NATIONAL HEART,
LUNG, AND BLOOD ADVISORY COUNCIL
MEETING MINUTES
OCTOBER 18 &
19, 2001
I. CALL TO ORDER
AND OPENING REMARKS – Dr. Claude Lenfant
Dr. Claude Lenfant opened the meeting and welcomed the
Council members to the 204th meeting of the National Heart, Lung, and Blood
Advisory Council (NHLBAC).
Member Updates
Dr. Alcalay, Dr. Austin, Dr. Lipscomb, Dr. Ramirez,
Dr. Roberts, Dr. Rosenberg, and Ms. Polite were not present for the
meeting.
Guests
Dr. Lenfant welcomed a number of guests including
representatives from the Institute's Federal Advisory committees. They
included: Dr. Cynthia Rand, who is on the faculty of the Division of Pulmonary
Disease and Critical Care Medicine of the Johns Hopkins University, is a member
of the Clinical Trials Review Committee; Dr. Paul Swerdlow, who is the Director
of the Red Cell Disorders Program at the Wayne State University School of
Medicine is the Chair of the Sickle Cell Disease Advisory Committee. Also
introduced were Dr. Richard
Childs, a member of the NHLBI intramural research program; and Dr. Elizabeth
Nabel, the Director of the NHLBI intramural Clinical Research Programs.
Personnel Announcements
Dr. Lenfant announced a number of new
appointments. Dr. Alving has been appointed the Deputy Director of the
Institute and Dr. Chuck Peterson was appointed as Acting Director of the
Division of Blood Diseases and Resources until a new Division Director is
selected. Dr. Peter Savage had been appointed Director of the Division of
Epidemiology and Clinical Application.
Dr. Deborah Beebe had been appointed the Director of
the Division of Extramural Affairs as of November 1. Dr. Lenfant expressed his
appreciation for what Mr. Ed Donohue had done as Acting DEA Director.
New Publications
Dr. Lenfant called the Council’s attention to the
various publications in the briefing book. These included legislative
updates, a report from the Senate and the House on the appropriation for
FY2002, a copy of the report on the Specialized Centers of Research to be
presented to the Council, material concerning the Skill Development Core, a
copy of the minutes for the September Board of Extramural Advisors meeting, the
final report of the Task Force on Research in Prevention of Cardiovascular
Disease, and information on the Loan Repayment Program which is available on
the web.
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II.
REVIEW OF CONFIDENTIALITY & CONFLICT OF INTEREST – Dr.Claude
Lenfant
The Council was reminded that according to Public Law
92-463, the Federal Advisory Committee Act, the meeting of the NHLBAC would be
open to the public except during consideration of grant applications. A
notice of this meeting was published in the Federal Register indicating
that it would start at 8:30 a.m. and remain open until approximately 2:00 p.m.
Dr. Lenfant also reminded the Council members that they are Special Government
Employees and are subject to departmental conduct regulations.
III.
REPORT OF THE DIRECTOR
The NHLBI budget for FY2001 showed the Actual-Estimate
to be $2.3 billion. The President’s budget for NHLBI in FY2002 is
$2.567 billion. The House allowance for the Institute is $2.548
billion. The proposed appropriation by the Senate Subcomittee is $2.619
billion. If accepted by the full Senate, it would be necessary to have a
conference to resolve the difference between the House and Senate
figures. At the time of the meeting, a continuing resolution was in
effect until the end of October.
The bulk of the budget is for research project grants.
The FY2002 President’s budget was identical to the House allowance for all
mechanisms except research contracts. Dr. Lenfant pointed out that the
research contracts would increase from $220 million to $259 million for FY2002
(President’s budget) due to a provision for the Loan Repayment
Program. This figure was $20 million lower in the House allowance because
a component for an evaluation step was removed. Last year, NHLBI awarded 1,023
competing grants. The projection for FY2002 is 911 competing
grants. This was due to the large increase in the projected noncompeting
grants.
Applicants for a Skills Development Core would be
eligible for an additional $100,000 in direct costs per year. The Core would be
directed by a Core Leader with strong educational and mentoring
credentials. The Core would be designed to develop the research
capabilities of new investigators (medical students, graduate students, and
post-graduate research fellows) through various activities. Salary
support for these individuals would be requested in the specific research
project. A Skills Development Core would be optional and a program
without such a Core would not be penalized. Applications containing a
Skills Development Core will be evaluated on the effectiveness of the programs
in developing the skills and research capabilities of new investigators.
