MINUTES OF THE SEVENTY-THIRD MEETING
OF THE
SICKLE CELL DISEASE ADVISORY COMMITTEE
Bethesda, Maryland
November 14, 1997

COMMITTEE MEMBERS PRESENT

Dr. Kenneth Bridges
Dr. Iris Buchanan
Dr. Jessica Davis
Dr. Joseph DeSimone
Dr. James Eckman
Dr. Mary Fabry
Dr. Cage Johnson
Dr. Vipul Mankad
Dr. William Mentzer

COMMITTEE MEMBERS ABSENT

None

EX-OFFICIO MEMBERS PRESENT

Dr. Martin Steinberg

EX-OFFICIO MEMBERS ABSENT

Dr. William Hannon
Dr. Scott Wegner

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:

Dr. Clarice D. Reid, DBDR; Dr. Carol H. Letendre, DBDR; Duane Bonds, SCRG; Dr. Junius
Adams, SCRG; Dr. Helena Mishoe, BDRG; Ms. Sonya I. Ross, Maryland, DHMH, Office of
Hereditary Diseases ; Ms. Patricia Penn, Maryland, DHMH, Office of Hereditary Diseases;
Dr. Yutaka Niihara, UCLA; Ms. Kaye VanderVen, RN, HRSA/MCHB/GSB.                   

Executive Secretary    - Dr. Clarice D. Reid
Secretary                    - Ms. Petronella A. Barrow

I.  INTRODUCTORY REMARKS

 Dr. Cage Johnson, Chairman, called the 73rd meeting of the Sickle Cell Disease Advisory
 Committee to order at 9:00 am.

II.  ANNOUNCEMENTS

Dr. Clarice Reid, Executive Secretary, read the mandatory conflict of interest statement and
reminded members to sign and return their forms to Ms. Barrow.  She noted that Dr. Jane Lin-Fu,
the committee representative from the Health Services and Resources Administration (HRSA), 
has recently retired. The HRSA representative will be Dr. Michele Puryear.  Dr. Jay Adams,
Health Scientist Administrator of the Sickle Cell Disease Scientific Research Group (SCDSRG) is
also retiring at the end of  December.  This is the last meeting for the chairman,  Dr. Cage
Johnson, who is moving from the Sickle Cell Disease Advisory Committee (SCDAC) to join the
National Heart, Lung, and Blood Advisory Council.   Dr. Reid commented on Dr. Johnson's
distinguished leadership to the SCDAC and noted that he will be one of three Blood
representatives on the Council. 

III.  CONSIDERATION OF MINUTES

The minutes of the last meeting were unanimously approved with correction of  Dr. Mankad's
location at the University of Kentucky at Lexington, not Louisville. 

IV.  CHAIRMAN'S REPORT

Dr. Johnson expressed his appreciation for the honor of serving as Chairman of the Sickle Cell
Disease Advisory Committee and his enjoyment during his short tenure in this role.  In his report,
he  stated that the year 1998 marked the 50th anniversary for the National Heart, Lung, and
Blood Institute (NHLBI).  The 25th anniversary meeting of the National Sickle Cell Disease
Program held in Washington D.C. in September kicked off  this 50th anniversary celebration. 
The meeting attracted over 900 participants world-wide and was  considered the best conference
held  to date highlighting progress and advances in sickle cell disease research and services.
During this same week,  Dr. Johnson pointed out that an announcement was made that
transfusion therapy is an effective regimen for the primary prevention of stroke in young children
with sickle cell disease.   He  referenced several  planned workshops and special emphasis
panels (SEPs) for the Division of Blood Diseases and Resources (DBDR).  These included topics
on managed care for hemoglobinopathies, stem cell dosing, thrombophilia, blood donor behavior,
sickle hemoglobin polymerization, risks in transfusion medicine and the genetic basis of variability
in heart, lung and blood diseases.  Dr. Johnson attended the October Council meeting and
envisions a  growing role of the Council in the affairs of the Institute.

V.  DIRECTOR'S REPORT

Dr. Reid,  Director of  the Division of  Blood Diseases and Resources, briefly reviewed with the
committee some of the NIH and NHLBI  activities. Specifically of interest has been priority setting
and decision-making focused on research areas of emphasis that cut across all Institutes. The
list of areas of emphasis was distributed to the committee and  Dr. Reid noted that initiatives are
proposed from each Institute in these areas. The area of  Genetic Medicine is significant for
potential opportunities in  sickle cell disease, particularly as it relates to genetic modifiers of
clinical expression.  The DBDR held a Special Emphasis Panel at the end of September that led
to identifying several research opportunities in hematology and many of the SEPS and
Workshops topics mentioned by Dr. Johnson were a by-product of this activity.  

