisms. To encourage junior level quantitative biologists to work on the
genetic aspects of tuberculosis, the Mentored Quantitative Research Career
Development Award (K25) has been included as one of the mechanisms of support
. Genetic
Modifiers of Single Gene Defect Diseases
A new RFA, initiated by NHLBI and cosponsored by
NIDDK, encourages studies to identify and characterize the genes responsible
for modifying the clinical progression and outcomes of heart, lung, and blood
diseases due to single gene defects. Examples of such single gene defect
diseases are cystic fibrosis; sickle cell disease; hemophilia;
alpha-1-antitrypsin deficiency; glucocorticoid remediable aldosteronism (GRA);
Liddles syndrome; and cardiac myopathies, dysplasias, and arrhythmias
that result in sudden cardiac death. The modifier genes are likely to encode a
wide variety of proteins that either interact directly with the disease gene,
influence pathways involving the disease gene, or affect metabolic processes
altered as a result of the disease gene defect. Identification of the genes
responsible for these differences should lead to a better understanding of
disease pathogenesis, earlier diagnosis, and improved treatment.
Novel Approaches to
Enhance Animal Stem Cell Research
A new PA, co-sponsored by ten institutes, encourages
studies to isolate, characterize, and identify totipotent and multipotent stem
cells from nonhuman biomedical research animal models and generate reagents and
techniques to characterize and separate them from other cell types. The PA
stresses innovative approaches to the problems of making multipotent stem cells
available from a variety of nonhuman sources, and innovative approaches to
creating reagents that will identify them across species and allow for
separation of multipotent stem cells from differentiated cell types.
Pathogenesis and
Treatment of Lymphedema
A new PA, initiated by NHLBI and co-sponsored by
NICHD, NIAMS, and NCI, encourages investigation of the pathogenesis of, and new
treatments for, primary and secondary lymphedema. The PA seeks to stimulate
research on the biology of the lymphatic system and to characterize at the
molecular, cellular, tissue, organ, and intact organism levels, the
pathophysiologic mechanisms that cause the disease, and to discover new
therapeutic interventions. Such knowledge will help to improve early diagnosis
of affected individuals, the choice and timing of treatment, and genetic
counseling. Pediatric Heart Disease Clinical Research
Network
A new RFA establishes a network of interactive
pediatric clinical research centers to promote the efficient evaluation of new
treatment methods and management strategies that offer potential benefit for
children with structural congenital heart disease, inflammatory heart disease,
heart muscle disease, and arrhythmias. Therapeutic trials and studies involve
investigational drugs, drugs already approved but not currently used, as well
as devices, interventional procedures, and surgical techniques. The network
approach, consisting of five to six clinical centers and a data coordinating
center, is an effective, flexible way to study adequate numbers of patients
with uncommon diseases such as congenital cardiovascular malformations.
Efficiencies are achieved through standardizing procedures to recruit,
characterize, monitor, and follow-up patients. Approximately 2,000 patients are
expected to participate in 6-12 different protocols over the 5-year project
period. The network also serves as a platform to train junior investigators in
pediatric clinical research and as a vehicle for rapid and wide-spread
dissemination of findings.
Initiatives Planned for the Future
Animal Models of
Antigen-Specific Tolerance for Heart and Lung Transplantation
A new PA in FY 2002 will encourage the development of
large animal models of antigen-specific tolerance induction for heart and lung
transplantation and small animal models of tolerance induction for lung
transplantation. Development of stable immune tolerance between donor and
recipient would decrease morbidity and mortality due to chronic rejection,
toxic effects of immunosuppressive therapy, and graft versus host disease.
Chemical Screens for
New Inducers of Fetal Hemoglobin for Treatment of Sickle Cell Disease and
Cooleys Anemia
A new PA in FY 2002 will support high-throughput
chemical activity screens for new pharmacologic inducers of fetal hemoglobin,
with the long-term objective of developing better drugs to treat sickle cell
disease and Cooleys anemia. The screens should include but not be limited
to compounds in the short chain fatty acid and carbonic acid classes. Promising
compounds identified through these Small Business Innovation Research (SBIR)
grants will later be subjected to toxicology and pharmacokinetic testing in
primates. Heritable Disorders of Connective Tissue
A new RFA, to be initiated by NIAMS and to be
co-sponsored by NHLBI in FY 2002, will promote research on heritable disorders
of connective tissue caused by abnormalities in the molecules involved in the
biosynthesis, processing, and degradation of structural macromolecules, as well
as abnormalities in regulatory and signaling molecules that reside within the
extracellular matrix. This initiative should increase understanding of, and
lead to novel therapeutic strategies for, the Mafan's and Ehler-Danlos
syndromes, diseases that involve alterations of the integrity of the connective
tissue compartments within the wall of the blood vessel and the subsequent
formation of aneurysms in the aorta and smaller arteries.