Programs eligible for the inclusion of Skills Development Cores should include
Specialized Centers of Research, Clinical Research Networks, Multicenter
Clinical Studies, and Special Large Solicited programs. The NHLBI will
publicly announce the availability of Skills Development Cores in large
programs through the NHLBI public website and publications.
Dr. Lenfant commented that it is a widely recognized
that young investigators who are part of a larger grant program learn about
research techniques and experimental protocols but not enough about other
considerations such as ethical issues, human subject protection, and grant
writing. Therefore, the intent of the Skill Development Core is to provide a
strong mentoring structure which covers all these considerations.
IV. SKILLS
DEVELOPMENT CORE IN LARGE PROGRAMS
Dr. John Fakunding gave a presentation on a Skills
Development Core for large NHLBI Programs as a followup to previous discussion
by the Advisory Council. The Skills Development Core for large grant
programs was recommended by a Workshop on training held by the NHLBI in
November 1999. Skills development in large programs would take advantage
of the unique multidisciplinary nature of these grant programs in providing new
investigative skills.
Applicants for a Skills Development Core would be
eligible for an additional $100,000 in direct costs per year. The Core would be
directed by a Core Leader with strong educational and mentoring
credentials. The Core would be designed to develop the research
capabilities of new investigators (medical students, graduate students, and
post-graduate research fellows) through various activities. Salary
support for these individuals would be requested in the specific research
project. A Skills Development Core would be optional and a program
without such a Core would not be penalized. Applications containing a
Skills Development Core will be evaluated on the effectiveness of the programs
in developing the skills and research capabilities of new investigators.
Programs eligible for the inclusion of Skills Development Cores should include
Specialized Centers of Research, Clinical Research Networks, Multicenter
Clinical Studies, and Special Large Solicited programs. The NHLBI will
publicly announce the availability of Skills Development Cores in large
programs through the NHLBI public website and publications.
Dr. Lenfant commented that it is a widely recognized
that young investigators who are part of a larger grant program learn about
research techniques and experimental protocols but not enough about other
considerations such as ethical issues, human subject protection, and grant
writing. Therefore, the intent of the Skill Development Core is to provide a
strong mentoring structure which covers all these considerations.
Council discussion was very favorable with most of the
discussion centered on the need for skills development and notification to the
extramural research community of the proposed program. Dr. Fakunding commented
that the measurement of the success of the program will be similar to that of
current training programs. The Institute is currently working on the
evaluation criteria for new applicants.
V.
COMMITTEE REPORT ON THE SPECIALIZED CENTERS OF RESEARCH (SCOR)
Dr. Gail D. Pearson, Division of Heart and Vascular
Diseases, gave a report from the Committee to Redefine the Specialized Centers
of Research (SCOR). She summarized the 30-year history of the SCOR program in
the Institute and noted that recent reviews of SCOR programs by panels of
extramural scientific experts had noted excellent scientific productivity but
little emphasis on clinical research. The Committee determined that the
SCOR program should continue because of its potential in facilitating
bench-to-bedside research and its ability to complement Program Project Grants
and Institute Clinical Research Networks. However, the committee
recommended that several changes be made and also recommended a new title to
reflect these changes: Specialized Centers of Clinically Oriented Research (
SCCOR).
The committee recommended that SCCORs should focus on
a clinically relevant theme which tests hypotheses related to the public health
mission of the NHLBI. The clinical and basic projects should be
well-integrated and at least 50% of the projects in a SCCOR should be
clinical. Clinical research would be defined as research on human
subjects with whom the principal investigator has direct contact.
Appropriate monitoring would be put in place for all of the clinical
projects. In addition to the standard cores there may also be the
possibility of a collaborative clinical core across all SCCOR centers in a
particular SCCOR program as well as a collaborative clinical project that
involves more than one SCCOR center. A Skills Development Core also may
be incorporated into SCCOR programs. Dr. Pearson noted that the budget
ceiling may need to be increased significantly (greater than $2 million in
direct costs per year) to accommodate the increased costs of clinical research.
Dr. Lenfant noted that the total funds available to the Institute for the
current SCOR programs is a relatively fixed line item in the Institute
budget. Therefore, if the budget cap is raised significantly, it is
likely that fewer SCCORs would be funded.
