Dr. David Wilcox, Medical College of Wisconsin
project is novel to gene
therapy because it is specifically concerned with replacing
the affected protein in GT by targeting synthesis of a normal
protein to platelets, which is the cell-type most affected
to last year, two patients with GT donated bone marrow derived
cells for our studies and we were able to demonstrate correction
of their cells grown in the laboratory following treatment
of the cells with our gene therapy protocol.
contributions have greatly furthered this effort by providing
support for research supplies, housing and caring for animals.
your efforts, we have restored platelet function in mice affected
with GT now at 6 months past transplantation of gene therapy corrected
cells into the animals. This is a very encouraging result and
was accepted for presentation at the annual meeting of the American
Society of Hematology in Philadelphia in December of 2002.
further tests, we will present this data for formal review by
my peers in the scientific community and publication in a scientific
journal. While results in the mice are very exciting, there are
several steps that still need to be taken before proposing to
correct GT in humans.
this year we will try to correct larger animals that have been
found to have GT. This is a very challenging goal but also very
necessary to ensure safety and clinical efficacy of our gene therapy
protocol. I hope that you continue to share in my enthusiasm for
this work and thank you once again for your support.
reported at each ISTH Congress are significant in terms
of developing cures for a range of disorders, some common, others
more rare. And the XIX Congress here in Birmingham will be noted
for progress made towards finding a cure for one of the rarer
conditions - Glanzrnann thrombasthcnia.
of this inherited disorder, first described in 1918, begin in
early childhood. Severe intermittent bleeding from the mucous
membranes occurs and, in some cases, gastrointestinal bleeding
and intercranial haemorrhage follow. It may be fatal.
options include platelet transfusion, bone marrow transplant and
recombinant Factor VIIa. But platelets can become refractory to
platelet therapy, bone marrow transplant carries complications
and Factor VIIa is expensive and short-lived.
Wilcox, assistant professor in the department of paediatrics at
the Medical College of Wisconsin in Milwaukee, presented findings
in a session earlier this week (Abstract, OC130), which demonstrates
a potential cure for Glanzrnann thrombasthenia - and other rare
bleeding disorders - may soon be possible.
He and his
colleagues transfectcd the gene for human integrin beta-3 subunit
into bone marrow mononuclcar cells from a beta 3-knock-out mouse.
By two weeks platlets were appearing in the circulation expressing
the mouse and human proteins in a GPIIb-HIa complex. These platelets
aggregated and prevented bleeding stably for eight months.
unique about our system is that we used a platelet-specific gene
promoter of the integrin alpha IIb gene which will target gene
expression in the megakaryocytes," says Professor Wilcox.
This approach offers a potential therapy for Glanzmann thrombasthcnia
and other rare genetic bleeding disorders affecting platlets such
as Bernard-Soulier syndrome.
are other practical applications for use of these methods in basic
research," adds Professor Wilcox. "In addition, we may
want to target drugs to platelets, such as Factor VIII, to deliver
it to the immediate site of an injury or develop strategics to
protect platelets from the harmful effects of chemotherapy in
College of Wisconsin has received a four-year, $1 million grant
from the National Heart, Lung and Blood Institute to investigate
the insertion of a gene into bone marrow stem cells to target
gene expression to platelets.
Hematopoietic stem cells that form platelets can also produce
red and white blood cells; therefore, it is anticipated that the
strategy followed in this study can be similarly tailored to correct
disorders and deficiencies affecting the other cell-types - disorders
and deficiencies that result in other common bleeding disorders
and cancers of the blood.
David Wilcox, PhD, Assistant Professor of Pediatrics (Hematology/Oncology)
and Associate Investigator of the Blood Research Institute, is
principal investigator for this project, entitled Therapeutic
Expression of a Platelet-Specific Integrin. The research will
focus on correcting the disease Glanzmann Thrombasthenia, which
causes a deficiency of a receptor that enables platelets to aggregate
and seal-up a wound. People with Glanzmann Thrombasthenia can
experience severe bleeding.
Gene therapy trials will be performed to correct bleeding in dogs
affected with thrombasthenia as a model for subsequent human studies.
Bryon Johnson, PhD, Assistant Professor of Pediatrics; and James
D. Henderson Jr., DVM, MS, Institutional Veterinarian of the Animal
Research Center, are also involved in this study.
Dr. Wilcox has also initiated related studies with Qizhen Shi,
MD, PhD, Postdoctoral Fellow in Pediatrics (Hematology/Oncology);
and Robert R. Montgomery, MD, Professor of Pediatrics, (Hematology/Oncology),
on targeting expression of other plasma proteins that might permit
the effective gene therapy of hemophilia and/or von Willebrand
Funds from the American Heart Association, Children's Hospital
Foundation, Glanzmann Research Foundation Inc., the MACC Fund,
and Medical College of Wisconsin have supported Dr. Wilcox's research
and helped him to generate preliminary data for the new award.
of Thrombosis and Haemostasis,
and therapeutic recombinant factor VIIa administration to patients
with Glanzmann’s thrombasthenia: results of an international
Background: Antibodies to glycoprotein (GP) IIb-IIIa
and/or HLA may render platelet transfusions ineffective to stop
bleeding or to cover surgery in patients with Glanzmann’s
thrombasthenia (GT). Anecdotal reports suggest recombinant factor
(rF)VIIa might be a therapeutic alternative in these situations.
Objectives: An international survey was conducted to evaluate
further the efficacy and safety of rFVIIa in GT patients. Patients:
We analyzed the use of rFVIIa during 34 surgical/invasive procedures
and 108 bleeding episodes in 59 GT patients including 29 with
current or previous antiplatelet antibodies, and 23 with a history
of refractoriness to platelet transfusion.
Journal Recommends Immunization for Patients with Bleeding Disorders
British journal Haemophilia outlined investigators' recommendations
appropriate for patients with bleeding disorders, saying that
the recommendations are different than those for people without
bleeding disorders. The difference lies in the risk of hematoma
formation at the vaccination site and the “unusual infective risks
associate with the potential, and past, exposure to blood products,”
said the report.
vaccinations can be given subcutaneously and this should be the
preferred route,” said one of the report's collaborators. “All
routine childhood vaccinations should be given at the appropriate
time. All patients with bleeding disorders should be vaccinated
against hepatitis A and B. HIV positive patients should receive
annual influenza vaccinations and should avoid the oral polio,
oral typhoid, BCG and yellow fever vaccines.”
Medical and Scientific Advisory Council (MASAC) recommends children
with bleeding disorders should receive a hepatits B at birth or
at the time of diagnosis, and primary immune response should be
documented. MASAC also recommends that all individuals two years
or older who are hepatitis A virus seronegative should receive
a hepatitis A vaccine.
study can be found in Haemophilia , 2003;9(5)541-46.
Source: “Recommended Immunization of Patients with Bleeding Disorders
Outlined.” Health & Medicine Week, November 24, 2003.
research by Dr. Wilcox here.