Multicenter Study of
Hydroxyurea in Sickle Cell Disease: Patient Follow-Up Extension
I
A renewal of an RFP in FY 2002 will continue the
follow-up study of the 299 adult patients who participated in the Multicenter
Study of Hydroxyurea in Sickle Cell Disease (MSH Trial) from 1992 to 1995 in
order to ascertain the long term toxic effects of hydroxyurea usage in this
patient population. The 240 patients known to be alive will be followed
annually for five additional years at the 21 MSH clinical centers to determine
health status, quality of life, incidence of malignancies, and birth defects in
their offspring. Mortality rates will be compared to the mortality data from
the Cooperative Study of Sickle Cell Disease adult cohort and the normal
African-American population. In addition, long term efficacy of hydroxyurea
will be estimated in terms of its effects on fetal hemoglobin levels (Hb F),
blood cell counts, and selected organ function.
Plasticity of Human Stem Cells in the Nervous
System
A new PA, to be co-sponsored by NHLBI and three other
institutes in FY 2002, will encourage studies on the plasticity and behavior of
human stem cells and the regulation of their replication, differentiation, and
function in the nervous system. Because of their ability to generate neurons
and glia, stem cells are promising candidates for the development of cellular
and genetic therapies for neurological disorders, including neuroregulatory
problems in heart, lung, and blood diseases, and sleep disorders. Studies will
be encouraged to confirm, extend, and compare the behavior of human stem cells
that are derived from different sources and ages or exposed to different
regimes in vitro and in vivo. In addition, studies will be encouraged to
develop methods for identifying, isolating, and characterizing specific human
precursor populations at intermediate stages of differentiation into neurons
and glia. Stem Cell
Plasticity in Hematopoietic and Non-Hematopoietic Tissue
A new RFA, to be initiated by NHLBI and to be
co-sponsored by NIDDK and NINDS in FY 2002, will encourage studies to elucidate
and characterize the molecular and cellular mechanisms that influence stem cell
plasticity or versatility. Stem cells are the most primitive cells in the bone
marrow from which all the various types of blood cells are derived. Studies are
needed to identify genes responsible for the maintenance of "stemness" and
genes responsible for initiating and/or maintaining the development of specific
cell types. Human adult stem cells could potentially be exploited to become
more embryonic-like and therefore useful for drug screening, replacement of
diseased or injured tissue, and gene therapy. Transactivation of
Fetal Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooleys
Anemia
A new RFA, to be initiated by NHLBI and co-sponsored
by NIDDK in FY 2002, will encourage studies to identify the transcriptional
regulatory proteins involved in fetal hemoglobin gene activation, determine
their mechanisms of action and the induction mechanisms of the structural genes
encoding the regulators, and identify drugs that induce fetal hemoglobin via
action on the regulators. A better understanding of the molecular basis of
fetal hemoglobin gene regulation, and of fetal to adult hemoglobin isoform
switching in development, will facilitate the development of new approaches to
cure beta-chain hemoglobinopathies such as SCD and Cooley's anemia.
Transfusion
Medicine/Hemostasis Clinical Research Network
A new RFA will establish in FY 2002 a network of
interactive clinical research groups to promote the efficient comparison of new
management strategies of potential benefit for children and adults with
hemostatic disorders and also to evaluate new as well as existing blood
products and cytokines for the treatment of hematologic disorders. Hemostasis,
the arrest of bleeding from an injured blood vessel, requires the combined
activity of vascular, platelet, and plasma factors counterbalanced by
regulatory mechanisms to limit the accumulation of platelets and fibrin in the
area of injury. Hemostatic abnormalities may be congenital; immune-mediated,
such as ITP and TTP; or due to coagulopathies resulting from chemotherapy,
surgery, or trauma and can lead to excessive bleeding or thrombosis. The
network will consist of a Data Coordinating Center and up to sixteen core
clinical centers to perform multiple clinical trials. Cell-Based Therapies for
Heart, Lung, Blood, and Sleep Disorders and Diseases
A new RFA will encourage in FY 2003 basic research on
stem cell biology and on the use of stem cells in cellular therapies for the
treatment of cardiovascular, lung, blood, and sleep disorders and diseases.
