• Principal Investigator
  • Male

Dr. P.J. Bosma

Position:
Main activities: Research
Specialisation:
foto P.J. Bosma is one of the AMC Principal Investigators
Focus of research:
  • Gene Therapy.
    My main focus is to develop Adeno Associated liver directed gene therapy to treat inherited unconjugated hyperbilirubinemia. This research is funded by the Dutch Najjar foundation and by ZonMw. In collaboration with the group of Prof.Dr Labrunne and the AFM we plan to start a phase 1 trial end 2016 or start 2017. Succesfull application of AAV in this patients will also enable us to use this strategy to treat other inherited liver diseases such as PFIC.
  • Liver function.
    The role of inter cellular signaling in the development of liver diseases and bile formation. Using in vitro and in vivo knock-down we will determine the role of liver specific transport proteins in liver function. In addition to their role in bile formatin we are investigating their potential role in inter cellular signaling for instance via the formation of exosomes and microvesicles. 
AMC themes: Metabolic disorders and gastrointestinal diseases
Departments: Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research
Bolier AR. The role of autotaxin in cholestatic pruritus. S.l.: s.n.; 2017. 178p. ISBN 9789461827975 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Oude Elferink RPJ, Beuers UHW; copromotor(s): Bosma PJ)
van Dijk R, Aronson SJ, de Waart DR, van de Graaf SF, Duijst S, Seppen J, Oude Elferink R, Beuers U, Bosma PJ, Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo. SCI REP-UK 2017;7 (1):1646 [PubMed]
Bolier R , Tolenaars D, Kremer AE, Saris J, Parés A, Verheij J, Bosma PJ, Beuers U, Oude Elferink RPJ, Enteroendocrine cells are a potential source of serum autotaxin in men. BBA-MOL BASIS DIS 2016;1862 (4):696-704 [PubMed]
de Waart DR, Naik J, Utsunomiya KS, Duijst S, Ho-Mok K, Bolier AR, Hiralall J, Bull LN, Bosma PJ, Oude Elferink RPJ, Paulusma CC, ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes. HEPATOLOGY 2016;64 (1):161-174 [PubMed]
Jorns C, Nowak G, Nemeth A, Zemack H, Mörk LM, Johansson H, Gramignoli R, Watanabe M, Karadagi A, Alheim M, Hauzenberger D, van Dijk R, Bosma PJ, Ebbesen F, Szakos A, Fischler B, Strom S, Ellis E, Ericzon BG, De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning. AM J TRANSPLANT 2016;16 (3):1021-1030 [PubMed]
Ronzitti G, Bortolussi G, van Dijk R, Collaud F, Charles S, Leborgne C, Vidal P, Martin S, Gjata B, Sola MS, van Wittenberghe L, Vignaud A, Veron P, Bosma PJ, Muro AF, Mingozzi F, A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. MOL THER-METH CLIN D 2016;3:16049 [PubMed]
Aronson SJ, Beuers U, Bosma PJ, Progress and challenges in gene therapy for Crigler-Najjar syndrome. EXPERT OPIN ORPHAN D 2015;3 (12):1387-1396
Naik J, de Waart DR, Utsunomiya K, Duijst S, Mok KH, Oude Elferink RPJ, Bosma PJ, Paulusma CC, ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function. DIGEST DIS 2015;33 (3):314-318 [PubMed]
van Dijk R, Beuers U, Bosma PJ, Gene replacement therapy for genetic hepatocellular jaundice. CLIN REV ALLERG IMMU 2015;48 (2-3):243-253 [PubMed]
van Dijk R, Kremer AE, Smit W, van den Elzen B, van Gulik T, Gouma D, Lameris JS, Bikker H, Enemuo V, Stokkers PCF, Feist M, Bosma P, Jansen PLM, Beuers U, Characterization and treatment of persistent hepatocellular secretory failure. LIVER INT 2015;35 (4):1478-1488 [PubMed]
