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STATEMENT OF DR. CLAUDE LENFANT
It is my pleasure to address this committee once again on behalf of the National Heart, Lung, and Blood Institute (NHLBI). I have much good news to report about our quest to reduce the impact of cardiovascular, pulmonary, and blood diseases on the American people. Indeed, this has been a year when we have consolidated many gains and moved ahead in a variety of new directions. Over the years, much attention has been focused upon the use of fundamental scientific approaches to understand the basis for health and disease. In the past, I have reported a number of innovative findings from such disciplines as cell biology, molecular biology, and genetic engineering that, while not always of immediate applicability, held great promise for future healthrelated dividends. Today, I am pleased to highlight the fulfillment of that scientific promise in a number of disease areas.
A recent development in asthma research offers a striking example of how basic understanding has provided a foundation for advances in treatment. NHLBI-supported basic research on the inflammatory mechanisms underlying asthma has implicated a class of chemical substances, the leukotrienes, in the pathobiology of asthma. The leukotrienes appear to trigger asthma attacks by causing airways in the lungs to tighten. Building upon this information, scientists recently experimented with the use of a newly developed inhibitor of leukotriene biosynthesis in experimentally induced asthma. The drugs significantly blunted asthma attacks without producing the side effects that can accompany current asthma therapy. Because this new approach addresses the basic mechanism underlying asthma, it offers much therapeutic potential for the millions suffering from this disorder. As we pursue this line of research, the National Asthma Education Program will continue its efforts to disseminate the most up-to-date information about the diagnosis and management of asthma. For example, the recent release of the Expert Panel Report on Asthma Management is expected to greatly facilitate treatment by primary care physicians.
Molecular biologists have recently reported the identity of a gene responsible for familial hypertrophic cardiomyopathy (FHC), one of the most common causes of sudden death in young athletes. Knowledge of the mutation responsible for FHC paves the way for the development of genetic tests for its
early detection and of animal models to facilitate detailed investigation of
The emerging area of gene therapy provides another example of how fundamental research may lead rapidly to clinical applications. Using techniques of molecular biology, it is now possible to analyze human DNA, to identify, isolate, and purify specific human genes, and to insert genes into the DNA of human cells. NHLBI intramural scientists, in collaboration with scientists from the National Cancer Institute, recently performed the first gene therapy on a patient with adenosine deaminase (ADA) deficiency, a condition characterized by severe lack of immune function. A normal gene for ADA was inserted into the patient's lymphocytes, which were grown in tissue culture and returned to the patient. Since treatment began last September, the patient has done well and the function of the cells of her immune system has improved steadily.
The current success of bone marrow transplantation between two different individuals had its origins in basic immunology research. Discovery of the human leukocyte antigens (HLA), used by the immune system to distinguish self from non-self, provided an answer to the puzzle of graft rejection and a foundation for "matching" marrow donors and recipients. The National Marrow Donor Program, originally initiated to demonstrate the feasibility of unrelated-donor transplants, has evolved into a major national resource with a registry of more than 240,000 potential marrow donors. During the past year, special donor recruitment measures adopted by the Institute increased the representation of racial and ethnic minorities in the registry fivefold. Institute has also undertaken a new research program to determine the degree of HLA matching required for a successful marrow transplant and to develop HLA typing procedures based on molecular biology techniques. The results of this
work will improve the efficiency and decrease the cost of HLA typing, and thereby increase the pool of potential marrow donors.
Although marrow transplantation and gene therapy have evolved separately, they are now coming together to provide a potentially powerful tool for treating, and perhaps curing, many human diseases. The NHLBI has taken the lead in this area by developing a marrow transplantation unit within its clinical hematology branch-a resource that will be shared with other interested components of the NIH. It will be the first research unit in the NIH clinical center devoted exclusively to the study of the fundamental biology and clinical application of marrow transplantation. At the same time, research on marrow transplantation will be closely integrated with an expanded research program directed toward gene therapy of human diseases. alterations of stem cells, the cells of the bone marrow that give rise to all blood cells, may be the key to successful treatment of hereditary blood disorders, such as Cooley's anemia, sickle cell anemia, and hemophilia. researchers have made significant strides in overcoming the many technical obstacles to clinical application of this approach. To appreciate the magnitude of this progress requires an understanding of the problems faced: fewer than one in 1,000 marrow cells is a stem cell; stem cells can incorporate new DNA only when they are dividing; and stem cells divide infrequently. Thus, producing large quantities of genetically altered stem cells has been a formidable task. During the past year, we have developed. techniques to purify (concentrate) stem cells 50-fold and have explored ways to accelerate the process of cell division. Moreover, a clinically useful protocol for inserting genes into stem cells has been developed.