Because of their plasticity, adult, embryonic, and fetal stem cells hold great
potential for use in new strategies to regenerate and repair damaged or
diseased cardiovascular, lung, and blood tissues, and for sleep disorders.
Areas supported would include the basic biology and characterization of
embryonic, fetal, and adult stem cells and progenitor cells important for
heart, lung, blood and sleep disorders; the use and differentiation of stem and
progenitor cells for cell transplantation; stem cell homing to sites of tissue
injury or specific tissue or organ sites, including the mechanisms underlying
the homing process; and tissue engineering using stem or progenitor cells.
Comprehensive
Sickle Cell Centers
A renewal of an RFA will continue in FY 2003 the
operation of a nationwide network of collaborative, comprehensive centers in
basic and translational research focused on the development of cures or
significantly improved treatments for SCD. The network of ten centers and a
statistics and data management core carries out basic research, inter-center
collaborative clinical research, and local clinical research focused on the
most promising biomedical and behavioral therapeutic modalities. The centers
also support career development of young investigators in SCD research and
support services including patient education, patient counseling, community
outreach, and hemoglobin diagnosis. This is the eighth re-competition of a
program that was established by a Presidential initiative and Congressional
mandate in 1972. Hutchinson-Gilford Progeria Syndrome (HGPS):
Exploratory/Developmental (R21) Grants
A new PA with Review, to be co-sponsored by four
Institutes, will encourage in FY 2003 studies to elucidate the molecular and
mechanistic bases of HGPS, an incurable and terminal premature aging disorder
characterized by short stature, abnormal skeletal and tooth development,
scleroderma-like skin changes, and cardiovascular disease. Children with the
disorder usually die of heart attacks or strokes at an average age of 13 years.
Little research has been done on the syndrome because it is extremely rare
(about 1 in 10 million births) and access to the patient population has been
limited. Fibroblast and lymphoblastoid cell lines from HGPS patients from ten
different families will be available to awardees. A better understanding of the
mode of inheritance, molecular basis, and pathomechanisms of HGPS could lead to
new insights into mechanisms of development, aging, and vascular occlusive
diseases. Mechanisms of Fetal Hemoglobin Gene Silencing for Treatment of
Sickle Cell Disease and Cooley's Anemia
A new RFA will encourage studies in FY 2003 to
delineate the mechanisms involved in fetal hemoglobin (gama-globin) gene
silencing during normal human development and develop therapeutic approaches to
inhibit silencing. Both cis- and trans-acting elements important in
gamma-globin gene silencing will be identified and their mechanisms of action
will be determined. Pharmacologic or gene-based approaches to interfere with
silencing may ultimately be pursued. Increased understanding of the molecular
basis of fetal hemoglobin silencing will facilitate the development of new
gene-based therapeutic approaches to increase fetal hemoglobin in red blood
cells and thereby cure beta-chain hemoglobinopathies. Mesenchymal Stem Cell
Biology
A new RFA will encourage studies in FY 2003 to conduct
basic research on mesenchymal cell biology in order to provide the basis for
clinical application of mesenchymal stem cells (MSCs) to hematopoietic and
non-hematopoietic stem cell transplantation. MSCs are pluripotent progenitor
cells located in bone marrow that can differentiate into a variety of
non-hematopoietic tissues including bone, cartilage, tendon, fat, muscle, and
early progenitors of neural cells. Preclinical studies suggest MSCs facilitate
hematopoietic stem cell transplantation while decreasing immune rejection of
allogeneic transplants. To realize the therapeutic potential of these results,
the initiative will support the identification of population and assay methods
to characterize the clinical potential of candidate human MSCs and the
development of isolation and characterization standards for use in
comparing. Molecular Target and Drug Discovery for Idiopathic Pulmonary
Fibrosis
A new RFA will encourage studies in FY 2003 to develop
new therapeutic approaches for IPF. One approach to inhibit progression or
reverse fibrosis in IPF patients would be to identify new agents, ranging from
small molecules to vaccines, that interact with previously identified molecules
or pathways known to be involved in the development of fibrosis. Other
promising approaches supported by this initiative would be to use new
technologies to identify additional molecular targets for treatment and to
identify agonists or antagonists that interact with the previously or newly
identified targets to attenuate, halt, or reverse the fibrotic process.