In discussing the budget, Dr. Reid indicated that the NIH is operating under a continuing
resolution.  At the first NHLBI Council of the year held in October,   grants were funded to a
payline of 17.8 percentile. There is general optimism, however,  that with the pending signing of
the FY 98 appropriation bill by Congress, the funding payline is likely to  improve. 

VI.  SCIENTIFIC PRESENTATIONS

 "Control of Globin Genes and Transacting Factors"- Dr. Joseph DeSimone, Professor of
Medicine, University of Illinois at Chicago College of Medicine.

Dr. DeSimone reviewed the current and emerging concepts of the role of transacting factors in
the switch from adult hemoglobin to fetal hemoglobin.  This topic is of critical importance, and the
Cooperative Study of Sickle Cell Disease (CSSCD) has shown that a major part of the clinical
variability of sickle cell disease is due to the level of Hb F. It further demonstrated that even
modest increases in the level of Hb F result in a decrease in the number of painful episodes. 
The CSSCD also reported  an association between the number of painful crises and early
mortality.  Thus, at present, the most promising approach to the amelioration of the clinical
expression of sickle cell disease and the related -thalassemia syndromes involves the
augmentation of Hb F synthesis.  Since it is the adult -globin chain that is affected in both of
these disorders, its replacement by the gamma globin chain that produces Hb F would be of
obvious clinical benefit.  Furthermore, Hb F inhibits the polymerization of sickle hemoglobin, the
primary basis of the pathophysiology of sickle cell disease. There have been a number of
transacting factors investigated, including GATA 1, GATA II, NFE2 and more recently EKLF.
Initially studies of these  transacting factors, which bind DNA regulatory sequences, were
considered to hold promise in elucidating the molecular mechanisms responsible for the fetal to
adult developmental hemoglobin switch.  However, when these factors are "knocked out" in mice,
there appears to be little effect on developmental globin gene expression.  These studies did
confirm  earlier work demonstrating that the methylation state of the promoter region of the
gamma globin gene of human fetal hemoglobin plays a critical role in the expression of this gene. 
Thus, studies of globin gene methylation, in addition to explaining the impressive reactivation of
Hb F in individuals with sickle cell disease treated with 5 azacytidine (a DNA demethylating
agent), could lead to an effective mechanism for reactivating fetal hemoglobin in individuals with
sickle cell disease.

 "The Effect of Oral L-glutamine Therapy in Sickle Cell Anemia" - Yutaka Niihara, M.D., Assistant
Professor of Medicine, Harbor UCLA Medical Center

An interesting presentation of a potential novel therapy was made by Dr. Yutaka Niihara, who
noted that sickle red blood cells have been shown to have an increase in total nicotinamide
adenine dinucleotide (NAD) content,  by an as yet unknown mechanism. Because glutamine is
an essential precursor in NAD biosynthesis, Dr. Niihara examined the rates of active red blood
cell glutamine transport and glutamine transport kinetics. The rate of active glutamate transport
in sickle RBCs increased threefold over that in high-reticulocyte red blood cell controls and
increased 15-fold over that in normal red blood cells.  Finally, the level of red blood cell glutamate
(a byproduct of glutamine in NAD synthesis) in the sickle group was significantly increased in
comparison with that in the high-reticulocyte control group, whereas the red blood cell glutamine
level was not. The higher glutamate level in sickle cells may reflect a higher glutamine turnover in
these cells. These results may indicate that sickle cells have an increased glutamine availability
and affinity that may facilitate the increase in total NAD in sickle cells.  These initial results
suggested that glutamine might be useful as a therapy for sickle cell disease.  Results from a
limited clinical study of seven individuals with sickle cell disease who were given glutamine
demonstrated fewer pain crises in these individuals and also resulted in the patients appearing to
feel better. Further studies are planned to examine whether this non-toxic amino acid,  glutamine, 
may be useful in the treatment of sickle cell disease.