Council discussion was very favorable. Most of
the discussion centered on review issues and notification to the extramural
research community of the proposed changes. Dr. Pearson indicated that an
increased proportion of reviewers on the Special Emphasis Panels (SEPs) that
review the SCCORs will have clinical research expertise in order to review the
increased number of clinical projects. The Institute plans to notify the
research community through a variety of mechanisms including a "Dear Colleague"
letter from Dr. Lenfant as well as possible journal articles and the
establishment of a web site on the NHLBI public site.
VI. REPORT OF THE PREVENTION OF CARDIOVASCULAR DISEASE TASK
FORCE
The Task Force on Research in Prevention of
Cardiovascular Disease (CVD) cochairs, Dr. Gregory Burke of the Wake Forest
University School of Medicine and Dr. Lori Mosca of New York Presbyterian
Hospital, described the task force recommendations for the NHLBI's prevention
research portfolio. The objectives of the Task Force were to develop a
research agenda and an action plan for NHLBI and for the NHLBI Advisory
Council. Topics on which the NHLBI could focus to strengthen its research
agenda include: integrating primary and secondary prevention activities and
clinical practice; reducing the obesity epidemic; preventing disease in early
life; removing barriers to optimal CVD prevention across age, gender, and
ethnic groups; applying subclinical or other markers of CVD risk to enhance
clinical interventions; identifying groups by genotype to optimize prevention
efforts; incorporating psychosocial factors into ongoing intervention trials;
and developing CVD prevention strategies for elderly persons. Other areas
of emphasis included obtaining DNA samples for both obervational studies as
well as prevention studies to learn more about the impact of gene-environment
interaction, investigating the origins of the psychosocial factors and
gene-environment interactions in youth, the impact of dietary factors on CVD
risk, prevention of CVD with hormone replacement therapy, and community-wide
determinants of health behaviors. Council commended the report and the
work of the Task Force. It was emphasized that the first priority was
health systems’ models to change physician behavior and incorporate
prevention strategies that work effectively.
VII. SCIENTIFIC PRESENTATION ON PERIPHERAL STEM CELL
TRANSPLANTATION
Dr. Richard Childs gave a presentation on peripheral
stem cell transplantation. Over the past three decades allogeneic bone marrow
transplantation has become an established and successful therapy to treat and
cure patients with otherwise fatal hematological malignancies. The
observation that even the most intense of conditioning regimens often does not
completely eradicate leukemic clones, as well as the demonstration that
patients with relapsed Chronic Myelogenous Leukemia post-transplant could be
induced back into remission following the infusion of donor lymphocytes, lend
credence to the concept that graft-vs-leukemia (GVL) or graft-vs-tumor (GVT)
effects occur following such procedures. Experimental transplants in
animals and in vitro studies in man have identified the GVL effect to be
mediated by donor T- cells and NK cells. Although many GVL antigens have now
been characterized, it is not yet known which, if any, represent the driving
force of the GVL response.
In the light of the high transplant-related mortality
following conventional myeloablative allogeneic marrow transplantation
(25%-35%), investigators have been understandably disinclined to test for
therapeutic GVT effects in non-hematological malignancies. However, data
from experimental animal models provide strong evidence that allogeneic
anti-tumor effects can be induced against some metastatic solid tumors.
Following the realization of the existence and
powerful nature of the GVT effect, the hypothesis was recently tested that low
intensity or nonmyeloablative allogeneic transplants (NST) could be effective
in eliminating malignancy entirely through this donor immune mediated
anti-tumor effect, without dose intensive conditioning. Low intensity
transplant NST has recently emerged as a safer treatment alternative over
conventional myeloablative regimens in patients with both malignant and
non-malignant hematological disorders. Molecular remissions achieved in
some patients following low intensity transplants provide definitive proof that
graft-vs-leukemia alone may be sufficient to cure some hematological
malignancies. The improved safety profile of such procedures now provides
the opportunity for the exploration of similar GVT effects following NST in
patients with advanced and incurable solid tumors.