Much evidence suggests that patients with either Cooley's anemia or sickle cell anemia may benefit from increased production of gamma hemoglobin, the normal hemoglobin produced in fetal life. Ongoing research is attempting to uncover ways to turn off the gene that produces the defective beta globin associated with these diseases and switch on the gamma globin production gene. The Institute has initiated a grant program to encourage investigators interested in gene therapy to refocus their efforts on the globin genes, with particular reference to Cooley's anemia. A parallel effort is also under way to develop pharmacologic methods to increase fetal hemoglobin production.
Researchers participating in a small, multicenter study of sickle cell anemia patients recently reported that fetal hemoglobin levels were raised to 15 percent or more through treatment with hydroxyurea, a common chemotherapy drug. If confirmed in larger studies, this approach may represent a significant stride in reducing both the suffering and the high hospitalization costs now incurred by sickle cell disease patients.
The identification and cloning of the defective gene in cystic fibrosis (CF), which normally codes for a protein called cystic fibrosis transmembrane conductance regulator (CFTR), have produced many research opportunities and raised hopes for a cure through gene therapy. NHLBI-supported researchers recently demonstrated that the insertion of the normal CFTR gene into cultured human CF airway epithelial cells corrected the CF defect in vitro. Further, investigators in the NHLBI intramural research program have reported success in inserting the CF gene into the airway epithelial cells of living rats and obtaining measurable indicators of gene expression in lung tissue.
advances have greatly improved the prospects for the possibility of gene therapy to cure the disease. The tools of molecular biology have also
produced two advances that may have applicability to the short-term clinical
management of CF. Administration of aerosolized alpha-1 antitrypsin into the airways of individuals with CF has been shown to counteract the enzymes that cause the tissue destruction associated with CF infections. Related work has demonstrated the effectiveness of DNase, an enzyme that digests DNA, in reducing the thickness of CF mucus. All together, these findings represent significant advances toward better treatment and ultimate cure of CF.
Studies of the natural history of atherosclerosis and hypertension have enhanced our understanding of the development of cardiovascular disease in American Blacks. An examination of autopsy material from young victims of accidental death found that arterial fatty streaks were much more extensive in Blacks than in whites of comparable age. The appearance of these lesions was significantly associated with elevated serum lipid levels and cigarette smoking. The association with smoking is a new observation that could provide powerful impetus for controlling smoking in the young. In other studies, measurements of 24-hour blood pressure patterns revealed that blood pressure is much less likely to drop at night in Blacks than in whites. It is of
considerable interest that this phenomenon seems to be unique to American Blacks and has not been observed in studies of Blacks born in other parts of the world. This so-called blunted nocturnal decline imposes additional cardiovascular strain which may help explain the greater morbid consequences of hypertension experienced by Blacks in the United States.
Women's health issues are being addressed in a number of new and ongoing research programs of the Institute. A pilot study to assess the efficacy of various treatment interventions for asymptomatic myocardial ischemia is of particular relevance to women in light of evidence that women experience unrecognized myocardial infarction more frequently than do men. As part of this study, an assessment of the psychophysiologic characteristics of myocardial ischemia will be conducted. The Institute also has a strong interest in how health-related behaviors become established and can be
modified. This year, NHLBI-supported researchers presented evidence that excess body weight is a strong, independent risk factor for coronary heart disease in women. A recent conference explored reasons for the greater prevalence and more serious consequences of obesity in minority women. Preliminary data from an NHLBI observational study comparing the development of obesity in Black and white preadolescent girls indicate that differences exist between the two races in height, body mass, and eating habits at ages 9-10 years. The Institute also recently sponsored a conference on smoking and body weight, a topic of considerable interest in light of the observation that smoking cessation results in more weight gain for women than for men.
Although the association between elevated cholesterol and heart disease is well established, the implementation of a nationwide strategy to lower cholesterol levels has been controversial. This past year, the NHLBI sponsored three conferences to reexamine the science base for the recommendations of the National Cholesterol Education Program (NCEP). The conferences assessed data concerning the extent to which serum cholesterol levels predict coronary heart disease in older persons and in women, reviewed the evidence for associations between low serum cholesterol levels and certain
specific causes of morbidity and mortality, and addressed the costs and health implications of cholesterol lowering. The conclusions reaffirmed the Institute's current approach to cholesterol lowering, and recommended