Cell Replacement Therapy: The Rationale for Encapsulated Porcine Islet Transplantation

Among the problems posed by chronic diseases today, one of the most daunting is that posed by diabetes mellitus, which is a very significant public health problem resulting in substantial morbidity and mortality (American Diabetes Association, 2011). With the increasing life-expectancy of the world's population, increasing exposure to environmental trigger factors, the rising incidence of obesity, and lifestyle changes such as unhealthy diets and decreased physical activity, the prevalence of diabetes has risen dramatically over recent years and is now reaching epidemic proportions globally. This rapid increase is a significant cause for concern, with an additional 7 million diagnosed each year (International Diabetes Federation, 2011). Diabetes is now the fourth or fifth leading cause of death in most developed countries (International Diabetes Federation 2000). Globally, it is estimated that more than 200 million adults now have diabetes and this number is expected to increase alarmingly in the coming decades. By the year 2025, it is estimated that almost 333 million people will have the disease (International Diabetes Federation 2006). Type 1 (insulin-dependent) diabetes accounts for 5% to 10% of all diagnosed cases. In 2003, approximately 4.9 million people (0.09% of the world’s population) were estimated to have type 1 disease, with Europe having the highest number of sufferers (1.27 million) followed by North America (1.04 million) and Southeast Asia (0.91 million). The highest prevalence of type 1 diabetes was in North America (0.25%) followed by Europe (0.19%) (International Diabetes Federation 2006). In 2002, there were an estimated 0.9 to 1.2 million people with type 1 diabetes in the USA (American Diabetes Association 2006). The incidence in recent years may have accelerated alarmingly as shown in a recent study from Finland where the rate increased from 31.4 per 100,000 per year in 1980 to 64.2 per 100,000 per year in 2005 (Harjutsalo et al, 2008). In New Zealand, the incidence of type 1 diabetes has doubled in the last 15 years, reflecting international trends. In 2003, the estimated prevalence of type 1 disease among the population aged <25 years was 0.18%, with the total number of sufferers in this age range numbering 2540. The majority, 85% (2158 people), were of European descent, while 9% were Maori, 2.9% were Pacific peoples, and 3.0% were Asian (Wu et al. 2005). Although the life-expectancy of patients with type 1 (insulin-dependent) diabetes mellitus has vastly improved since the introduction of insulin, the ability of insulin injections to

[1]  Gorka Orive,et al.  Microcapsules and microcarriers for in situ cell delivery. , 2010, Advanced drug delivery reviews.

[2]  J. Platt Prospects for xenotransplantation , 1999, Pediatric transplantation.

[3]  Donald W. Fink FDA Regulation of Stem Cell–Based Products , 2009, Science.

[4]  Jaakko Tuomilehto,et al.  Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study , 2008, The Lancet.

[5]  Shinya Yamanaka,et al.  Immunogenicity of induced pluripotent stem cells. , 2011, Circulation research.

[6]  P. Brunetti,et al.  Transplantation of Pancreatic Islets Contained in Minimal Volume Microcapsules in Diabetic High Mammalians , 1999, Annals of the New York Academy of Sciences.

[7]  R. Elliott Towards xenotransplantation of pig islets in the clinic. , 2011, Current opinion in organ transplantation.

[8]  Denis Dufrane,et al.  Alginate Macroencapsulation of Pig Islets Allows Correction of Streptozotocin-Induced Diabetes in Primates up to 6 Months Without Immunosuppression , 2010, Transplantation.

[9]  Alan W Moore,et al.  NO EVIDENCE FOR INFECTION OF HUMAN CELLS WITH PORCINE ENDOGENOUS RETROVIRUS (PERV) AFTER EXPOSURE TO PORCINE FETAL NEURONAL CELLS1 , 2000, Transplantation.

[10]  B. Lapin,et al.  Porcine endogenous retrovirus (PERV) was not transmitted from transplanted porcine endothelial cells to baboons in vivo , 1998, Transplant international : official journal of the European Society for Organ Transplantation.

[11]  E. Setter,et al.  A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha-galactosyl natural antibody , 1995, The Journal of experimental medicine.

[12]  W. Heneine,et al.  No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts , 1998, The Lancet.

[13]  J. Denner Porcine endogenous retroviruses (PERVs) and xenotransplantation: screening for transmission in several clinical trials and in experimental models using non-human primates. , 2002, Annals of transplantation.

[14]  Gustav Steinhoff,et al.  Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells , 1998, The Lancet.