Although most NST trials in humans with metastatic,
treatment-refractory solid tumors are just beginning, convincing evidence for
the existence of a GVT effect in metastatic renal cell carcinoma following NST
has recently been established. Disease regression in renal cell carcinoma
(RCC) patients following NST has been typically delayed in onset (median 5
months: range 1-9), followed the withdrawal of CSA and conversion to complete
donor T-cell chimerism, associated with Graft Versus Host Disease (GVHD) and
has been durable and complete in some patients. The first patient
transplanted with metastatic RCC remains in complete remission 44 months
post-transplant. Knowledge about the exact mechanisms contributing to
disease regression in patients with RCC following this approach is currently
incomplete. Preliminary laboratory data suggest that donor T-cell
populations, distinct from those mediating GVHD and possibly tumor-specific,
may be involved in this GVT effect. The characterization of the exact
tumor antigens being targeted by these T-cell populations could lead to future
targeted allogeneic immunotherapy approaches.
The regression of metastatic RCC observed following
low intensity allogeneic stem cell transplantation suggests that allogeneic
immune based therapy may be as or more potent than strategies designed to
enhance autologous anti-tumor immunity. Whether similar clinically
meaningful GVT effects can be induced against other incurable metastatic solid
tumors remains unanswered and continues to be explored.
Council received the presentation
enthusiastically.
VIII. INITIATIVES FOR
FISCAL YEAR 2002/2003
Dr. James Kiley, Director of Division of the Lung
Diseases, introduced the findings of the Board of Extramural Advisors (BEA) who
reviewed the following initiatives at their last meeting.
1. Ancillary Pharmacogenetics Studies in Heart,
Lung, Blood, and Sleep Disorders Trials
Dr. Stephen Mockrin, Director of the Division of Heart
and Vascular Diseases, presented this initiative. The goal of this
initiative is to encourage ancillary pharmacogenetic studies in ongoing
clinical trials related to heart, lung, blood, and sleep disorders.
Pharmacogenetics has the potential to change how
health care is provided. It is moving from treatment with a drug based on
an average response of the total population to a more optimal therapy that is
developed or targeted to an individuals' unique genetic architecture and
constellation of environmental factors. The initiative is not designed to
start new clinical trials. It is designed to build upon the existing
infrastructure of ongoing clinical trials. Council was decidedly more
enthusiastic about this initiative than the BEA.
2. Basic Research on Mesenchymal Stem Cell
Biology
Dr. Barbara Alving, Deputy Director of the National
Heart, Lung, and Blood Institute, presented the next initiative which would
support basic research on mesenchymal stem cell biology in order to provide the
scientific basis for new clinical applications for stem cell
transplantation. Preclinical studies suggest that mesenchymal stem cells
facilitate hematopoietic stem cell engraftment while decreasing immune
rejection of allografts. Studies on tolerance induction by mesenchymal
stem cells could include potential application to both stem cell and solid
organ transplants.
This initiative as well as the initiative on
"Cell-Based Therapies for Heart, Lung, Blood and Sleep Disorders and Diseases"
are the first two to be proposed as part of the NHLBI Strategic Plan for
Cellular Therapies which is currently being developed. Council was very
supportive of this initiative.
3. Cell-Based Therapies for Heart, Lung,
Blood, and Sleep Disorders and Diseases
Dr. Alving presented this initiative which would
support basic research on stem cell biology and the use of stem cells in
cellular therapies for the treatment of cardiovascular, lung, blood, and sleep
disorders. It is intended to integrate and focus NHLBI efforts in order
to support and accelerate translational research leading to the use of cellular
therapies for regenerative medicine. One suggestion was to write the RFA
broadly to include other tissue sources besides embryonic stem (ES) cells and
adult stem cells.
A key area of this initiative, which was not addressed
by a previous RFA on Stem Cell Plasticity in Hematopoietic and
Non-Hematopoietic Tissue, is the embryonic stem (ES) cell. This
initiative should invite applications that compare human ES cells and adult
stem cells to define the limits and potential of both types of stem
cells. Other Institutes would also be invited to participate in this
initiative. A multi-institute approach would encourage the use of
different tissue sources and take full advantage of stem cell plasticity to
determine the best approaches to heart, lung, and blood regeneration.
Council was also very enthusiastic about this initiative and considered it to
be very important and timely.
