Implantable Microcapsules for Gene Therapy for Hemophilia

  • Gonzalo Hortelano
  • Tracy Stockley

Abstract

Hemophilia is an X-linked recessive disorder caused by the deficiency of blood clotting factors VIII (hemophilia A) or IX (hemophilia B), which affects about 1 in 5000 live male births (Furie and Furie 1988, Hedner and Davie, 1989). Patients with severe hemophilia suffer from lifelong episodes of spontaneous bleeding. Common presentations include hematomas, bleeding into the joints, and intracranial hemorrhage, with the latter being a common cause of death. Long-term complications include chronic hemophilie arthropathy and progressive degeneration of the joints, leading to severe crippling deformity. Typically, one or more joints are affected in patients before the age of 12. Hemophilia is a debilitating disease imposing a heavy burden on both patients and families.

Keywords

Cellulose Porosity Recombinate Adenosine Barium 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Al-Hendy A, Hortelano G, Tannenbaum GS, Chang PL. 1995. Correction of the growth defect in dwarf mice: A novel approach to somatic gene therapy. Human Gene Therapy 6:165–175.PubMedCrossRefGoogle Scholar
  2. Anderson WF. 1984. Prospects for human gene therapy. Science 226:401–409.PubMedCrossRefGoogle Scholar
  3. Anson DS, Hock RA, Smith KJ, Brownlee GG, Verma IM, and Miller AD. 1987. Towards gene therapy for hemophilia B. Molecular Biology in Medicine 4(1): 11–20.Google Scholar
  4. Awrey DE. 1993. Alginate-poly-1-lysine-alginate microcapsules. M.Sc. Thesis. McMaster University, Hamilton, Ontario, Canada.Google Scholar
  5. Awrey DE, Tse M, Hortelando G, Chang PL. 1996. Permeability of alginate microcapsules to secretory recombinant products. Biotechnology and Bioengineering 52:472–484.PubMedCrossRefGoogle Scholar
  6. Bastedo L, Sands MS, Hortelano G, Al-Hendy A, Chang PL. 1994. Partial correction of murine mucopolysaccharidosis VII with microencapsulated non-autologous recombinant fibroblasts. American Journal of Human Genetics 55(3):A210.Google Scholar
  7. Blau HM, Dhawan J, Pavlath GK. 1993. Myoblasts in pattern formation and gene therapy. Trends in Genetics 9:269–274.PubMedCrossRefGoogle Scholar
  8. Bowie KM. 1997. Differentiation of recombinant myoblasts in alginate microcapsules. M.Sc. Thesis. McMaster University, Hamilton, Ontario, Canada.Google Scholar
  9. Brinkhous KM, Davis PD, Graham JB, Dodds WJ. 1973. Expression and linkage of genes for X-linked hemophilia A and B in the dog. Blood 41:577–585.PubMedGoogle Scholar
  10. Brownlee GG. 1995. Prospects for gene therapy for hemophilia A and B. British Medical Bulletin 51(1):91–105.PubMedGoogle Scholar
  11. Campioni EG, Nobrega JN, Sefton MV 1998. HEMA/MMMA microcapsule implants in hemiparkinsonian rat brain: Biocompatibility assessment using [3H]PK11195 as a marker for gliosis. Biomaterials 19(7–9):829–37.CrossRefGoogle Scholar
  12. Carr-Brendel VE, Geller RL, Thomas TJ, Boggs DR, Yong SK, Crudele J, Martinson LA, Maryanor DA, Johnson RC, Brauker JH. 1997. Transplantation of cells in an immunoisolation device for gene therapy. Methods in Molecular Biology 63:373–387.PubMedGoogle Scholar
  13. Chang PL. 1995. Nonautologous somatic gene therapy. In: Somatic gene therapy, PL Chang, Ed. pp 203–233. Boca Raton, Florida: CRC Press.Google Scholar
  14. Chang PL, Hortelano G, Tse M, Awrey DE. 1994. Growth of recombinant fibroblasts in alginate microcapsules. Biotechnology and Bioengineering 43:925–933.PubMedCrossRefGoogle Scholar
  15. Chang PL, Shen N, Westcott AJ. 1993. Delivery of recombinant gene products with microencapsulated cells in vivo. Human Gene Therapy 4:433–440.PubMedCrossRefGoogle Scholar
  16. Cornetta K. 1992. Safety aspects of gene therapy. British Journal of Haematology 80(4):421–426.PubMedCrossRefGoogle Scholar
  17. Dwarki VJ, Belloni P, Nijjar T, et al. 1995. Gene therapy for hemophilia A: Production of therapeutic levels of human factor VIII in vivo in mice. Proceedings of the National Academy of Sciences USA 92:1023–1027.CrossRefGoogle Scholar
  18. Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. 1989. Canine hemophilia B resulting from a point mutation with unusual consequences. Proceedings of the National Academy of Sciences USA 86:10095–10099.CrossRefGoogle Scholar
  19. Fallaux, FJ, Hoeben RC, Briet E. 1995. State and prospects of gene therapy for the hemophilias. Thrombosis and Haemostasis 74(1):263–27Google Scholar
  20. Fang B, Eisensmith RC, Wang H, Kay MA, Cross RE, Landen CN, Gordon G, Bellinger DA, Read MS, Hu PC, Brinkhous KM, Woo SLC. 1995. Gene therapy for hemophilia B: Host immunosuppression prolongs the therapeutic effect of adenovirus-mediated factor IX expression. Human Gene Therapy 6(8): 1039–44.PubMedCrossRefGoogle Scholar
  21. Furie B, Furie BC. 1988. The molecular basis of blood coagulation. Cell 53:505–518.PubMedCrossRefGoogle Scholar