van Dijk R, Mayayo-Peralta I, Aronson SJ, Kattentidt-Mouravieva AA, van der Mark VA, de Knegt R, Oruc N, Beuers U, Bosma PJ, Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia. J HEPATOL 2015;63 (6):1525-1529 [PubMed]
Montenegro-Miranda PS, Pichard V, Aubert D, ten Bloemendaal L, Duijst S, de Waart DR, Ferry N, Bosma PJ, In the rat liver, Adenoviral gene transfer efficiency is comparable to AAV. GENE THER 2014;21 (2):168-174 [PubMed]
Montenegro-Miranda PS, Pañeda A, ten Bloemendaal L, Duijst S, de Waart DR, Aseguinolaza GG, Bosma PJ, Adeno-associated viral vector serotype 5 poorly transduces liver in rat models. PLOS ONE 2013;8 (12):e82597 [PubMed]
Sokolović A. Pathogenesis and reversal of liver fibrosis: effects of genes and environment. s.l.: s.n.; 2013. 125p. ISBN 9789461916235 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Oude Elferink RPJ; copromotor(s): Bosma PJ)
Sokolović A, Rodriguez-Ortigosa CM, Bloemendaal LT, Oude Elferink RPJ, Prieto J, Bosma PJ, Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4(-/-) mice. BBA-MOL BASIS DIS 2013;1832 (6):697-704 [PubMed]
van Dijk R, Montenegro-Miranda PS, Riviere C, Schilderink R, ten Bloemendaal L, van Gorp J, Duijst S, de Waart DR, Beuers U, Haisma HJ, Bosma PJ, Polyinosinic acid blocks adeno-associated virus macrophage endocytosis in vitro and enhances adeno-associated virus liver-directed gene therapy in vivo. HUM GENE THER 2013;24 (9):807-813 [PubMed]
Montenegro Miranda PS. Gene therapy with adeno-associated viral vectors for inherited hyperbilirubinemia. Towards a clinical trial for Crigler-Najjar syndrome. s.l.: s.n.; 2012. 197p. ISBN 9789090266633 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Oude Elferink RPJ; copromotor(s): Bosma PJ)
Montenegro-Miranda PS, Sneitz N, de Waart DR, ten Bloemendaal L, Duijst S, de Knegt RJ, Beuers U, Finel M, Bosma PJ, Ezetimibe: A biomarker for efficacy of liver directed UGT1A1 gene therapy for inherited hyperbilirubinemia. BBA-MOL BASIS DIS 2012;1822 (8):1223-1229 [PubMed]
Seppen J, Bosma P, Bilirubin, the Gold Within. CIRCULATION 2012;126 (22):2547-2549 [PubMed]
Sokolović A, Montenegro-Miranda PS, de Waart DR, Cappai RMN, Duijst S, Sokolović M, Bosma PJ, Overexpression of insulin like growth factor binding protein 5 reduces liver fibrosis in chronic cholangiopathy. BBA-MOL BASIS DIS 2012;1822 (6):996-1003 [PubMed]
Montenegro-Miranda P, ten Bloemendaal L, Kunne C, de Waart DR, Bosma PJ, Mycophenolate Mofetil Impairs Transduction of Single-Stranded Adeno-Associated Viral Vectors. HUM GENE THER 2011;22 (5):605-612 [PubMed]
van Geer MA. Adenovirus targeting for gene therapy of pancreatic cancer. s.l.: s.n.; 2011. 173p. ISBN 9789490371623 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Oude Elferink RPJ; copromotor(s): Bosma PJ)
Sneitz N, Bakker CT, de Knegt RJ, Halley DJJ, Finel M, Bosma PJ, Crigler-Najjar syndrome in The Netherlands: Identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. HUM MUTAT 2010;31 (1):52-59 [PubMed]
Sokolovic A, Sokolovic M, Boers W, Oude Elferink RPJ, Bosma PJ, Insulin-like growth factor binding protein 5 enhances survival of LX2 human hepatic stellate cells. FIBROGENESIS TISSUE REPAIR 2010;3 (3):1-13 [PubMed]
