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Novel Therapeutic Options for X-Linked Agammaglobulinemia

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Agammaglobulinemia

Part of the book series: Rare Diseases of the Immune System ((RDIS,volume 4))

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Abstract

Current treatment for XLA includes subcutaneous or intravenous immunoglobulin (IVIG) infusion and prompt antibiotic administration to combat infections, which are only partially effective and not curative. Therefore, novel treatment options including bone marrow transplantation and gene therapy are being developed. For gene therapy, autologous stem cells in which lentiviruses are used to correct the BTK gene deficiency are in preclinical stage. Alternative approaches, using antisense oligonucleotides for BTK splice site mutations and gene-editing approaches, are creative solutions to correct and repair BTK gene defects ex vivo.

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References

  1. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL et al (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288(5466):669–672

    Article  CAS  PubMed  Google Scholar 

  2. Fischer A (2004) Human primary immunodeficiency diseases: a perspective. Nat Immunol 5(1):23–30

    Article  CAS  PubMed  Google Scholar 

  3. Gaspar HB, Thrasher AJ (2005) Gene therapy for severe combined immunodeficiencies. Expert Opin Biol Ther 5(9):1175–1182

    Article  CAS  PubMed  Google Scholar 

  4. Aoki Y, Isselbacher KJ, Cherayil BJ, Pillai S (1994) Tyrosine phosphorylation of Blk and Fyn Src homology 2 domain-binding proteins occurs in response to antigen-receptor ligation in B cells and constitutively in pre-B cells. Proc Natl Acad Sci U S A 91(10):4204–4208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Conley ME, Fitch-Hilgenberg ME, Cleveland JL, Parolini O, Rohrer J (1994) Screening of genomic DNA to identify mutations in the gene for Bruton’s tyrosine kinase. Hum Mol Genet 3(10):1751–1756

    Article  CAS  PubMed  Google Scholar 

  6. Conley ME, Rohrer J, Rapalus L, Boylin EC, Minegishi Y (2000) Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol Rev 178:75–90

    Article  CAS  PubMed  Google Scholar 

  7. de Weers M, Brouns GS, Hinshelwood S, Kinnon C, Schuurman RK, Hendriks RW, Borst J (1994) B-cell antigen receptor stimulation activates the human Bruton’s tyrosine kinase, which is deficient in X-linked agammaglobulinemia. J Biol Chem 269(39):23857–23860

    PubMed  Google Scholar 

  8. de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, Hendriks RW (1993) The Bruton’s tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 23(12):3109–3114

    Article  PubMed  Google Scholar 

  9. Hendriks RW, de Bruijn MF, Maas A, Dingjan GM, Karis A, Grosveld F (1996) Inactivation of Btk by insertion of lacZ reveals defects in B cell development only past the pre-B cell stage. Embo J 15(18):4862–4872

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Middendorp S, Dingjan GM, Hendriks RW (2002) Impaired precursor B cell differentiation in Bruton’s tyrosine kinase-deficient mice. J Immunol 168(6):2695–2703

    Article  CAS  PubMed  Google Scholar 

  11. Spaargaren M, Beuling E, Rurup ML, Meijer HP, Klok MD, Middendorp S, Hendriks RW, Pals S (2003) The B-cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med 198(10):1539–1550

    Google Scholar 

  12. Middendorp S, Zijlstra AJ, Kersseboom R, Dingjan GM, Jumaa H, Hendriks RW (2005) Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity. Blood 105(1):259–265

    Article  CAS  PubMed  Google Scholar 

  13. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG et al (1993) Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science 261(5119):358–361

    Article  CAS  PubMed  Google Scholar 

  14. Kerner JD, Appleby MW, Mohr RN, Chien S, Rawlings DJ, Maliszewski CR, Witte ON, Perlmutter RM (1995) Impaired expansion of mouse B cell progenitors lacking Btk. Immunity 3(3):301–312

    Article  CAS  PubMed  Google Scholar 

  15. Khan WN, Alt FW, Gerstein RM, Malynn BA, Larsson I, Rathbun G, Davidson L, Muller S, Kantor AB, Herzenberg LA et al (1995) Defective B cell development and function in Btk-deficient mice. Immunity 3(3):283–299

    Article  CAS  PubMed  Google Scholar 

  16. Wicker LS, Scher I (1986) X-linked immune deficiency (xid) of CBA/N mice. Curr Top Microbiol Immunol 124:87–101

    CAS  PubMed  Google Scholar 

  17. Witkowski J, Forrester LM, Ansell JD, Micklem HS (1985) Influence of the xid mutation on B lymphocyte development in adult mice. Adv Exp Med Biol 186:47–55

