Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques

Matthew A Bochenek; Omid Veiseh; Arturo J Vegas; James J McGarrigle; Meirigeng Qi; Enza Marchese; Mustafa Omami; Joshua C Doloff; Joshua Mendoza-Elias; Mohammad Nourmohammadzadeh; Arshad Khan; Chun-Chieh Yeh; Yuan Xing; Douglas Isa; Sofia Ghani; Jie Li; Casey Landry; Andrew R Bader; Karsten Olejnik; Michael Chen; Jennifer Hollister-Lock; Yong Wang; Dale L Greiner; Gordon C Weir; Berit Løkensgard Strand; Anne Mari A Rokstad; Igor Lacik; Robert Langer; Daniel G Anderson; Jose Oberholzer

doi:10.1038/s41551-018-0275-1

Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques

Nat Biomed Eng. 2018 Nov;2(11):810-821. doi: 10.1038/s41551-018-0275-1. Epub 2018 Aug 13.

Authors

Matthew A Bochenek^#^{1

2

3

4

5}, Omid Veiseh^#^{3

4

5

6

7}, Arturo J Vegas^{3

4

5

8}, James J McGarrigle^{1

9}, Meirigeng Qi¹, Enza Marchese¹, Mustafa Omami¹, Joshua C Doloff^{3

4

5}, Joshua Mendoza-Elias^{1

2}, Mohammad Nourmohammadzadeh^{1

2

10}, Arshad Khan¹, Chun-Chieh Yeh¹, Yuan Xing^{1

2

11}, Douglas Isa^{1

9}, Sofia Ghani^{1

9}, Jie Li^{3

4

5

6

7}, Casey Landry^{3

4

5}, Andrew R Bader^{3

4

5}, Karsten Olejnik^{3

4

5

6

7}, Michael Chen^{3

4

5}, Jennifer Hollister-Lock¹², Yong Wang^{1

2

11}, Dale L Greiner¹³, Gordon C Weir¹², Berit Løkensgard Strand¹⁴, Anne Mari A Rokstad^{15

16}, Igor Lacik¹⁷, Robert Langer^{3

4

5

18

19

20}, Daniel G Anderson^{21

22

23

24

25

26}, Jose Oberholzer^{27

28

29}

Affiliations

¹ Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA.
² Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
³ David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
⁶ Sigilon Therapeutics, Inc., Cambridge, MA, USA.
⁷ Department of Bioengineering, Rice University, Houston, TX, USA.
⁸ Chemistry Department, Boston University, Boston, MA, USA.
⁹ CellTrans Inc., Chicago, IL, USA.
¹⁰ Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA.
¹¹ Department of Surgery and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
¹² Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA.
¹³ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
¹⁴ Department of Biotechnology and Food Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁵ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁶ Centre of Obesity, Clinic of Surgery, St. Olavs University Hospital, Trondheim, Norway.
¹⁷ Polymer Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
¹⁸ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
¹⁹ Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁰ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
²¹ David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²³ Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu.
²⁴ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. dgander@mit.edu.
²⁵ Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²⁶ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²⁷ Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. JO5JE@hscmail.mcc.virginia.edu.
²⁸ Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA. JO5JE@hscmail.mcc.virginia.edu.
²⁹ Department of Surgery and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. JO5JE@hscmail.mcc.virginia.edu.

^# Contributed equally.

Abstract

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type-I diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in diabetic rodent models; yet human patients transplanted with equivalent microsphere formulations have experienced only transient islet-graft function, owing to a vigorous foreign-body reaction (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing, in non-human primate (NHP) models, of seven alginate formulations that were efficacious in rodents, including three that led to transient islet-graft function in clinical trials. Although one month post-implantation all formulations elicited significant FBR and PFO, three chemically modified, immune-modulating alginate formulations elicited reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.

Abstract

Grants and funding