van Geer MA, Brevoord D, Kuhlmann KFD, Bakker CT, Mizuguchi H, Wesseling JG, ten Kate FJ, Gouma DJ, Oude Elferink RPJ, Bosma PJ, A fiber modified adenovirus vector that targets to the EphrinA2 receptor reveals enhanced gene transfer to ex vivo pancreatic cancer. INT J ONCOL 2010;36 (1):233-244 [PubMed]
Kuhlmann KFD, van Geer MA, Bakker CT, Dekker JEM, Havenga MJE, Elferink RPJO, Gouma DJ, Bosma PJ, Wesseling JG, Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma. CANCER GENE THER 2009;16 (7):585-597 [PubMed]
Miranda PSM, Bosma PJ, Towards Liver-Directed Gene Therapy for Crigler-Najjar Syndrome. CURR GENE THER 2009;9 (2):72-82 [PubMed]
van Geer MA, Bakker CT, Koizumi N, Mizuguchi H, Wesseling JG, Oude Elferink RPJ, Bosma PJ, Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo. WORLD J GASTROENTERO 2009;15 (22):2754-2762 [PubMed]
van Geer MA, Kuhlmann KFD, Bakker CT, ten Kate FJW, Oude Elferink RPJ, Bosma PJ, Ex-vivo evaluation of gene therapy vectors in human pancreatic (cancer) tissue slices. WORLD J GASTROENTERO 2009;15 (11):1359-1366 [PubMed]
Marsman WA, Wesseling JG, El Bouch A, Bosma PJ, van Lanschot JJB, Adenoviral serotypes in gene therapy for esophageal carcinoma. J SURG RES 2007;140 (1):50-54 [PubMed]
Boers W, Aarrass S, Linthorst C, Pinzani M, Elferink RO, Bosma P, Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins. J BIOL CHEM 2006;281 (24):16289-16295 [PubMed]
Lie-A-Ling M, Bakker CT, Deurholt T, Hoekstra R, Wesseling JG, Afford SC, Bosma PJ, Selection of tumour specific promoters for adenoviral gene therapy of cholangiocarcinoma. J HEPATOL 2006;44 (1):126-133 [PubMed]
Marsman WA. Barrett's battle gene therapy and diagnostic endoscopy. S.l.: s.n.; 2006. 219p. ISBN 90-9021282--5 [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): van Lanschot JJB; copromotor(s): Bosma PJ, Bergman JJGHM)
Seppen J, Bakker C, de Jong B, Kunne C, van den Oever K, Vandenberghe K, de Waart R, Twisk J, Bosma P, Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats. MOL THER 2006;13 (6):1085-1092 [PubMed]
Buskens CJ, Marsman WA, Bosma PJ, van Lanschot JJB, The current state of cancer gene therapy and its application in esophageal carcinoma. DIGEST SURG 2005;22 (4):222-233 [PubMed]
Lie-A-Ling M. Gene therapy for cholangiocarcinoma. S.l.: s.n.; 2005. 152p. [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): Oude Elferink RPJ; copromotor(s): Bosma PJ)
Lie-A-Ling M, Bakker CT, Wesseling JG, Bosma PJ, AdEasy-based cloning system to generate tropism expanded replicating adenoviruses expressing transgenes late in the viral life cycle. GENE THER 2005;12 (17):1347-1352 [PubMed]
Marsman WA, Buskens CJ, Wesseling JG, van Lanschot JJB, Bosma PJ, Gene therapy for barrett's esophagus: adenoviral gene transfer in different intestinal models. CANCER GENE THER 2005;12 (9):778-786 [PubMed]
Buskens CJ. The development of new treatment strategies for oesophageal cancer. S.l.: s.n.; 2004. 304p. ISBN ? [UvA Dissertations Online] Proefschrift Universiteit van Amsterdam. (Promotor(s): van Lanschot JJB, ten Kate FJW; copromotor(s): Bosma PJ)
Koshy A, Bosma PJ, Oude-Elferink RPJ, Crigler-Najjar syndrome type 1 associated with combined 1070A-->G, Q357R and (TA)7 mutation in Kuwaiti Bedouin families indicate a founder effect in Arabs. J CLIN GASTROENTEROL 2004;38 (5):465-467 [PubMed]
