BloodCenter Grayscale Logo

Robert R. Montgomery, M.D.

 Potrait Montgomery

Robert R. Montgomery, M.D.

Senior Investigator
Blood Research Institute
BloodCenter of Wisconsin


Professor of Pediatric Hematology

Department of Pediatrics
Medical College of Wisconsin

 

 

 

 

 

 

 

  

Selected Publications

Selected Book Chapters
Selected Abstracts
Grant Support
Invited Lectures
Laboratory Staff
Contact Information

 

Research Interests
Our laboratory's focus is on the molecular and cell biology of Factor VIII (FVIII) and von Willebrand factor in hemostasis and their contributions to von Willebrand Disease (VWD) and hemophilia.
 

While most prior investigations focused on the plasma relationships of FVIII and VWF, we have further identified their intracellular relationships and the conditions that modify their associations.  The VWF propeptide (VWFpp or historically - VW:AgII) orchestrates the assembly of VWF into high molecular weight multimers, the trafficking of VWF into regulated storage granules in platelets and endothelial cells, and modulates the association of VWF with FVIII.

 

This cellular relationship between FVIII and VWF occurs in the endothelial cell where both proteins are synthesized, but not in the megakaryocytes platelets where only VWF is normally synthesized and stored.  Knowing the intracellular relationships in endothelial cells, our lab has exploited their interaction in the megakaryocytes/platelets for the gene therapy of hemophilia.  If hematopoietic stem cells (HSCs) are transduced with the cDNA for FVIII under the control of a platelet specific, αIIb-promoter, FVIII is synthesized and follows VWF into the α-granules of platelets and not released into plasma.  When vascular injury occurs, the platelets adhere and are activated at the site of injury and release the stored FVIII where it can locally support the normalization of blood clotting.  Even more interesting is that this storage is protected against any circulating inhibitory, anti-FVIII antibodies – something that occurs in 35% of hemophilia patients.  Even 5 Bethesda Units (BU) of inhibitor will render standard treatment with transfused FVIII ineffectual, but the 2b-FVIII transduced platelets will normalize hemostasis even in the presence of 100,000 BU.

 

Platelet-directed 2b-FIX gene therapy of hemophilia B mice will correct the hemostatic defect similar to 2b-FVIII but with hemophilia B inhibitory antibodies, there is little protection of the FIX from the antibodies because FIX doesn’t have a carrier molecule as VWF serves for FVII.

 

Gene therapy in hemophilia A has also been demonstrated using endothelial-targeting of FVIII in hemophilia A mice.  When FVIII is expressed in endothelial cells, plasma VWF levels are normalized, but the benefits in the presence of FVIII inhibitory antibodies is not of the same magnitude as FVIII expression in platelets.

 

Our lab also studies VWD through our large, NIH-supported, international PPG.  More than 600 families with diagnosed VWD have been enrolled and studied for the molecular causes of abnormal VWF synthesis and processing.  This study is called the Zimmerman Program for the Molecular and Clinical Biology of VWD – a name in honor of the role of Ted Zimmerman in the initial identification and characterization of the defective VWF protein in VWD in the early 1970s.

 

As part of this PPG study, polymorphisms in VWF identified in more than 60% of African Americans cause their VWF to be incorrectly quantified by VWF activity assays using the ristocetin cofactor measurement of VWF – VWF:RCo.  Alternative assays have been developed that avoid such non-physiologic quantitative assays.
  