SCOR in (a) Neurobiology of
Sleep and Sleep Apnea and (b) Airway Biology and Pathogenesis of Cystic
Fibrosis
A renewal of an RFA to foster multidisciplinary basic
and clinical research in FY 2003 enabling basic science findings to be more
rapidly applied to clinical problems of sleep and CF. The objective of the
sleep SCOR is to integrate clinical research on the etiology and pathogenesis
of sleep disorders, particularly sleep apnea, with molecular, cellular, and
genetic approaches to the study of sleep. The objective of the CF SCOR is to
use our current knowledge of the CF transmembrane conductance regulator (CFTR)
as a focus to promote advances in research on the pathogenesis of CF, the role
of CFTR in airway biology, and the development of new treatment strategies.
Each SCOR must consist of three or more projects, all of which are directly
related to the SCOR program topic. This will be the second and final 5-year
solicitation for these two SCORs.
Rare Disease-Related Program Activities
A Task Force on Research in Pediatric
Cardiovascular Disease was held in January 2001. The Task Force
identified the following eight research priorities for the next 5 years:
Fundamental studies of the formation of heart
and blood vessels Development and use of new and improved
technologies to image the heart Advanced repair of congenital heart
defects in infants and children Refined surgical treatment of human
fetuses with heart defects Exploration of stem cell biology for the
repair of heart tissues Creation of improved biomaterials through
tissue engineering Translational research to enhance clinical care
Definition of the childhood antecedents and risk factors for
atherosclerotic heart disease in adults.
A symposium called Lamposium 2001", held in
March 2001 in Cincinnati Ohio, was co-sponsored by NHLBI and the LAM
Foundation.
An RFA meeting for Clinical Research for
Cooleys Anemia and Biology of Iron Overload was held in April
2001.
A workshop on AAT Deficiency: The Challenge Of
Genetic Conditions, held in June 2001, and co-sponsored by the Alpha One
Foundation, NHLBI, NIDDK, and ORD, was designed to promote a multi-disciplinary
understanding of psychosocial and scientific challenges of AAT deficiency.
A workshop on Host Response in Sickle Cell
Disease, held in June 2001, discussed the clinical manifestations of
problems with the immune response in SCD. Specific topics included resistance
to pneumococcus, genetic modifiers of the immune response, loss of
splenic function in SCD, and the response to encapsulated bacteria, iron
overload, autoimmune disorders, developmental immunity, white blood cell
function in SCD, and consequences of chronic transfusions. It was recommended
that research be pursued to ascertain the genetic factors that modify
phenotypic differences in the responsiveness of SCD patients to infections.
A workshop on Protein Processing and Degradation
in Pulmonary Health and Disease, held in September 2001, and cosponsored
by NHLBI and ORD, was designed to evaluate the current state of knowledge of
protein biosynthetic processing and intracellular degradation.
A working group on Targeting Technologies for
Repair of Single Nucleotide Mutations in Single Gene-Defect Blood
Diseases, held in September 2001, assessed the potential of various
approaches for correction of pathogenic single nucleotide mutations in SCD,
beta-thalassemia, hemophilia A and B, and hemochromatosis.
A research training program designed for clinicians
interested in performing biomedical research related to PH will be co-sponsored
by NHLBI and the Pulmonary Hypertension Association. The training will be
supported by the Mentored Clinical Scientist Development Award (NIH
activity code K08).
A working group on translational research in PPH,
sponsored by the ORD and NHLBI, is planned for FY2003.