Marsman WA, Birjmohun RS, van Rees BP, Caspers E, Johan G, Offerhaus A, Bosma PJ, Jan J, van Lanschot B, Loss of heterozygosity and immunohistochemistry of adenocarcinomas of the esophagus and gastric cardia. CLIN CANCER RES 2004;10 (24):8479-8485 [PubMed]
Marsman WA, Buskens CJ, Wesseling JG, Offerhaus GJA, Bergman JJGHM, Tytgat GNJ, van Lanschot JJB, Bosma PJ, Gene therapy for esophageal carcinoma: the use of an explant model to test adenoviral vectors ex vivo. CANCER GENE THER 2004;11 (4):289-296 [PubMed]
Bosma P, The association of elevated serum bilirubin levels and coronary heart disease - Reply. J HEPATOL 2003;39 (5):882
Bosma PJ, Inherited disorders of bilirubin metabolism. J HEPATOL 2003;38 (1):107-117 [PubMed]
Bosma PJ, van der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC, UGT1A1*28 allele and coronary heart disease: The Rotterdam study. CLIN CHEM 2003;49 (7):1180-1181 [PubMed]
Buskens CJ, Marsman WA, Wesseling JG, Offerhaus GJA, Yamamoto M, Curiel DT, Bosma PJ, van Lanschot JJB, A genetically retargeted adenoviral vector enhances viral transduction in esophageal carcinoma cell lines and primary cultured esophageal resection specimens. ANN SURG 2003;238 (6):815-824 [PubMed]
Medina JF, Recalde S, Prieto J, Lecanda J, Saez E, Funk CD, Vecino P, van Roon MA, Ottenhoff R, Bosma PJ, Bakker CT, Elferink RPJO, Anion exchanger 2 is essential for spermiogenesis in mice. P NATL ACAD SCI USA 2003;100 (26):15847-15852 [PubMed]
Rutjes SA, Bosma PJ, Rohn JL, Noteborn MHM, Wesseling JG, Induction of insolubility by herpes simplex virus VP22 precludes intercellular trafficking of N-terminal Apoptin-VP22 fusion proteins. J MOL MED-JMM 2003;81 (9):558-565 [PubMed]
Wesseling JG, Lie-A-Ling M, Havenga MJ, Bosma PJ. Tergeting cancer with viral vectors in: Anonymous Falk Workshop 132B. Dordrecht: Kluwer Academic Publishers; 2003., p. 171-181
Buskens CJ, van Rees BP, Sivula A, Reitsma JB, Haglund C, Bosma PJ, Offerhaus GJA, van Lanschot JJB, Ristimäki A, Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. GASTROENTEROLOGY 2002;122 (7):1800-1807 [PubMed]
Jacquemin E, de Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, Scheffer GL, Paul M, Burdelski M, Bosma PJ, Bernard O, Hadchouel M, Elferink RP, The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. GASTROENTEROLOGY 2001;120 (6):1448-1458 [PubMed]
Persico M, Persico E, Bakker CT, Rigato I, Amoroso A, Torella R, Bosma PJ, Tiribelli C, Ostrow JD, Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1. HEPATOLOGY 2001;33 (3):627-632 [PubMed]
Wesseling JG, Bosma PJ, Krasnykh V, Kashentseva EA, Blackwell JL, Reynolds PN, Li H, Parameshwar M, Vickers SM, Jaffee EM, Huibregtse K, Curiel DT, Dmitriev I, Improved gene transfer efficiency to primary and established human pancreatic carcinoma target cells via epidermal growth factor receptor and integrin-targeted adenoviral vectors. GENE THER 2001;8 (13):969-976 [PubMed]
Wesseling JG, Yamamoto M, Adachi Y, Bosma PJ, van Wijland M, Blackwell JL, Li H, Reynolds PN, Dmitriev I, Vickers SM, Huibregtse K, Curiel DT, Midkine and cyclooxygenase-2 promoters are promising for adenoviral vector gene delivery of pancreatic carcinoma. CANCER GENE THER 2001;8 (12):990-996 [PubMed]
de Vree JM, Ottenhoff R, Bosma PJ, Smith AJ, Aten J, Oude Elferink RP, Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. GASTROENTEROLOGY 2000;119 (6):1720-1730 [PubMed]