4. Centers of Excellence in Biomedical
Science Education in Heart, Lung, Blood and Sleep Disorders for
Underrepresented Minorities (R25)
Dr. Barbara Alving also presented this
initiative. Past efforts to recruit and retain underrepresented
minorities into scientific research careers have not succeeded in increasing
substantially the numbers of minorities in these fields. In an attempt to
review successful and unsuccessful initiatives and to formulate an action plan
based on effective programs, the NHLBI held a workshop in May, 2001 on the
recruitment and retention of African Americans, Hispanic Americans and Native
Americans into scientific research careers, which is summarized in a report,
"Workshop on Recruitment and Retention of African Americans, Hispanic
Americans, and Native Americans in Scientific Research Careers Relevant to
Heart, Lung, Blood, and Sleep Disorders: What Works, What Doesn’t and What
Should We Do?" One of the most widely discussed suggestions among
workshop participants was the idea of NHLBI-funded investigators becoming
involved in biomedical science education in grades K-12. The consensus of
participants was that this would serve a critical need to expose children early
in their school years to science, and to provide them with the experiences,
skills and knowledge to pursue science education in college and beyond.
The goal of this initiative is to encourage collaboration among research
universities, minority colleges, local school districts, K-12 students and
their families, to develop, provide and evaluate state-of-the-art biomedical
science education for K-12 students who are underrepresented minorities.
Council was very supportive of this initiative.
5. Clinical Course of Hemoglobinopathy
Patients after BMT
Dr. Charles Peterson, Acting Director of the Division
of Blood Diseases and Resources, presented this initiative. The objective of
this proposed initiative is to track the number and clinical course of
hematopoietic stem cell transplants performed for hemoglobinopathy
patients. This initiative would allow the collection of data by
supporting patient-related costs for assessment of brain function (magnetic
resonance imaging of brain and neuropsychometric testing) and liver and spleen
function (liver and spleen scan). Support would be provided to a
statistical support center for coordination of data collection and statistical
analyses. In addition, modest support would be supplied to each
participating clinical site for principal investigator travel to one Steering
Committee meeting per year. Council was only moderately enthusiastic
about this initiative.
6. Community-Responsive Interventions for
Heart, Lung, and Blood Diseases in American Indians and Alaskan Natives
Dr. Peter Savage, Director of the Division of
Epidemiology and Clinical Applications, presented this initiative. The purpose
of this initiative is to plan and implement intervention studies that address
important heart, lung, blood, or sleep disorders and/or risk factors control in
American Indian/Alaska Native (AI/AN) communities, that are responsive to the
perceived needs of these communities, and that have the potential for reducing
health disparities in AI/AN. A two-phase effort is proposed including a
three-year feasibility study followed by a four-year randomized clinical trial
focused on a health need perceived by the community to be of public health
importance. Council was supportive of this initiative which is very relevent to
the mission of the NHLBI.
7. Genetics in Medicine Academic Awards
Dr. Savage also presented this initiative. The
purpose of this initiative is to enhance the clinical application of genetics
and genomics to the prevention or reduction of morbidity from heart, lung,
blood and sleep (HLBS) disorders by promoting development of continuing
education programs, medical curricula, and interdepartmental programs in the
application of genomics to clinical medicine. While Council considered
this area important, it recommended that the initiative be redesigned.
8. Histopathological Characterization of the
Lung in Early Chronic Obstructive Pulmonary Disease COPD) Lung Cellular and
Molecular Changes in Early COPD
Dr. Gail Weinmann, Program Director in the Division of
Lung Diseases, presented two initiatives which are linked. One initiative
is a step in a strategic plan for COPD research that was developed through a
working group meeting in March 2001. Histopathological comparisons of
lung tissues from smokers with and without COPD, using advanced molecular
technologies, were considered to be critical for evaluations of new concepts of
COPD pathogenesis and for investigations of factors responsible for disease
susceptibility and heterogeneity. This initiative will establish a consortium
of researchers to compare the clinical status of subjects to molecular
characteristics of their resected lung tissues and to establish a tissue/data
repository for further molecular histopathological analyses.
The other initiative is a Request for Information
(RFI) related to lung cell and molecular changes in early COPD and will solicit
scientific input that is needed to develop the histopathological
characterization of the lung in early COPD. Council was enthusiastic
about these two initiatives on COPD which has been hampered by a lack of
understanding about the basic biology.
9. Molecular Mechanisms of Mucous Cell
Metaplasia and Excess Mucin Secretion
Dr. Weinmann presented this initiative. The
purpose of this initiative is to elucidate the molecular and cellular
mechanisms of mucous cell metaplasia and the pathways involved in the excess
mucin secretion of airway diseases. Mucous cell metaplasia with mucin
hypersecretion is a dominant manifestation of many common diseases of the upper
and lower airways, including chronic bronchitis, asthma, and sinusitis.
