Senior Scientist, Department of Pathology and Molecular Medicine
Queen’s University, Kingston Ontario Canada
I have two primary research interests. The first centers on evaluating the efficacy of various gene and stem cell strategies as possible therapeutic modalities for hemophilia A. The second is aimed at gaining a better understanding of the mechanisms involved in immunological tolerance to FVIIII, as well as the adverse immune response to factor VIII (FVIII) that occurs in some hemophilia A patients after they receive FVIII replacement therapy. I am using this knowledge to develop novel immune modulating strategies to either prevent the development of, or eradicate anti-FVIII antibodies.
In our research laboratory we isolate late outgrowth endothelial progenitor cells obtained from hemophilia A peripheral blood samples. These cells are then genetically modified using a lentiviral vector delivery system that contains the FVIII transgene. The cells are then surgically implanted into various sites in order that they can produce the therapeutic FVIII and correct the bleeding phenotype. We are currently optimizing this strategy by investigating alternative sources of cells, including induced pluripotent stem (iPS) cells, as well as investigating ways to enhance the cell viability and optimize the transgene cassette to increase FVIII transgene expression levels.
Our research laboratory is interested in the delicate balance between FVIII tolerance and an adverse anti-FVIII immune response. We have investigated mechanisms associated with long-term tolerance to FVIII after systemic delivery of lentiviral vectors to neonates. In addition we have evaluated differences in the splenic cytokine microenvironment after intravenous delivery of FVIII. These studies have illustrated the role that regulatory T cells play in modulating the immune response to FVIII. We continue to investigate mechanisms involved with maintaining FVIII tolerance and explore strategies to enhance tolerogenic presentation of FVIII with the view to prevent the adverse immune response to FVIII replacement therapy.
Lai JD, Moorehead PC, Sponagle K, Steinitz KN, Reipert BM, Hough C, Lillicrap D. Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A. Blood. 2016;127(26):3439-49.
Nichols TC, Hough C, Agersø H, Ezban M, Lillicrap D. Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies. J Thromb Haemost. 2016;14(5):894-905.
Georgescu MT, Lai JD, Hough C, Lillicrap D. War and peace: Factor VIII and the adaptive immune response. Cell Immunol. 2016;301:2-7.
Lai JD, Georgescu MT, Hough C, Lillicrap D. To clear or to fear: An innate perspective on factor VIII immunity.Cell Immunol. 2016 Mar;301:82-9.
Crawford B, Ozelo MC, Ogiwara K, Ahlin J, Albanez S, Hegadorn C, Harpell L, Hough C, Lillicrap D. Transgene-host cell interactions mediate significant influences on the production, stability, and function of recombinant canine FVIII. Mol Ther Methods Clin Dev. 2015; 2:15033.
Ozelo MC, Vidal B, Brown C, Notley C, Hegadorn C, Webster S, Harpell L, Ahlin J, Winterborn A, Handforth J, Arruda VR, Hough C, Lillicrap D. Omental implantation of BOECs in hemophilia dogs results in circulating FVIII antigen and a complex immune response. Blood. 2014 Jun 26;123(26):4045-53.
Matsui H, Hegadorn C, Ozelo M, Burnett E, Tuttle A, Labelle A, McCray PB Jr, Naldini L, Brown B, Hough C, Lillicrap D. A microRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of Hemophilia A. Mol Ther. 2011 Apr;19(4):723-30.
Qadura M, Waters B, Burnett E, Chegeni R, Hough C, Othman M, Lillicrap D. Immunoglobulin isotypes and functional anti-FVIII antibodies in response to FVIII treatment in Balb/c and C57BL/6 haemophilia A mice. Haemophilia. 2011 Mar;17(2):288-95.
Berber E, James PD, Hough C, Lillicrap D. An assessment of the pathogenic significance of the R924Q von Willebrand factor substitution. J Thromb Haemost. 2009 Oct;7(10):1672-9.
Matsui H, Shibata M, Brown B, Labelle A, Hegadorn C, Andrews C, Chuah M, VandenDriessche T, Miao CH, Hough C, Lillicrap D. A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells. Blood: 2009 Jul 16;114(3):677-85.
Qadura M, Waters B, Burnett E, Chegeni R, Bradshaw S, Hough C, Othman M, Lillicrap D. Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood. 2009 Jul 23;114(4):871-80.
Waters B, Qadura M, Burnett E, Chegeni R, Labelle A, Thompson P, Hough C, Lillicrap D. Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. Blood. 2009 Jan 1;113(1):193-203.
Qadura M, Othman M, Waters B, Chegeni R, Walker K, Labelle A, Ozelo M, Hough C, Lillicrap D. Reduction of the immune response to factor VIII mediated through tolerogenic factor VIII presentation by immature dendritic cells. J Thromb Haemost. 2008 Dec;6(12):2095-104.