  22. Giles AR, Tinlin S, Greenwood R. 1982. A canine model of hemophilie (factor VIII:C deficiency) bleeding. Blood 60:727–730.PubMedGoogle Scholar
  23. Hedner U Davie EW. 1989. Introduction to hemostasis and the vitamin K-dependent coagulation factors. In: Scriver CR, Beaudet AL, Sly WS, et al (eds), The metabolic basis of inherited disease, vol II, ed 6. New York: McGraw-Hill, p 2107.Google Scholar
  24. Hoeben RC, Einerhand MPW, Briet E, van Ormondt H, Valerio D, van der Eb AJ. 1992. Toward gene therapy in haemophilia A: Retrovirus-mediated transfer of a factor VIII gene into murine haematopoietic progenitor cells. Thrombosis and Haemostasis 67(3):341–345.PubMedGoogle Scholar
  25. Hortelano G, Al-Hendy A, Ofosu FA, Chang PL. 1996. Delivery of human factor IX in mice by encapsulated recombinant myoblasts: A novel approach towards allogeneic gene therapy of hemophilia B. Blood 87(12):5095–5103.PubMedGoogle Scholar
  26. Hughes M, Vassilakos A, Andrews DW, Hortelano G, Belmont JM, Chang PL. 1994. Delivery of a secretable adenosine deaminase through microcapsules: A novel approach to somatic gene therapy. Human Gene Therapy, 5(12): 1445–1455.PubMedCrossRefGoogle Scholar
  27. Kay MA, Rothenberg S, Landen CN, Bellinger DA, Leland F, Toman C, M. et al. 1993. In vivo gene therapy for hemophilia B: Sustained partial correction in factor IX deficient dogs. Science 262:117–119.PubMedCrossRefGoogle Scholar
  28. Kingdon HS. 1997. Gene therapy avoidance: Implanting allogeneic cells within a device. First International Symposium on Gene Therapy for Hemophilia. September 4–6, 1997, Chapel Hill, NC, USA, p. 17.Google Scholar
  29. Liu H, Ofosu FA, Chang PL. 1993. Expression of human factor IX by microencapsulated recombinant fibroblasts. Human Gene Therapy 4:291–301.PubMedCrossRefGoogle Scholar
  30. Meulien P. 1990. XIX International Congress of the World Federation of Hemophilia, Washington, DC, USA, p. 70.Google Scholar
  31. Nelson DM, Metzger ME, Donahue RE, Morgan RA. 1997. In vivo retrovirus-mediated gene transfer into multiple hematopoietic lineages in rabbits without preconditioning. Human Gene Therapy 8(6):747–754.PubMedCrossRefGoogle Scholar
  32. O’Shea G, Sun A. 1986. Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice. Diabetes 35:943–946.PubMedCrossRefGoogle Scholar
  33. Peirone MA, Delany K, Kwiecin J, Fletch A, Chang PL. 1997a. Delivery of recombinant gene products to canines with non-autologous microencapsulated cells. Manuscript submitted.Google Scholar
  34. Peirone MA, Fitzgerald P, Chang PL. 1997b. Delivery of recombinant gene product to canines using solid core calcium-alginate gel spheres. Manuscript submitted.Google Scholar
  35. Pelegrin M, Marin M, Noel D, Del Rio M, Sailer R, Stange J, Mitzner S, Gunzburg WH, Piechaczyk M. 1998. Systemic long-term delivery of antibodies in immunocompetent animals using cellulose sulphate capsules containing antibody-producing cells. Gene Therapy 5(6):828–34.PubMedCrossRefGoogle Scholar
  36. Pijnappels MIM, Briet E, van der Zwet GT, Huisden R, van Tilburg NH, Eulderink F. 1986. Evaluation of the cuticle bleeding time in canine haemophilia A. Thrombosis and Haemostasis 55:70–73.PubMedGoogle Scholar
  37. Roberts, HR, Eberst ME. 1993. Current management of hemophilia B. Hematology/Oncology Clinics of North America 7(6): 1269–1279.PubMedGoogle Scholar
  38. Roman M, Axelrod JH, Dai Y, Naviaux RK, Friedmann T, Verma IM. 1992. Circulating human or canine factor IX from retrovirally transduced primary myoblasts and established myoblast cell lines grafted into murine skeletal muscle. Somatic and Cellular Molecular Genetics 18(3):247–258.CrossRefGoogle Scholar
  39. Smith TA, White BD, Gardner JM, Kaleko M, McClelland A. 1996. Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector. Gene Therapy 3(6):496–502.PubMedGoogle Scholar
  40. Snyder RO, Miao CH, Patijn GA. et al. 1997. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nature Genetics 16:270–276.PubMedCrossRefGoogle Scholar
  41. Tinlin S, Webster S, Giles AR. 1993. The development of homologous (canine/anti canine) antibodies in dogs with haemophilia. A (factor VIII deficiency): A tenyear longitudinal study. Thrombosis and Haemostasis 69(1):21–24.Google Scholar
  42. Uludag H, Sefton MV. 1993. Metabolic activity and proliferation of CHO cells in hydroxyethyl methacrylatemethyl methacrylate (HEMA-MMA) microcapsules. Cell Transplantation 1993 Mar–Apr;2(2): 175–82.PubMedGoogle Scholar
  43. White G, Shapiro A, Ragni M, Garzone P, Goodfellow J, Tubridy K, Courter S. 1998. Clinical evaluation of recombinant factor IX. Seminars in Hematology 35(2 Suppl 2):33–8.Google Scholar
  44. Yao S, Kurachi K. 1992. Expression of human factor IX in mice after injection of genetically modified myoblasts. Proceedings of the National Academy of Sciences USA 89:3357–3361.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Gonzalo Hortelano
  • Tracy Stockley

There are no affiliations available

Personalised recommendations