Selected Publications (from 130 publications)

  • Montgomery RR, Zimmerman TS:  von Willebrand's disease antigen II   a new plasma and platelet antigen deficient in severe von Willebrand's disease.  J Clin Invest 61:1498 1507, 1978. 
  • Rosenberg JB, Foster PA, Kaufman RJ, Vokac EA, Kroner PA, Montgomery RR:  Intracellular trafficking of Factor VIII to von Willebrand factor storage granules.  J Clin Invest 101: 613-624, 1998. (PMCID: PMC508605)
  • Montgomery RR and Cox Gill J:  Interactions Between von Willebrand factor and factor VIII: Where did they first meet?  J Pediatr Hematol Oncol 22(3):269-275, 2000. 
  • Haberichter SL, Fahs SA, Montgomery RR: Von Willebrand factor (vWF) storage and multimerization: Two independent intracellular processes.  Blood 96(5):1808-1815, 2000.   
  • Rosenberg JB, Greengard JS, and Montgomery RR:  Genetic induction of a releasable pool of factor VIII in human endothelial cells.  Arterioscler Thromb Vasc Biol. 20:2689-2695, 2000.   
  • Haberichter SL, Jozwiak MA, Rosenberg JB, Christopherson PA, Montgomery RR:  The von Willebrand Factor Propeptide VWFpp Traffics An Unrelated Protein to Storage.  Arterioscler Thromb Vasc Biol 22:921-926, 2002.   
  • Haberichter SL, Jacobi P, and Montgomery RR:  Critical Independent Regions in the VWF Propeptide and Mature VWF That Enable Normal VWF Storage.  Blood 101(4):1384-1391, 2003.   
  • Shi Q, Wilcox DA, Fahs SA, Kroner PA, Montgomery RR:  Expression of Human Factor VIII under Control of the αIIb Platelet-Specific Promoter in Megakaryocytic Cell Line as well as Storage Together with VWF.  Molecular Genetics and Metabolism 79:25-33, 2003.     
  • Wilcox DA, Shi Q, Nurden P, Haberichter SL, Rosenberg JB, Johnson BD, Nurden AT, White II GC, Montgomery RR:  Induction of Megakaryocytes to Synthesize and Store a Releasable Pool of Human Factor VIII.  J Thromb Haemost 1:2477-2489, 2003.   
  • Shi Q, Wilcox DA, Morateck PA, Fahs SA, Kenny D, Montgomery RR:  Targeting Platelet GPIbα Transgene Expression to Human Megakaryocytes and Forming a Complete Complex with Endogenous GPIbβ and GPIX.  J Thromb Haemost 2004; 2(11):1989-1997, 2004.   
  • Haberichter SL, Merricks EP, Fahs SA et al. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 105:145-152, 2005.    
  • Shi Q, Wilcox DA, Fahs SA, Weiler H, Wells CW, Cooley BC, Desai D, Morateck PA, Gorski J, Montgomery RR:  Factor VIII Ectopically Targeted Top Platelets is Therapeutic in Hemophilia A With High-Titer Inhibitory Antibodies.  J Clin Invest 116:1974-82, 2006.
  • Haberichter SL, Balistreri M, Christopherson P, Morateck P, Gavazova S, Manco-Johnson MJ, Gill JC, Montgomery RR:  Assay of the von Willebrand Factor (VWF) Propeptide to Identify Type 1 von Willebrand Disease Patients with Decreased VWF Survival.  Blood. 108: 3344-3351, 2006.   (PMCID: PMC1895439)
  • Shi Q, Wilcox DA, Fahs SA, Fang J, Johnson BD, Du LM, Desai D, Morateck PA, Montgomery RR.  Lentivirus-mediated Platelet-derived factor VIII (FVIII) Gene Therapy in Murine Hemophilia A.  J Thromb Haemost, 5:352-361 2007.   
  • Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, and Yawn BP:  Von Willebrand Disease (VWD): Evidence-Based Diagnosis and Management Guidelines from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA).  Haemophilia, 14(2):171-232, 2008.   
  • Haberichter SL, Allmann AM, Jozwiak MA, Montgomery RR, Gill JC:  Genetic Alteration of the D2 Domain Abolishes von Willebrand Factor Multimerization and Trafficking into Storage.  J Thromb Haemost, 7:641-50, 2009.   
  • 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 112:7, 2713-2721 2008.
  • Flood VH, Friedman KD, Gill JC, Morateck PA, Wren JS, Scott JP, Montgomery RR. Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J.Thromb.Haemost. 2009, 7:1832-1839.
  • Flood VH, Lederman CA, Wren JS, Christopherson PA, Friedman KD, Hoffmann RG, Montgomery RR. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. J.Thromb.Haemost. 2010, 8:1431-1433.
  • 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, 116:1235-1243.  
  • Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Branchford BR, Hoffmann RG, Abshire TC, DiPaola JA, Hoots WK, Leissinger C, Lusher JM, Ragni MV, Shapiro AD, Montgomery RR for the Zimmerman Program for the Molecular and Clinical Biology of VWD:  VWF Exon 28 Polymorphisms in African Americans Affecting the VWF:RCo/VWF:Ag Ratio. Blood 2010, 116(2):280-286. 
  • Montgomery RR, Monahan PE, Ozelo MC:  Unique Strategies for Therapeutic Gene Transfer in Haemophilia A and Haemophilia B.   Haemophilia 2010; 16-S5 529-534.
  • 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.
  • Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Hoffmann RG, Montgomery RR. Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Blood 2011;117(6):e67-e74.  (PMCID: PMC3056647).
  • Flood VH, Gill JC, Bellissimo DB, Haberichter SL, Friedman KD, Montgomery RR.  VWD in the United States:  A Perspective from Milwaukee, Wisconsin.  Submitted 2011.
  • Shi Q, Kuether EL, Schroeder JA, Zhang G, Fahs SA, Montgomery RR.  Intraperitoneal Injection and Recovery of VWF and FVIII and Differences from Intravenous and Subcutaneous Injection in Mice.  Haemophilia, 2011.
  • Bellissimo DB, Christopherson PA, Flood VH, Gill JC, Friedman KD, Haberichter SL, Shapiro AD, Abshire TC, Leissinger C, Hoots WK, Lusher JM, Ragni MV, Montgomery RR.  Von Willebrand Factor Mutations and New Sequence Variations Identified in Healthy Controls Enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB-VWD) are More Frequent in the African American Population, 2011.
  • Flood VH, Gill JC, Christopherson PA, Wren JS, Friedman KD, Haberichter SL, Lentz SR, Hoffmann RG, Montgomery RR.  VWF Mutations Can Selectively Alter Binding to Type VI or Types I and III Collagen, 2011.
  • Kuether EL, Fahs SA, Cooley BC, Schroeder JA, Montgomery RR, Wilcox DA, Shi Q.    Sustained Phenotypic Correction of Murine Hemophilia A with Pre-existing Factor VIII (FVIII) Inhibitors Using Lentivirus-Mediated Platelet-Derived FVIII Gene Therapy, 2011.
  • Kanaji S, Kuether EL, Fahs SA, Schroeder JA, Ware J, Montgomery RR, Shi Q.  Correction of Murine Bernard Soulier Syndrome by Lentavirus-mediated Gene Therapy.  Molecular Therapy, 2011.