Paulusma CC, Kothe MJ, Bakker CT, Bosma PJ, van Bokhoven I, van Marle J, Bolder U, Tytgat GN, Oude Elferink RP, Zonal down-regulation and redistribution of the multidrug resistance protein 2 during bile duct ligation in rat liver. HEPATOLOGY 2000;31 (3):684-693 [PubMed]
de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, Oude Elferink RP, Hadchouel M, Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. P NATL ACAD SCI USA 1998;95 (1):282-287 [PubMed]
Gantla S, Bakker CT, Deocharan B, Thummala NR, Zweiner J, Sinaasappel M, Roy Chowdhury J, Bosma PJ, Roy Chowdhury N, Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. AM J HUM GENET 1998;62 (3):585-592 [PubMed]
Tada K, Chowdhury NR, Neufeld D, Bosma PJ, Heard M, Prasad VR, Chowdhury JR, Long-term reduction of serum bilirubin levels in Gunn rats by retroviral gene transfer in vivo. LIVER TRANSPL SURG 1998;4 (1):78-88 [PubMed]
Tada K, Roy-Chowdhury N, Prasad V, Kim BH, Manchikalapudi P, Fox IJ, van Duijvendijk P, Bosma PJ, Roy-Chowdhury J, Long-term amelioration of bilirubin glucuronidation defect in Gunn rats by transplanting genetically modified immortalized autologous hepatocytes. CELL TRANSPLANT 1998;7 (6):607-616 [PubMed]
Jansen PL, Bosma PJ, Bakker C, Lems SP, Slooff MJ, Haagsma EB, Persistent unconjugated hyperbilirubinemia after liver transplantation due to an abnormal bilirubin UDP-glucuronosyltransferase gene promoter sequence in the donor. J HEPATOL 1997;27 (1):1-5 [PubMed]
Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ, Tytgat GN, Borst P, Baas F, Oude Elferink RP, A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. HEPATOLOGY 1997;25 (6):1539-1542 [PubMed]
Seppen J, Tada K, Ottenhoff R, Sengupta K, Chowdhury NR, Chowdhury JR, Bosma PJ, Oude Elferink RP, Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase: correction of genetic deficiency and tumor formation. HUM GENE THER 1997;8 (1):27-36 [PubMed]
Arts J, Grimbergen J, Bosma PJ, Rahmsdorf HJ, Kooistra T, Role of c-Jun and proximal phorbol 12-myristate-13-acetate-(PMA)-responsive elements in the regulation of basal and PMA-stimulated plasminogen-activator inhibitor-1 gene expression in HepG2. EUR J BIOCHEM 1996;241 (2):393-402 [PubMed]
Kim BH, Takahashi M, Tada K, Bosma PJ, Roy-Chowdhury J, Roy-Chowdhury N, Cell and gene therapy for inherited deficiency of bilirubin glucuronidation. J PERINATOL 1996;16 (3 Part 2):S67-S72 [PubMed]
Paulusma CC, Bosma PJ, Zaman GJ, Bakker CT, Otter M, Scheffer GL, Scheper RJ, Borst P, Oude Elferink RP, Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. SCIENCE 1996;271 (5252):1126-1128 [PubMed]
Seppen J, Steenken E, Lindhout D, Bosma PJ, Elferink RP, A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP-glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler-Najjar type II. FEBS LETT 1996;390 (3):294-298 [PubMed]
Seppen J, Tada K, Hellwig S, Bakker CT, Prasad VR, Roy Chowdhury N, Roy Chowdhury J, Bosma PJ, Oude Elferink RP, Bilirubin glucuronidation by intact Gunn rat fibroblasts expressing bilirubin UDP-glucuronosyltransferase. BIOCHEM J 1996;314 ( Pt 2):477-483 [PubMed]
Vítek L, Bosma P, de Boer A, Jirsa M, Brodanová M, Kotal P, První prípad Criglerova-Najjarova syndromu v Ceské republice. CAS LEK CESK 1996;135 (4):114-116 [PubMed]
Bosma P, Chowdhury JR, Jansen PH, Genetic inheritance of Gilbert's syndrome. LANCET 1995;346 (8970):314-315 [PubMed]