    CAS  PubMed  Google Scholar 

  18. Conley ME, Howard V (2002) Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr 141(4):566–571

    Article  PubMed  Google Scholar 

  19. Conley ME, Puck JM (1988) Carrier detection in typical and atypical X-linked agammaglobulinemia. J Pediatr 112(5):688–694

    Article  CAS  PubMed  Google Scholar 

  20. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, Conley ME, Cunningham-Rundles C, Ochs HD (2006) X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 85(4):193–202

    Article  Google Scholar 

  21. Fiorini M, Franceschini R, Soresina A, Schumacher RF, Ugazio AG, Rossi P, Plebani A, Notarangelo LD (2004) BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia. Hum Mutat 23(3):286

    Article  PubMed  Google Scholar 

  22. Bayrakci B, Ersoy F, Sanal O, Kilic S, Metin A, Tezcan I (2005) The efficacy of immunoglobulin replacement therapy in the long-term follow-up of the B-cell deficiencies (XLA, HIM, CVID). Turk J Pediatr 47(3):239–246

    PubMed  Google Scholar 

  23. Kanegane H, Futatani T, Wang Y, Nomura K, Shinozaki K, Matsukura H, Kubota T, Tsukada S, Miyawaki T (2001) Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. J Allergy Clin Immunol 108(6):1012–1020

    Article  CAS  PubMed  Google Scholar 

  24. Conley ME, Brown P, Pickard AR, Buckley RH, Miller DS, Raskind WH, Singer JW, Fialkow PJ (1986) Expression of the gene defect in X-linked agammaglobulinemia. N Engl J Med 315(9):564–567

    Article  CAS  PubMed  Google Scholar 

  25. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, Cazzola G, Consolini R, De Mattia D, Dell’Erba G et al (2002) Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 104(3):221–230

    Article  CAS  PubMed  Google Scholar 

  26. Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, Weerkamp F, Karlsson S, Wagemaker G, Williams DA (2004) Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 9(1):5–13

    Article  CAS  PubMed  Google Scholar 

  27. Howard V, Myers LA, Williams DA, Wheeler G, Turner EV, Cunningham JM, Conley ME (2003) Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol 107(2):98–102

    Article  CAS  PubMed  Google Scholar 

  28. Aiuti A (2002) Advances in gene therapy for ADA-deficient SCID. Curr Opin Mol Ther 4(5):515–522

    CAS  PubMed  Google Scholar 

  29. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360(5):447–458

    Article  CAS  PubMed  Google Scholar 

  30. Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M (2010) 20 years of gene therapy for SCID. Nat Immunol 11(6):457–460

    Article  CAS  PubMed  Google Scholar 

  31. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M et al (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348(3):255–256

    Article  PubMed  Google Scholar 

  32. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302(5644):415–419

    Article  CAS  PubMed  Google Scholar 

  33. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K et al (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118(9):3132–3142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Blank U, Karlsson G, Karlsson S (2008) Signaling pathways governing stem-cell fate. Blood 111(2):492–503

    Article  CAS  PubMed  Google Scholar 

  35. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M et al (2007) Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 117(8):2233–2240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Thrasher AJ, Gaspar HB, Baum C, Modlich U, Schambach A, Candotti F, Otsu M, Sorrentino B, Scobie L, Cameron E et al (2006) Gene therapy: X-SCID transgene leukaemogenicity. Nature 443(7109):E5–E6; discussion E-7

    Article  CAS  Google Scholar 

  37. Baum C (2007) Insertional mutagenesis in gene therapy and stem cell biology. Curr Opin Hematol 14(4):337–342

    Article  CAS  PubMed  Google Scholar 

  38. Staal FJ, Pike-Overzet K, Ng YY, van Dongen JJ (2008) Sola dosis facit venenum. Leukemia in gene therapy trials: a question of vectors, inserts and dosage? Leukemia 22(10):1849–1852

    Article  CAS  PubMed  Google Scholar 

  39. Ciuffi A (2008) Mechanisms governing lentivirus integration site selection. Curr Gene Ther 8(6):419–429

    Article  CAS  PubMed  Google Scholar 

  40. Yu PW, Tabuchi RS, Kato RM, Astrakhan A, Humblet-Baron S, Kipp K, Chae K, Ellmeier W, Witte ON, Rawlings DJ (2004) Sustained correction of B cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer. Blood