Problem Areas Related to Rare Diseases
Alpha-1-Antitrypsin
Deficiency
Research needs include better animal models of the
disease, identification of biomarkers, and development of chemical chaperones
that could specifically enhance the secretion of the mutant alpha-1 antitrypsin
protein. Arrhythmogenic Right Ventricular Dysplasia
A concerted multi-laboratory program, combining basic,
clinical, and genetic approaches, is needed to identify the causes of this
highly lethal form of cardiomyopathy. Once contributing factors are found, the
next challenge will be to begin a search for therapies. Additional clinical
centers, and perhaps a national registry, would be useful to investigators who
are already studying the origins of ARVD and potential treatments.
Congenital
Central Hypoventilation Syndrome
A significant limitation is the difficulty of
recruiting CCHS subjects for clinical research. CCHS is a very rare condition
often presenting within a few hours of birth. Only 150 surviving CHS patients
are estimated to exist world-wide. Relocation to clinical research sites is
made difficult by the spectrum of clinical symptoms associated with CCHS and
related dysfunction of the autonomic nervous system.
Congenital
Diaphragmatic Hernia
As a result of advances in ultrasonography, CDH is now
diagnosed before birth with increasing frequency. Development of micro surgical
techniques has made it possible to execute surgical repair in utero.
With multiple options currently available to families, accurate counseling on
the expected outcome is crucial. Scientific information must be provided to
assist affected families in making decisions about management.
Congenital Heart
Disease
Long-term follow-up studies are required to answer
certain types of questions, but, because congenital heart disease is often
repaired in infancy, such studies are difficult to initiate. Additional
research is needed on adult congenital heart disease, pulmonary malformations
in congenital heart disease, and pediatric ventricular assist devices.
Creutzfeldt-Jakob
Disease
A standardized reference material repository is needed
to validate assay systems to detect TSE. Materials under consideration to
calibrate in-house reference materials of individual laboratories to a single
international standard include human brain tissue, human blood, animal tissues,
and animal blood. Blind panels are needed for validation of all assays,
specifically the validation of their sensitivity, reproducibility, and
predictive abilities. NHLBI is presently developing an initiative to support
the establishment of a standardized reference TSE material repository.
Graft versus Host
Disease
Promising agents that could be used to treat GvHD are
also under investigation for use in other diseases, for example, arthritis.
Pharmaceutical companies are reluctant to allow transplant research
investigators access to these investigational drugs for fear that the
complications experienced by HCT patients will interfere with the approval
process for new agents. Infectious Myocarditis
Dilated cardiomyopathy is thought to be a consequence
of myocarditis in a subgroup of genetically predisposed people. Identification
of the genetic basis for more severe disease may allow clinicians to target
patients who would benefit from more aggressive therapy. There is a need for
more specific and sensitive noninvasive methods for diagnosis. The current gold
standard is endomyocardial biopsy but this procedure suffers from limited
specificity and sensitivity. Also, the concept of myocarditis as an autoimmune
phenomenon is supported by studies linking persistence of viral RNA in the
myocardium to the induction of autoantibodies. More research is needed to
determine the effectiveness of immunosuppressive modalities in myocarditis.
NHLBI-supported investigators are tackling several of these problem areas.
Long QT
Syndrome
Access and identification of sufficient numbers of new
patients for studies remain a problem. Identification of mutant gene carriers
would be greatly facilitated by accurate means of screening individuals in
afflicted families for specific founder mutations. Improved means of
identifying new mutations in the various genes involved would also be helpful.
Investigators are working to increase the visibility of an international LQTS
registry in minority communities.
Lymphangioleiomyomatosis
LAM tissue is scarce and cell lines are difficult to
establish and maintain. Currently no animal models of LAM exist.
Primary Pulmonary
Hypertension
A detailed understanding of the function of the BMPR-2
gene has not yet been achieved, and how this gene may cause the structural and
functional changes in the lungs of PPH patients is not clear. Although progress
is being made, no animal models have been developed that completely mimic PPH
in humans. The etiology and pathogenesis of PPH must be understood before
successful therapies can be developed. Current therapies are cumbersome and
expensive and are not effective for all patients. Innovative mechanisms are
needed to accelerate the translation of new findings into better treatments for
PPH. Systemic Lupus
Erythematosus (SLE)
The fear of miscarriage is a great concern for many
pregnant women with SLE. Anticoagulation therapy of high risk pregnant women
with antibodies to phospholipids needs to be evaluated.
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