Selected Book Chapters 2010-present (from 44 publications)

  • Montgomery RR, Flood VH:  Biological Diagnosis of VWD.  Textbook of Hemophilia, 2nd Edition.  Eds.  Lee C, Berntorp E, Hoots K.  Wiley-Blackwell Publishing.   In Press January 2010.
  • Haberichter SL, Montgomery RR:  Chapter 2.  Biosynthesis and Organization of VWF.  von Willebrand Disease:  Basic and Clinical Aspects, 1st Edition.  Eds. Federici AB, Lee, C, Berntorp E, Lillicrap D, Montgomery RR.  Wiley-Blackwell Publishing, 2011.
  • Montgomery RR,  Haberichter SL:  Chapter 3.  VWF Structure and Function.  Textbook of Hemophilia, 2nd Edition.  Eds. Federici AB, Lee C, Berntorp E, Lillicrap D, Montgomery RR. Wiley-Blackwell Publishing, 2011.
  • Montgomery RR, Shi Q:  New Strategies for Gene Therapy of Hemophilia.  ASH State of the Art Book, December 2010.
  • Haberichter SL, Montgomery RR:  Structure and Function of von Willebrand Factor.  Hemostasis and Thrombosis – Basic Principles and Clinical Practice, 6th Edition.  Eds.  Coleman, Marder, Clowes, George, and Goldhaber. Lippincott, Williams, Wilkins, Philadelphia PA, 2011.

