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Dr. David Wilcox, Medical College of Wisconsin

My 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 by GT.

Prior 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.

Your contributions have greatly furthered this effort by providing support for research supplies, housing and caring for animals.

Because of 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.

Following 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.

Beginning 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.

Findings 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.

The effects 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.

Current treatment 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.

However, David 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.

"What's 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.

"There 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 cancer treatment.'

The Medical 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 disease.

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.

Journal of Thrombosis and Haemostasis, 2: 1096–1103

Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann’s thrombasthenia: results of an international survey

Summary. 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.             (read more...)

November 24, 2003

British Journal Recommends Immunization for Patients with Bleeding Disorders

The 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.

“Most 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.”

NHF's 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.

The 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.

Additional research by Dr. Wilcox here.

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