VII.  COMMITTEE REPORT - Initiatives for Genetic Education

Dr. Jessica Davis reviewed the work of the ELSI subcommittee in which she participated as a
representative of the Council of Regional Networks (CORN), a clinical geneticist and as a
consumer. The final report entitled "Promoting Safe and Effective Genetic Testing in the United
States" has been issued and focuses on predictive genetic tests. There was general concern
about issues of informed consent, confidentiality and discrimination based on genetic test results
and implications for newborn screening. Dr. Davis pointed out the shortcoming of quality control
of  genetic testing  in view of the lack of CLIA regulations and any central genetics laboratory.
There is increased need for genetic education at all levels with a stronger partnership between
professional organization and the genetics community.  A National Coalition for Education and
Genetic Health Care Professionals is a new initiative in that direction and has received the
attention of the AMA . Dr. Davis shared a copy of  the report with the committee and  urged 
members to obtain the report, become familiar with all the ramifications and seek to have a voice
in discussions at all levels.  The report is also on the Internet.

VIII.  AGENCY REPORTS

Health Resources and Services Administration (HRSA)

Ms. VanderVen reported that Dr. Michelle  Puryear, a pediatrician and geneticist, joined the
Genetic Services Branch in September.  Dr. Puryear is very interested in education and will likely
have plans in this area along the lines discussed by Dr. Davis.  With respect to the grant
program, sickle cell disease remains a priority. The last grant cycle focused on comprehensive
care and integration of sickle cell services at the community level.  Eight applications were
received; eight approved and seven were funded with a cap of $100,000 each.  The Branch also
supports nine grants introducing genetics into primary care.  

Department of Veterans Affairs (VA)

Dr. Martin Steinberg reported that there has been an increase in the VA screening, education
and counseling program.  The overall program is decentralized. His laboratory serves as a
reference laboratory and conducts a quality proficiency program. 

Department of Defense (DoD)

No representative present.

Centers for Disease Control and Prevention.

No representative present.

IX.  PROGRAM ACTIVITIES

Dr. Junius Adams, Health Scientist Administrator, noted that the annual RFA grantees meetings
were held during the September Sickle Cell Conference. He reported on  progress in the area of
coagulation using "knock-out techniques " to develop sickle cell mice with  plasminogen and
fibrinogen defects.  Others areas of investigation include lipid alterations in the red cell to obtain
a procoagulant surface; the role of tissue factor procoagulant; and association of elevated HbF
levels in infants with protection of platelet activation.   In gene therapy, investigators continue to
focus on improving vectors. One group has applied a novel approach to gene therapy using
ribosomes,  based on decreasing hemoglobin synthesis either before or simultaneously with
introduction of anti-sickle hemoglobin. 

Dr. Duane Bonds, Leader of the Sickle Cell Research Group, summarized a number of clinical
research meetings, including the Cooperative Study of Sickle Cell Disease and the follow up 
of the Multi center Study of Hydroxyurea (MSH).   Data from the MSH  will be presented to the
Oncology Drug  Advisory Committee of the FDA in December to consider the approval of
hydroxyurea for adults with sickle cell disease.  It is important for obtaining third party insurance
coverage for this therapy that sickle cell be listed as an indication for use.   

The pediatric hydroxyurea safety and dosing study is nearing completion and at least 50 children
have been on maximum tolerated dose for at least one year. Data will be available in early 1988.
Dr. Bonds reported on the Stroke Prevention Trial (STOP) which was terminated early. The
committee discussed the potential false TCD positives and correlations with abnormal MRIs,
TCD training and standardization, and problems of iron overload. General interest was expressed
in other clinical research related to preventing strokes with other agents, such as  hydroxyurea.  

There was extensive discussion of a number of proposed clinical  studies and the need to
establish priorities. These included the new conjugate pneumococcal vaccine, preventing end
organ damage with hydroxyurea in children and other questions related to transfusion therapy to
prevent  primary stroke. The committee recommended that a small working group be convened,
with representation from the committee,  to review these studies and to consider a possible
clinical network as a structure to carry out clinical research. 

At the close of the meeting, Dr. Reid expressed her appreciation to Dr. Johnson as a member
and chair of the Sickle Cell Disease Advisory Committee,  and presented a letter and certificate
from the NHLBI Director, Dr. Claude Lenfant. 

The meeting was adjourned at 3:30 pm.

FUTURE MEETING DATES

June 8, 1998
November 13, 1998

I hereby certify that to the best of  our knowledge, the foregoing minutes are accurate and
complete.

___________________________                                    _____________
Cage S. Johnson, M.D.                                                             Date
Chairman
Sickle Cell Disease Advisory Committee

___________________________                                     ______________
Clarice D. Reid, M.D.                                                                 Date
Executive Secretary
Sickle Cell Disease Advisory Committee
.