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NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

STATEMENT OF DR. CLAUDE LENFANT, DIRECTOR

BUDGET REQUEST Senator HARKIN. Dr. Lenfant, we have your budget request of $1.2 billion with $54.5 million of that increase delayed for obligation until September 19. Your request is an increase of about 6 percent. Most of your Institute's increase is proposed for research project grants with funding for centers and training held relatively flat. My compliments to you, as well as Dr. Broder, for the successful gene therapy experiment that was conducted last fall, and any other insights on that that you might have I would be pleased to know. Please proceed with your statement.

GENE THERAPY

Dr. LENFANT. Thank you, Mr. Chairman. I am very pleased to have the opportunity to report about some of our programs.

Indeed, taking the example of gene therapy, I wanted to spend some time on the case which has been described to you by Dr. Broder. So, I will not repeat what he has said except that I would like to underscore that, indeed, we have cause for optimism with regard to the particular patient he mentioned. The reason for it is that a few weeks ago this little girl and her family all developed a respiratory infection. The little girl came out from this respiratory infection with flying colors, if I can say that, and hadn't she been treated before, probably the evolution would have been quite different. So, that really gives us a good cause for being optimistic about the effectiveness of the gene transplant she received.

Now, I would like to take two other examples where gene therapy is giving us some prospects for important clinical advances.

The first one concerns cystic fibrosis. One of our researchers has successfully inserted the cystic fibrosis gene into the airways epithelial cells of living animals. Measurable indicators of gene expression in the lung tissue of these animals have been obtained.

Another example concerns alpha-1-antitrypsin deficiency. And, indeed, in just a few weeks, a report will be published demonstrating the direct insertion and expression of the human gene for alpha-1-antitrypsin in the respiratory epithelium on living animals. Now, the absence of this gene in a human being is a cause of a certain form of chronic obstructive pulmonary disease which affects approximately 30,000 to 40,000 Americans.

So, we view that as some very significant advances which in the future would allow us to hopefully offer a cure for these conditions. But already in our Institute we are investigating the possibility of extending our efforts in gene therapy to other hereditary disorders such as sickle cell disease, Cooley's anemia, hypercholesterolemia, hemophilia, and other cardiovascular conditions. So, these are some examples which I wanted to mention to you because clearly they illustrate the impact of basic research on clinical advances.

PREPARED STATEMENT

Now, as you know, the Institute has numerous prevention and education programs. And I just would like to state in concluding that these programs have a very positive impact, and we are confident that our dissemination strategies to address cardiovascular risk factor reduction, control of sudden heart attack morbidity and mortality, and asthma management and treatment will continue to pay very handsome dividends. And in our view these dividends can be measured both in terms of health care cost reduction, but perhaps more importantly, in terms of better lives for the patients.

Thank you, Mr. Chairman. [The statement follows:]

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 health

related 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

this disorder.

Moreover, understanding the molecular basis of FHC may provide

clues to the treatment of other disorders that cause heart enlargement, such

as hypertension, atherosclerosis, and valvular heart disease.

The NHLBI also

supports population-based studies that are using new echocardiographic

techniques to assess cardiac structure.

The findings will improve our

understanding of why heart enlargement is a major, independent risk factor for

subsequent cardiovascular events.

The emerging area of gene therapy provides another example of how

fundamental research may lead rapidly

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.

The

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.

Genetic

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.

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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

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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.

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