Matsui H, Shibata M, Brown B, Labelle A, Hegadorn C, Andrews C, Hebbel RP, Galipeau J, Hough C, Lillicrap D. Ex vivo gene therapy for hemophilia A that enhances safe delivery and sustained in vivo factor VIII expression from lentivirally engineered endothelial progenitors. Stem Cells. 2007 Oct;25(10):2660-9.
Rawle FE, Pratt KP, Labelle A, Weiner HL, Hough C, Lillicrap D. Induction of partial immune tolerance to factor VIII through prior mucosal exposure to the factor VIII C2 domain. J Thromb Haemost. 2006 Oct;4(10):2172-9.
Hough C, Lillicrap D. Gene therapy for hemophilia: an imperative to succeed. J Thromb Haemost. 2005 Jun;3(6):1195-205. Review.
Rawle FE, Shi CX, Brown B, McKinven A, Tinlin S, Graham FL, Hough C, Lillicrap D. Heterogeneity of the immune response to adenovirus-mediated factor VIII gene therapy in different inbred hemophilic mouse strains. J Gene Med. 2004 Dec;6(12):1358-68.
Notley C, Killoran A, Cameron C, Wynd K, Hough C, Lillicrap D. The canine factor VIII 3'-untranslated region and a concatemeric hepatocyte nuclear factor 1 regulatory element enhance factor VIII transgene expression in vivo. Hum Gene Ther. 2002 Sep 1;13(13):1583-93.
Hough C, Kamisue S, Cameron C, Notley C, Tinlin S, Giles A, Lillicrap D. Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: similarities with the intron 22 inversion mutation in human hemophilia. Thromb Haemost. 2002 Apr;87(4):659-65.
Gallo-Penn AM, Shirley PS, Andrews JL, Tinlin S, Webster S, Cameron C, Hough C, Notley C, Lillicrap D, Kaleko M, Connelly S. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood. 2001 Jan 1;97(1):107-13.
Gallo-Penn AM, Shirley PS, Andrews JL, Kayda DB, Pinkstaff AM, Kaloss M, Tinlin S, Cameron C, Notley C, Hough C, Lillicrap D, Kaleko M, Connelly S. In vivo evaluation of an adenoviral vector encoding canine factor VIII: high-level, sustained expression in hemophiliac mice. Hum Gene Ther. 1999 Jul 20;10(11):1791-802.
Cameron C, Notley C, Hoyle S, McGlynn L, Hough C, Kamisue S, Giles A, Lillicrap D. The canine factor VIII cDNA and 5' flanking sequence. Thromb Haemost. 1998 Feb;79(2):317-22.
Berber E, James PD, Hough C, Lillicrap D. An assessment of the pathogenic significance of the R924Q von Willebrand factor substitution. J Thromb Haemost. 2009 Jul 17.
Hough C, Cameron CL, Notley CR, Brown C, O'Brien L, Keightley AM, Berber E, Lillicrap D. Influence of a GT repeat element on shear stress responsiveness of the VWF gene promoter. J Thromb Haemost. 2008 Jul;6(7):1183-90.
James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54.
Hough C, Cuthbert CD, Notley C, Brown C, Hegadorn C, Berber E, Lillicrap D. Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor. Blood. 2005 Feb 15;105(4):1531-9.
James PD, O'Brien LA, Hegadorn CA, Notley CR, Sinclair GD, Hough C, Poon MC, Lillicrap D. A novel type 2A von Willebrand factor mutation located at the last nucleotide of exon 26 (3538G>A) causes skipping of 2 nonadjacent exons. Blood. 2004 Nov 1;104(9):2739-45.
O'Brien LA, Sutherland JJ, Hegadorn C, Benford K, Racz H, Rapson D, Hough C, Lillicrap D. A novel type 2A (Group II) von Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers. J Thromb Haemost. 2004 Jul;2(7):1135-42.
Brown BD, Shi CX, Rawle FE, Tinlin S, McKinven A, Hough C, Graham FL, Lillicrap D. Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice. J Thromb Haemost. 2004 Jan;2(1):111-8.
O'Brien LA, James PD, Othman M, Berber E, Cameron C, Notley CR, Hegadorn CA, Sutherland JJ, Hough C, Rivard GE, O'Shaunessey D, Lillicrap D; Association of Hemophilia Clinic Directors of Canada. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood. 2003 Jul 15;102(2):549-57.
Hough CA, White BN, Holden JJ. Absence of lambda immunoglobulin sequences on the supernumerary chromosome of the "cat eye" syndrome. Am J Med Genet. 1995 Sep 11;58(3):277-81.
Hough CA, White BN, Holden JJ. Characterization of a lymphoblastoid line deleted for lambda immunglobulin genes. Immunogenetics. 1995;41(6):359-65.
Duncan AM, Hough CA, White BN, McDermid HE. Breakpoint localization of the marker chromosome associated with the cat eye syndrome. Am J Hum Genet. 1986 Jun;38(6):978-80.
Davies PL, Hough C, Scott GK, Ng N, White BN, Hew CL. Antifreeze protein genes of the winter flounder. J Biol Chem. 1984 Jul 25;259(14):9241-7.