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. NEW ENGL J MED 1995;333 (18):1171-1175 [PubMed]
Jansen PL, Bosma PJ, Chowdhury JR, Molecular biology of bilirubin metabolism. PROG LIVER DIS 1995;13:125-150 [PubMed]
Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL, Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J BIOL CHEM 1994;269 (27):17960-17964 [PubMed]
Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR, Jansen PL, Oude Elferink RP, Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J CLIN INVEST 1994;94 (6):2385-2391 [PubMed]
Bosma PJ, Goldhoorn B, Oude Elferink RP, Sinaasappel M, Oostra BA, Jansen PL, A mutation in bilirubin uridine 5'-diphosphate-glucuronosyltransferase isoform 1 causing Crigler-Najjar syndrome type II. GASTROENTEROLOGY 1993;105 (1):216-220 [PubMed]
van Es HH, Bout A, Liu J, Anderson L, Duncan AM, Bosma P, Oude Elferink R, Jansen PL, Chowdhury JR, Schurr E, Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37. CYTOGENET CELL GENET 1993;63 (2):114-116 [PubMed]
Bosma PJ, Chowdhury JR, Huang TJ, Lahiri P, Elferink RP, van Es HH, Lederstein M, Whitington PF, Jansen PL, Chowdhury NR, Mechanisms of inherited deficiencies of multiple UDP-glucuronosyltransferase isoforms in two patients with Crigler-Najjar syndrome, type I. FASEB J 1992;6 (10):2859-2863 [PubMed]
Bosma PJ, Chowdhury NR, Goldhoorn BG, Hofker MH, Oude Elferink RP, Jansen PL, Chowdhury JR, Sequence of exons and the flanking regions of human bilirubin-UDP-glucuronosyltransferase gene complex and identification of a genetic mutation in a patient with Crigler-Najjar syndrome, type I. HEPATOLOGY 1992;15 (5):941-947 [PubMed]
Bosma PJ, Kooistra T, Different induction of two plasminogen activator inhibitor 1 mRNA species by phorbol ester in human hepatoma cells. J BIOL CHEM 1991;266 (27):17845-17849 [PubMed]
Bosma PJ, Kooistra T, Siemieniak DR, Slightom JL, Further characterization of the 5'-flanking DNA of the gene encoding human plasminogen activator inhibitor-1. GENE 1991;100:261-266 [PubMed]
Kooistra T, Bosma PJ, Toet K, Cohen LH, Griffioen M, van den Berg E, le Clercq L, van Hinsbergh VW, Role of protein kinase C and cyclic adenosine monophosphate in the regulation of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and platelet-derived growth factor mRNA levels in human endothelial cells. Possible involvement of proto-oncogenes c-jun and c-fos. ARTERIOSCLER THROMB 1991;11 (4):1042-1052 [PubMed]
Kooistra T, Bosma PJ, Jespersen J, Kluft C, Studies on the mechanism of action of oral contraceptives with regard to fibrinolytic variables. AM J OBSTET GYNECOL 1990;163 (1 Part 2):404-413 [PubMed]
Kooistra T, Bosma PJ, Töns HA, van den Berg AP, Meyer P, Princen HM, Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. THROMB HAEMOSTASIS 1989;62 (2):723-728 [PubMed]
Bosma PJ, Rijken DC, Nieuwenhuizen W, Binding of tissue-type plasminogen activator to fibrinogen fragments. EUR J BIOCHEM 1988;172 (2):399-404 [PubMed]
Bosma PJ, van den Berg EA, Kooistra T, Siemieniak DR, Slightom JL, Human plasminogen activator inhibitor-1 gene. Promoter and structural gene nucleotide sequences. J BIOL CHEM 1988;263 (19):9129-9141 [PubMed]
Bron S, Bosma P, van Belkum M, Luxen E, Stability function in the Bacillus subtilis plasmid pTA 1060. PLASMID 1987;18 (1):8-15 [PubMed]
Key publications