Chronic bronchitis and asthma alone are responsible for one million
hospitalizations in the U.S. per year. The development of therapies for
mucin hypersecretion is particularly challenging because little is known
regarding the specific molecular pathways involved in the regulation of mucin
secretion in airway diseases, particularly COPD. Council was enthusiastic about
this initiative which focuses on a very important area.
10. Immune Reconstitution following
HLA-mismatched Stem Cell Transplantation
Dr. Liana Harvath, Program Director, in the Division
of Blood Diseases and Resources, presented this initiative. The intent of this
initiative is to encourage research on redevelopment of the immune system in
recipients of HLA-mismatched hematopoietic stem cell transplants.
Although the clinical data regarding engraftment and Graft versus Host Disease
(GVHD) are steadily increasing, basic studies are needed to characterize the
transplanted cell populations and the course of immune reconstitution in these
patients. Council was supportive of this initiative which deals with a
central issue in hematopoietic stem cell transplantation.
11. Immunobiology of Transfusion
Medicine
Dr. Harvath also presented this initiative. The
objective of this initiative is to encourage investigations to elucidate the
mechanisms involved in immune responses affected by transfused cellular blood
components or plasma derivatives. Council supported this initiative which
deals with the important problem of alloimmunization.
12. Inflammation in Thromboembolic
Disorders
Dr. Harvath presented this initiative. The goal
of this initiative is to support studies on the interplay between inflammation
and thrombosis, and encourage translation of this knowledge to the management
of thromboembolic disorders utilizing a combination of anticoagulant and
anti-inflammatory agents. Recent data indicate that inflammation is
linked to blood coagulation and is not a late event dependent on excessive
generation of protease activity. The product of one pathway can
significantly regulate the other. For example, overexpression of
P-selectin leads to a hypercoagulable state. Conversely, P-selectin
knockout mice tend to bleed. Thus, P-selectin is no longer a marker of platelet
activation and inflammation, but also is a direct regulator of coagulant
activity related to vascular and thrombotic diseases. The management of
patients with thromboembolic disorders is mainly based on anticoagulant therapy
with warfarin, which has many drawbacks. These observations offer the
opportunity to develop a better approach to the management of these patients
with a combination of anticoagulant and antiinflammatory drugs. Council
was supportive of this initiative.
13. Innovative Therapy Development for Rare
Diseases
Dr. Alving presented this initiative. This
initiative proposes limited support, not to exceed $100,000 in direct costs per
grant per year for up to two years, for research that would test innovative
ideas and explore novel approaches to rare heart, lung, blood, and sleep
disorders. Meritorious studies would be supported that are designed to
provide preliminary results that demonstrate the feasibility of new therapeutic
approaches to rare diseases. Council was very enthusiastic about this
initiative and was in favor of expedited review of such grants.
14. Iron Replacement in Women Blood Donors -
Increasing Blood Donor Availability
Dr. Harvath presented this initiative. The
objective of this initiative is to determine the operational feasibility, at a
blood center level, of implementing a program of carbonyl iron replacement for
women blood donors of child-bearing age. The overall goal of iron
replacement in these women is to prevent iron deficiency, their most common
medical cause of deferral from donation, and to enhance their retention and
commitment as blood donors. Council was not enthusiastic about this
initiative.
15. Mechanisms of Fetal Hemoglobin Gene
Silencing for Treatment of Sickle Cell Disease and Cooley’s Anemia
Dr. Peterson presented this initiative. This is
the 4th of 11 initiatives in the Strategic Plan for a Gene-Based Cure for
Beta-Chain Hemoglobinopathies that was submitted to the Institute by extramural
investigators in December 1999. The justification for this effort is
two-fold: first, to rebuild and stimulate a field that has decreased in size by
about 5-fold in the last 20 years; and second, to encourage a systematic,
thorough approach toward the development of gene-based cures for these serious
and chronic diseases. The goal of this initiative is to stimulate
research regarding the delineation of mechanisms involved in fetal hemoglobin
(gamma-globin) gene silencing during normal human development and to develop
therapeutic approaches for inhibition of silencing. Increased understanding of
the molecular basis of fetal hemoglobin silencing will facilitate the
development of new methods to inhibit silencing, in order to increase fetal
hemoglobin in red blood cells, and thus to cure beta-chain
hemoglobinopathies. This initiative will include research to: 1) identify
the cis elements of the gamma-globin gene that are involved in gamma gene
silencing, 2) delineate the transcriptional factors and other proteins that
participate in the formation of the gamma gene silencing complex, and 3) in
later stages, once an aspect of the mechanism of silencing has been revealed,
develop rational, structure-based pharmacologic approaches that will result in
inhibition of silencing. DBDR currently supports only 3 grants whose
scope in part overlaps with this initiative. Council was very supportive
of this initiative because of the need for new therapeutic approaches in this
area.
