Versiti Blood Research Institute Articles
Developing New Gene Therapies for Patients with Bleeding Disorders
How understanding the genetics behind hemophilia A and von Willebrand disease will help inform patient treatment and develop gene therapies.
Hemophilia, a bleeding disorder, affects 1 in 5,000 male births in the United States. Once known as the “royal’s disease,” it was spread throughout Europe by Queen Victoria’s descendants, most notoriously affecting Prince Alexei, the only son of Nicholas II, the last tsar of Russia. Alexei’s mother, Princess Alix (Queen Victoria’s granddaughter), went to great lengths to cure her son’s disease, even employing the mystic Rasputin.
These days, however, the treatment options for hemophilia are rooted in science and not the mystic arts. Versiti Blood Research Institute Senior Investigator Robert Montgomery, MD, has spent his career treating patients with Factor VIII deficiency in hemophilia A, as well as von Willebrand disease.
Factor VIII (FVIII) is a protein in the blood that is essential for blood clotting. FVIII is carried by von Willebrand factor (VWF), the gene that causes von Willebrand disease, which is the most common bleeding disorder. VWF sticks to platelets, collagen and other things underneath the blood vessel wall. When a healthy person cuts themselves, the cut creates a hole in that wall; VWF sticks to it, which increases the concentration of FVIII and platelets, thereby causing the blood to clot. However, if someone lacks VWF, FVIII disappears rapidly, and they continue to bleed. One of Dr. Montgomery’s current research topics is to study how VWF hands off FVIII at the local level, where it is needed to stop bleeding.
Normally, when physicians treat patients with hemophilia A and von Willebrand disease, they use recombinant FVIII, or FVIII that has been developed in a laboratory, which helps normalize the coagulation process. Sometimes, these patients’ bodies identify recombinant FVIII as a foreign substance and develop an antibody to it, which prevents it from working the way it is intended. Sometimes, it’s possible to trick the patient’s immune system into thinking recombinant FVIII is a good thing, by giving them overwhelming amounts of it. However, some patients cannot tolerate it at all, and must then receive recombinant Factor VIIa, an expensive substitute.
Dr. Montgomery and his colleagues sought a better, more accessible, way to treat these patients. “We have developed a gene therapy approach for hemophilia that targets patients who have inhibitory antibody,” he says. To accomplish this, he and his colleagues sought to remove the entire FVIII gene – something that has never been done before – in a model of hemophilia A. When they attempted to do this, rather than removing the gene, they flipped it, which caused it to be ineffective. Based on this, they realized that 50% of hemophilia patients have hemophilia that is based on an inversion of the FVIII gene. “Now, we’ve created an inversion that can be studied,” Dr. Montgomery said, giving new hope to patients who require alternate treatment options.
About the expert: Robert Montgomery, MD, is a senior investigator at Versiti Blood Research Institute and Professor of Pediatric Hematology in the Department of Pediatrics at the Medical College of Wisconsin.
- Baumgartner CK, Zhang G, Kuether EL, Weiler H, Shi Q, Montgomery RR. Comparison of platelet-derived and plasma FVIII efficacy using a novel native whole blood thrombin generation assay. J.Thromb.Haemost. 2015
- Shi Q, Schroeder JA, Kuether EL, Montgomery RR. The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies. J.Thromb.Haemost. 2015;13(7):1301-1309. (PMCID: PMC4496307).
- Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 2014;123(24):3706-3713. (PMCID: PMC4055921).
- Shi Q, Kuether EL, Chen Y, Schroeder JA, Fahs SA, Montgomery RR. Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 2014;123(3):395-403. (PMCID: PMC3894495).
- Kuether EL, Schroeder JA, Fahs SA, Cooley BC, Chen Y, Montgomery RR, Wilcox DA, Shi Q. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-factor VIII immunity. J.Thromb.Haemost. 2012;10(8):1570-1580. (PMCID: PMC3419807).
- Montgomery RR, Shi Q. Platelet and endothelial expression of clotting factors for the treatment of hemophilia. Thromb.Res. 2012;129 Suppl 2S46-S48. (PMCID: PMC3581347).
- Shi Q, Kuether EL, Schroeder JA, Fahs SA, Montgomery RR. Intravascular recovery of VWF and FVIII following intraperitoneal injection and differences from intravenous and subcutaneous injection in mice. Haemophilia. 2012;18(4):639-646. (PMCID: PMC3323668).
- Shi Q, Kuether EL, Schroeder JA, Perry CL, Fahs SA, Cox GJ, Montgomery RR. Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo. J.Thromb.Haemost. 2012;10(11):2328-2337. (PMCID: PMC3670966).
- Montgomery RR, Shi Q. Alternative strategies for gene therapy of hemophilia. Hematology.Am.Soc.Hematol.Educ.Program. 2010;2010197-202. (PMCID: PMC3383974).
- Shi Q, Montgomery RR. Platelets as delivery systems for disease treatments. Adv.Drug Deliv.Rev. 2010;62(12):1196-1203. (PMCID: PMC2991519).
- Shi Q, Fahs SA, Kuether EL, Cooley BC, Weiler H, Montgomery RR. Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A. Blood 2010;116(16):3049-3057. (PMCID: PMC2974610).
- Zhang G, Shi Q, Fahs SA, Kuether EL, Walsh CE, Montgomery RR. Factor IX ectopically expressed in platelets can be stored in alpha-granules and corrects the phenotype of hemophilia B mice. Blood 2010;116(8):1235-1243. (PMCID: PMC2938234).
- Du LM, Nichols AJ, Haberichter SA, Jacobi E, Jensen AL, Fang B, Shi BZ, Montgomery RR, Wilcox DA. Plateletitargeted expression of human BDD-FVIII reduces bleeding in canine hemophilia. Blood 2009;114289.
- Shi Q, Fahs SA, Wilcox DA, Kuether EL, Morateck PA, Mareno N, Weiler H, Montgomery RR. Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity. Blood 2008;112(7):2713-2721.