Selected Abstracts 2011-present (from 280 abstracts)

  • Shi Q, Kuether EL, Cooley BC, Montgomery RR, Wilcox DA, Fahs SA, Schroeder J.  Gene Therapy of Hemophilia A Mice with Pre-existing Immunity Using Lentivirus-Mediated Platelet-Specific Gene Transfer.  Submitted  for presentation at the 14th Annual Meeting of American Society of Gene and Cell Therapy, Seattle, May 2011.
  • Johnasson MW, Han S-T, Gunderson KA, Montgomery RR, Busse WW, Jarjour NN, Mosher DF.  Platelet Activation, P-selectin Mmobilization, and Eosinophil β1 Integrin Activation Occur in Asthma and are Associated with Clinical Phenotypes.  Presented at the American Thoracic Society Meeting, Denver, Colorado, May 2011 .
  • Bellissimo DB, Chin E, Hegde MR, Christopherson PA, Haberichter SL, Montgomery RR, and Zimmerman Program Investigators.  Detection of VWF Copy Number Variations by Microarray Analysis in Von Willebrand Disease Type 3 Index Cases.  ASH 2011.
  • Chen Y, Kuether EL, Schroeder JA, Montgomery RR, Scott DW, Shi Q.  Targeting FVIII Expression to Platelets Induces Immune Tolerance in Hemophilia A Mice with or without Pre-Existing Anti-FVIII Immunity.   ASH 2011.
  • Flood VH, Gill JC, Friedman KD, Christopherson PA, Jacobi PM, Montgomery RR, Haberichter SL.  Von Willebrand Factor Collagen Binding Provides a Sensitive Screen for Identification of Type 2A and 2B Von Willebrand Disease.  ASH 2011.
  • Shi Q, Kuether EL, Fahs SA, Schroeder JA, Montgomery RR.  Targeting FVIII Expression to Human Platelets Corrects the Hemophilic Phenotype in an Immunocompromised Hemophilia A Mouse Model Transplanted with Genetically Manipulated Human Cord Blood Stem Cells.  ASH 2011.
  • Montgomery RR, Christopherson PA, Haberichter SL, Flood VH, Gill JC, and The Zimmerman Investigators.  Diagnostic Fidelity of Historically Diagnosed Patients with VWD Enrolled from 27 Centers in the ZPMCB-VWD.  ASH 2011.
  • Haberichter SL, Jacobi PM, Endres JL, Covill S, Flood VH, Montgomery RR, Gill JC, Friedman KD.  Discrimination between VWD Subtypes by Quantitative Analysis of VWF Multimer Structure.  Submitted to Thrombosis and Hemostasis North America Summit, 2011.

Grant Support

  • P01 HL81588, NIH, Zimmerman Program for the Molecular and Cellular Biology of VWD
  • P01 HL44612, NIH, Molecular and Cellular Mechanisms in Transfusion Medicine, Project 5: Critical Molecular Interactions of VWF and FVIII