16. Optimization of Fetal Hemoglobin Gene
Therapy Cassettes for Treatment of Sickle Cell Disease and Cooley’s
Anemia
Dr. Peterson presented this initiative. This is
the 5th of 11 initiatives in the Strategic Plan for a Gene-Based Cure for
Beta-Chain Hemoglobinopathies. The goal of this initiative is to expedite
research to optimize hemoglobin gene transfer cassettes for therapeutic use in
viral gene transfer vectors to cure beta-chain hemoglobinopathies such as
sickle cell disease (SCD) and Cooley’s anemia (CA). While the
phenotypes of mouse models of CA can now be significantly moderated with
lentiviral globin vectors in a hematopoietic transplant setting, further
optimization of gene expression per cell is necessary before human trials can
begin. In addition, the cure of SCD will likely require even higher
levels of expression than for CA. Optimization of the delivery of
functional fetal hemoglobin genes in model systems will facilitate the
development of new gene-based therapeutic approaches to cure human beta-chain
hemoglobinopathies. The field of globin gene therapy has recently
experienced a significant boost in enthusiasm with the report last summer in
Nature of the partial cure of a mouse model of CA using lentiviral
vector-mediated globin gene therapy. This initiative will support grants
to optimize the design of retroviral and lentiviral fetal hemoglobin gene
transfer vectors. The following specific objectives will be addressed: 1)
identify the minimal DNA sequences from the beta-globin locus control region
(LCR), gamma-globin promoter region, and other regions that, acting alone or in
combination, can guarantee maximal fetal hemoglobin expression; 2) develop
expression cassettes that contain these minimal DNA sequences and display
maximal expression when in the context of lentiviral or retroviral vectors; and
3) validate these vectors in cell lines, animal models, and primary human
cells. Council was similarly very supportive of this initiative because
of the need for new therapeutic approaches in this area.
17. Molecular Target and Drug Discovery For
Idiopathic Pulmonary Fibrosis (IPF)
Dr. Dorothy Gail, Program Director, Division of Lung
Diseases, presented this initiative. The objective of this initiative is
to establish a program that would stimulate a broad research effort to develop
new therapeutic approaches for IPF. Investigators will be encouraged to
employ strategies based on targeting molecules known to be important in the
pathogenesis of IPF, as well as identify new molecular targets for treatment
and agonists or antagonists that interact with them. This initiative was
enthusiastically supported by Council since there are no effective therapies
for IPF.
18. Partnership Programs of Excellence in
Minority Cardiovascular Health Research
Dr. Mockrin presented this initiative which is a joint
one with DECA. The program is intended to promote and expedite improved
cardiovascular disease outcomes in minority populations. This will be
accomplished through a partnership between a research intensive medical center
(RIMC) with a track record of NIH-supported research and a minority health care
serving system (MSS) capable of measuring improvements in cardiovascular
disease (CVD) outcomes. Participants will collaborate to: 1) promote
interdisciplinary investigations of complex biological and social factors that
contribute to CVD health disparities, 2) facilitate research within the MSS to
improve minority CVD outcomes, and 3) provide training and career development
of investigators focused on minority CVD. Council was very supportive of
this initiative which addresses an extremely important issue of health
disparities.
19. Pathophysiologic Mechanisms of
Obesity-Associated Cardiovascular Disease
Dr. Mockrin presented this initiative. The
objective of this initiative is to stimulate new, mechanistic research
approaches to clarify the biologic bases of various obesity-related
cardiovascular diseases. Council was uniformly enthusiastic about this
initiative which is in an area of tremendous importance to public health.
20. Standard Test Materials for Transmissible
Spongiform Encephalopathies (TSEs)
Dr. Harvath presented this initiative. The
purpose of this initiative is to support the establishment of a central
laboratory/repository for the preparation of standardized reference materials
to facilitate the development of methods for screening and diagnosis and for
better understanding of TSE diseases, as well as for validation of the
sensitivity, specificity, reproducibility and predictive value of candidate
diagnostic and screening assays. Council supported this initiative which
complements an RFA currently supporting three laboratories.