    Google Scholar 

  41. Ellmeier W, Jung S, Sunshine MJ, Hatam F, Xu Y, Baltimore D, Mano H, Littman DR (2000) Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. J Exp Med 192(11):1611–1624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Kerns HM, Ryu BY, Stirling BV, Sather BD, Astrakhan A, Humblet-Baron S, Liggitt D, Rawlings DJ (2010) B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood 115(11):2146–2155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Moreau T, Barlogis V, Bardin F, Nunes JA, Calmels B, Chabannon C, Tonnelle C (2008) Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. Gene Ther 15(12):942–952

    Article  CAS  PubMed  Google Scholar 

  44. Ng YY, Baert MR, Pike-Overzet K, Rodijk M, Brugman MH, Schambach A, Baum C, Hendriks RW, van Dongen JJ, Staal FJ (2010) Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK. Leukemia 24(9):1617–1630

    Article  CAS  PubMed  Google Scholar 

  45. Scher I, Ahmed A, Strong DM, Steinberg AD, Paul WE (1975) X-linked B-lymphocyte immune defect in CBA/HN mice. I. Studies of the function and composition of spleen cells. J Exp Med 141(4):788–803

    CAS  PubMed  Google Scholar 

  46. Scher I, Steinberg AD, Berning AK, Paul WE (1975) X-linked B-lymphocyte immune defect in CBA/N mice. II. Studies of the mechanisms underlying the immune defect. J Exp Med 142(3):637–650

    Article  CAS  PubMed  Google Scholar 

  47. Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJ, Staal FJ (2007) New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 15(11):1910–1916

    Article  CAS  PubMed  Google Scholar 

  48. Berglof A, Turunen JJ, Gissberg O, Bestas B, Blomberg KE, Smith CI (2013) Agammaglobulinemia: causative mutations and their implications for novel therapies. Expert Rev Clin Immunol 9(12):1205–1221

    Article  PubMed  Google Scholar 

  49. Bestas B, Moreno PM, Blomberg KE, Mohammad DK, Saleh AF, Sutlu T, Nordin JZ, Guterstam P, Gustafsson MO, Kharazi S et al (2014) Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model. J Clin Invest 124(9):4067–4081

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Hoffman EP, Connor EM (2013) Orphan drug development in muscular dystrophy: update on two large clinical trials of dystrophin rescue therapies. Discov Med 16(89):233–239

    PubMed  Google Scholar 

  51. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M (2012) The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 119(11):2590–2594

    Article  PubMed  Google Scholar 

  52. Harrison C (2012) Trial watch: BTK inhibitor shows positive results in B cell malignancies. Nat Rev Drug Discov 11(2):96

    Article  CAS  PubMed  Google Scholar 

  53. Hendriks RW (2011) Drug discovery: new Btk inhibitor holds promise. Nat Chem Biol 7(1):4–5

    Article  CAS  PubMed  Google Scholar 

  54. Shinohara M, Chang BY, Buggy JJ, Nagai Y, Kodama T, Asahara H, Takayanagi H (2014) The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. Bone 60:8–15

    Article  CAS  PubMed  Google Scholar 

  55. van den Akker E, van Dijk TB, Schmidt U, Felida L, Beug H, Lowenberg B, von Lindern M (2004) The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity. Biol Chem 385(5):409–413

    Article  PubMed  Google Scholar 

  56. Wodarz D, Garg N, Komarova NL, Benjamini O, Keating MJ, Wierda WG, Kantarjian H, James D, O’Brien S, Burger JA (2014) Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood 123(26):4132–4135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Genovese P, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC et al (2014) Targeted genome editing in human repopulating haematopoietic stem cells. Nature 510(7504):235–240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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  1. Department of Immunohematology and Blood Bank, L3-35, Leiden University Medical Center, Albinusdreef 2, 9600, Leiden, 2300 RC, The Netherlands

    Frank J. T. Staal

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Correspondence to Frank J. T. Staal .

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  1. Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili of Brescia, Brescia, Italy

    Alessandro Plebani

  2. Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili of Brescia, Brescia, Italy

    Vassilios Lougaris

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Staal, F.J.T. (2015). Novel Therapeutic Options for X-Linked Agammaglobulinemia. In: Plebani, A., Lougaris, V. (eds) Agammaglobulinemia. Rare Diseases of the Immune System, vol 4. Springer, Cham. https://doi.org/10.1007/978-3-319-22714-6_6

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  • DOI: https://doi.org/10.1007/978-3-319-22714-6_6

  • Publisher Name: Springer, Cham

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