 Invited Lectures 2010-present

  • “Laboratory Testing and diagnosis of vWD”  Symposium  Co-Chair, Contemporary Challenges in the Diagnosis and Management of von Willebrand Disease, Montreal, Quebec, Canada April, 2010.
  • “Pathophysiology of Type 1 VWD” Canadian Von Willebrand Disease Update, Toronto, Canada, April, 2010. 
  • “Alternative Assays for GP1-Binding of VWD”, 56th Annual Meeting Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, Cairo, Egypt, May 2010.
  • “Accelerated Clearance of VWF”, XXIX International Congress of the World Federation of Hemophilia – Hemophilia 2010, Buenos Aires, Argentina, July 2010.
  • “Therapeutic Gene Transfer”, XXIX International Congress of the World Federation of Hemophilia – Hemophilia 2010, Buenos Aires, Argentina, July 2010.
  • “Platelet-Based Gene Therapy”, XXIX International Congress of the World Federation of Hemophilia – Hemophilia 2010, Buenos Aires, Argentina, July 2010.
  • “von Willebrand Disease – the Diagnostic Relevance of the Phenotype” UK NEQAS for Blood Coagulation Annual Scientific Meeting, Sheffield, UK, September, 2010.
  • “Gene Therapy Through Platelet Drug Delivery in Hemophilia A & B”, Seminar Series, University of North Carolina at Chapel Hill, September, 2010.
  • “Classification of VWD” The Aland Islands Meeting, Mariehamm, the Aland Islands, Finland, September, 2010.
  • “Fidelity of VWD Diagnosis – from ristocetin to collagen”, 7th Bari International Conference, Pugnochiuso, Vieste, Italy, May 2011
  • “The Trojan Horse Approach to Gene Therapy of Hemophilia A and B”, 2011 Annual BIIB Hemophilia Research Seminar Series, Biogen Idec Inc., Waltham, Massachusetts, June 7, 2011.
  • “The Fidelity of VWD Diagnosis”, 2011 Annual BIIB Hemophilia Research Seminar Series, Biogen Idec, Inc., Waltham, Massachusetts, June 7, 2011.
  • “Zimmerman Project (ZPMCB-VWD) Update on Activities”, von Willebrand Factor SSC Meeting, XXIII Congress and 57th Annual SSC Meeting, International Society of Thrombosis and Hemostasis (ISTH), Kyoto, Japan, July 24, 2011. 
  • “Gene Therapy of Hemophilia through Platelet-targeted Gene delivery”, Bayer Hemophilia Care Innovation Summit, Budapest, Hungary, October 13, 2011.
  • “Hemophilias and von Willebrand Disease”, Continuing Education in Thrombosis & Hemostasis ISTH-ESH Joint Advanced Training Course, Cascais, Portugal, November 7, 2011.
     

 

Lab Photo Montgomery

Back Row: Crystal Perry, Pam Christopherson, Bob Montgomery, Scot Fahs, Jeff Wren, Guowei Zhang, Erin Kuether; Middle Row: Rashmi Sood, Carissa Schubert, Patti Morateck, Sandy Ingram, Paula Jacobi, Ann Leeder; Front Row: Anthony Lee, Mary Jozwiak, Sandy Haberichter, Qizhen Shi, Veronica Flood

 

Laboratory Staff

 

Qizhen Shi, M.D., Ph.D.qizhen.shi@bcw.eduMCW Asst. Professor
Sachiko Kanaji, M.D., Ph.D.sachiko.kanaji@bcw.eduPostdoctoral Fellow
Scot Fahsscot.fahs@bcw.eduSr. Research Technologist
Mary Jozwiakmary.jozwiak@bcw.eduSr. Research Technologist
Pam Christophersonpam.christopherson@bcw.eduSr. Research Technologist
Patricia Morateckpatti.morateck@bcw.eduSr. Research Technologist
Sandy Ingramsandy.ingram@bcw.eduAsst. Research Coordinator
Erin Kuethererin.kuether@bcw.eduResearch Technologist
Crystal Perrycrystal.perry@bcw.eduResearch Technologist
Jocelyn Schroederjocelyn.schroeder@bcw.eduResearch Technologist
Veronica Floodveronica.flood@bcw.eduMCW Asst. Professor 
Carissa Schubertcarissa.schubert@bcw.eduResearch Technologist
Hanna Lincolnhannah.lincoln@bcw.eduAsst. Research Technologist

 

Employment Opportunities
If opportunities are available, they will be listed on the Employment page.

 

Contact Information
Phone: (414) 937-6318
Fax: (414) 937-6284
E-mail: bob.montgomery@bcw.edu