21. Spironolactone Therapy for the Treatment
of Heart Failure with Preserved Systolic Function
Dr. Jeffrey Cutler, Program Director in the Division
of Epidemiology and Clinical Applications, presented this initiative. The
objective of this initiative is to evaluate the effectiveness of spironolactone
therapy in reducing all cause mortality and rehospitalization for heart failure
in patients with preserved systolic function. There have been no heart
failure trials evaluating clinical treatment for this form of heart
failure. All other clinical trials have been limited to pateints with
reduced systolic function or in heart failure patients without evaluation of
systolic function. The trial proposes a treatment targeting the
renin-angiotensin-aldosterone access, an important part of the compensatory
response to reduce cardiac outbreak. Spironolactone is a potassium
sparing diuretic that acts on the site of aldosterone action, the distal
tubule. Council was enthusiastic about this trial since there is no
effective way of treating this form of congestive heart failure.
22. The Role and Mechanisms of Stress in
Asthma
Dr. Weinmann presented this initiative. The
purpose of this initiative is to stimulate research to examine the role and
mechanisms of stress in the onset and exacerbation of asthma. Research
that explores the contribution of stress to the disproportionate severity of
asthma among minority populations and persons living in poverty will also be
encouraged. Council was not supportive of this initiative due to the
complexity and multi-dimensional nature of stress in this context.
23. Worksite Intervention Trials for
Overweight and Obesity Prevention and Control
Dr. Cutler also presented this initiative. The
goal of this initiative is to support controlled trials to collect data on
feasibility and preliminary evidence on the effectiveness of worksite
interventions that include environmental strategies for preventing or treating
overweight and obesity in adults. Council was not supportive of this
initiative due to the complexity of the issue.
24. Health Disparities and Culteral
Competency Academic Awards
Dr. Kiley presented this initiative which was brought
back to Council at their request. This initiative would establish
programs to help health care providers understand the factors underlining the
health disparities and provide them the cultural sensitivity and competence to
address these disparities. The program would provide support to medical
school faculties to produce relevant curriculum materials and other
resources. The program would also ensure that resources developed in
Phase I are evaluated and disseminated to the practicing physicians through
workshops, training sessions or other means. Council enthusiastically
endorsed this revised initiative.
IX. Lung Specialized
Centers of Research
Dr. Kiley presented the SCOR in Neurobiology of Sleep
and Sleep Apnea, Airway Biology, and Pathogenesis of Cystic Fibrosis (CF) and
Functional Genomics in Acute Lung Injury. This is a renewal of a cluster
of lung SCOR programs. The goal is to foster multi-disciplinary basic and
clinical research so that advances in the basic sciences, are rapidly
translated to clinical needs. The justification for these programs is based on
recommendation from the SCOR evaluation panel in CF and sleep and SCOR
coordination meetings that have been held over the past several years.
The recommendations for the Acute Lung Injury SCOR have emerged from an
evaluation group that was held in 2000. Council strongly endorsed this
initiatve.
X. Other
Initiatives
Dr. Fakunding presented the Research Scientist Award
for Minority Institutions. The objective is to increase the research
capacity at the minority institutions and ultimately to reduce health
disparities and increase the number of minority investigators. Council
was uniformly in favor of this initiative.
CLOSED PORTION
This portion of the meeting was closed to the public
in accordance with the determination that it was concerned with matters exempt
from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5,
U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended
(5 U.S.C. appendix 2).
There was a discussion of procedures and policies
regarding voting and confidentiality of application materials, committee
discussions and recommendations. Members absented themselves from the
meeting during discussion of and voting on applications from their own
institutions, or other applications in which there was a potential conflict of
interest, real or apparent. Members were asked to sign a statement to
this effect.
XI.
REVIEW OF APPLICATIONS
The Council considered 1069 applications requesting
$1,096,573,599 in total direct costs. The Council recommended 720
applications with total direct costs of $826,949,077. A summary of
applications by activity code may be found in Attachment B.
ADJOURNMENT
The meeting was adjourned at 10:30 a.m. on October 19,
2001.
CERTIFICATION
I hereby certify that the foregoing minutes are
accurate and complete.
Claude Lenfant, M.D.
Chariperson
National Heart, Lung, and Blood Advisory
Council
on 01/10/02
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