[15]  D. Lamb Animal-to-human Transplants: the Ethics of Xenotransplantation , 1997 .

[16]  J. Nyman,et al.  A health‐economic analysis of porcine islet xenotransplantation , 2010, Xenotransplantation.

[17]  Eduardo Bracho-Blanchet,et al.  Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. , 2005, European journal of endocrinology.

[18]  A. Vasconcellos,et al.  Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. , 2005, Transplantation proceedings.

[19]  J. Logan Prospects for xenotransplantation. , 2000, Current opinion in immunology.

[20]  R. Pierson,et al.  The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes-- executive summary. , 2009, Xenotransplantation.

[21]  L. Scobie,et al.  Porcine Endogenous Retrovirus (PERV) and its Transmission Characteristics: A Study of the New Zealand Designated Pathogen-Free Herd , 2008, Cell transplantation.

[22]  Angelika Berg,et al.  Sensitive and specific immunological detection methods for porcine endogenous retroviruses applicable to experimental
and clinical xenotransplantation , 2001, Xenotransplantation.

[23]  J. Denner,et al.  Absence of transmission of potentially xenotic viruses in a prospective pig to primate islet xenotransplantation study , 2008, Journal of medical virology.

[24]  R. Calafiore Perspectives in Pancreatic and Islet Cell Transplantation for the Therapy of IDDM , 1997, Diabetes Care.

[25]  E. Opara,et al.  Immunoisolation techniques for islet cell transplantation , 2002, Expert opinion on biological therapy.

[26]  G. Andersson,et al.  Porcine Endogenous Retrovirus Transmission Characteristics of an Inbred Herd of Miniature Swine , 2002, Journal of Virology.

[27]  G. Korbutt,et al.  Testicular sertoli cells protect islet beta-cells from autoimmune destruction in NOD mice by a transforming growth factor-beta1-dependent mechanism. , 2000, Diabetes.

[28]  C. Buchanan,et al.  Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation , 2007, Xenotransplantation.

[29]  W. Heneine,et al.  Evidence of porcine endogenous retroviruses in porcine factor VIII and evaluation of transmission to recipients with hemophilia. , 2001, The Journal of infectious diseases.

[30]  A. Sun,et al.  Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. , 1996, The Journal of clinical investigation.

[31]  W. Heneine,et al.  Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. , 1999, Science.

[32]  L. Martignat,et al.  Long-term follow-up failed to detect in vitro transmission of full-length porcine endogenous retroviruses from specific pathogen-free pig islets to human cells , 2001, Diabetologia.

[33]  U. Christians,et al.  Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates , 2006, Nature Medicine.

[34]  A. Monaco,et al.  Novel Delivery of Pancreatic Islet Cells to Treat Insulin-Dependent Diabetes Mellitus , 1995, Clinical pharmacokinetics.

[35]  R. Kurth,et al.  Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells. , 2003, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[36]  P. Brunetti,et al.  Standard technical procedures for microencapsulation of human islets for graft into nonimmunosuppressed patients with type 1 diabetes mellitus. , 2006, Transplantation proceedings.

[37]  G. Boiteau,et al.  J. Virol. Methods , 1996, Journal of Virological Methods.

[38]  G. Weir,et al.  Scientific and Political Impediments to Successful Islet Transplantation , 1997, Diabetes.

[39]  R. Elliott,et al.  No Evidence of Infection with Porcine Endogenous Retrovirus in Recipients of Encapsulated Porcine Islet Xenografts , 2000, Cell transplantation.

[40]  B. Torbett,et al.  Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice , 2000, Nature.

[41]  R. Weiss,et al.  No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys , 1998, The Lancet.

[42]  A. Karlas,et al.  Monitoring for Presence of Potentially Xenotic Viruses in Recipients of Pig Islet Xenotransplantation , 2004, Journal of Clinical Microbiology.

[43]  M. Goosen,et al.  Injectable microencapsulated islet cells as a bioartificial pancreas , 1984, Applied biochemistry and biotechnology.

[44]  A. Sun,et al.  Porcine pancreatic islets: isolation, microencapsulation, and xenotransplantation. , 2008, Artificial organs.

[45]  S J M Skinner,et al.  Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma , 2009, Journal of neural engineering.

[46]  O. Garkavenko,et al.  Multiplex high resolution melting assay for estimation of Porcine Endogenous Retrovirus (PERV) relative gene dosage in pigs and detection of PERV infection in xenograft recipients. , 2011, Journal of virological methods.