Seppen J, Bosma P, Bilirubin, the Gold Within. CIRCULATION 2012;126 (22):2547-2549 [PubMed]
Sneitz N, Bakker CT, de Knegt RJ, Halley DJJ, Finel M, Bosma PJ, Crigler-Najjar syndrome in The Netherlands: Identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. HUM MUTAT 2010;31 (1):52-59 [PubMed]
Montenegro-Miranda P, ten Bloemendaal L, Kunne C, de Waart DR, Bosma PJ, Mycophenolate Mofetil Impairs Transduction of Single-Stranded Adeno-Associated Viral Vectors. HUM GENE THER 2011;22 (5):605-612 [PubMed]
van Dijk R, Mayayo-Peralta I, Aronson SJ, Kattentidt-Mouravieva AA, van der Mark VA, de Knegt R, Oruc N, Beuers U, Bosma PJ, Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia. J HEPATOL 2015;63 (6):1525-1529 [PubMed]
van Dijk R, Beuers U, Bosma PJ, Gene replacement therapy for genetic hepatocellular jaundice. CLIN REV ALLERG IMMU 2015;48 (2-3):243-253 [PubMed]


All Publications

Research programmes

Novel therapies for liver disease

Adeno Associated Virus (AAV) mediated liver directed gene therapy for inherited unconjugated hyperbilirubinemia in Crigler-Najjar syndrome type-1(CNS-1) , a model for inherited metabolic liver disorders.


Gene therapy

Unconjugated hyperbilirubinemia in CNS-1 is caused by deficiency for UGT1A1, a liver enzyme that catalyses the conjugation of bilirubin, an essential step for efficient biliary excretion. To investigate if gene therapy is a feasible treatment option, we injected 5 x10e12 gc/kg of rAAV encoding the human UGT1A1 gene into the portal vein of the relevant animal model for CN syndrome, the Gunn rat. A single injection proved sufficient for life-long correction of serum bilirubin levels. In addition we showed that immune responses towards the human UGT1A1 protein were prevented by restricting its expression to the hepatocytes using a liver specific promoter. In collaboration with GENETHON a novel vector has been developed that provides therapeutic efficiency with a dose shown to be safe. The GMP production of this vector is ongoing and upon the tox studies in 2015 and in the start of 2016, a phase 1 trial is planned for the end of 2016 beginning 2017.  Screening of CN patients that are intereted for this upcoming trial has started and will allow efficient inclusion of patient in this trial. In addition to CN other gene therapy for other inherited liver disorders like PFIC is developed.

Liver function and bile transport.

In vivo knock-down using AAV mediated expression of Sh constructs is used to reduce the expression of liver speicfic transporters to clarify their role in liver function and especially in bile formation. Efficient knock down of for instance  P4 type ATPases is used to clarify their role in biliary transport.    

Themes: Gastro-intestinal diseases and Metabolic Disorders

Faculty
Dr. P.J. Bosma

PhD Students
S.J. Aronson
R. van Dijk
J.A.G.M. Langedijk
Drs. J. Naik
X. Shi
Drs. S. Berlingieri (TIGEM, Napels, The Open University)

Others
L. ten Bloemendaal

Other research related activities
  • Membership of medical or scientific committee, Dutch Society for Gene Therapy (NVGT), secretary NVGCT
Current research funding
  • Alexion Pharmaceuticals, Inc.
  • Stichting Metakids
  • ZonMw