Type 1 Diabetes

Type 1 Diabetes

Type 1 diabetes is a fatal disease caused by autoimmune destruction of the insulin-producing beta cells within the islets of Langerhans located in the pancreas. Lack of insulin prevents cellular uptake and utilization of glucose resulting in persistent elevations of blood glucose that, along with other metabolic abnormalities, are lethal within weeks to months. Following the discovery of the hormone insulin a century ago, daily administration of exogenous insulin has made it possible to manage T1D for decades-long periods of time although serious, and often fatal, complications of the heart, blood vessels, kidneys, nerves, and eyes develop in most patients. Statistics show life spans are shortened by more than twenty years.  Approximately 3 million Americans have Type 1 diabetes; the worldwide number is estimated to be in the tens of millions.

A major focus of research and development at XOStem is the treatment of Type 1 diabetes by the transplantation of single islet encapsulations in a biocompatible alginate with exosomes to safely house insulin producing cells. The encapsulated islets are implanted into the peritoneal cavity where they can remain in place for long periods of time (8years in previous research) responding the glucose and secreting insulin. The encapsulated islets are transgenic swine-derived beta cells, induced to produce insulin when exposed to elevated glucose levels. Our islet encapsulation with exosomes is designed and fabricated to provide immunologic protection and nutrition/oxygenation to the insulin-producing cells contained within it.

The XOStem encapsulation is designed to allow for the insulin-producing cells to act independently without additional treatments, potentially prolonging its usefulness for an extended period of years. The previous studies have shown to total eliminate hypoglycemic events which makes it possible to eliminate the frequent glucose monitoring and parenteral or inhaled insulin administration currently required by all Type 1 diabetes patients. The potential impact of this technology on the management of Type 1 diabetes can be prodigious.

Application of Exosomes in Type I Diabetes Research

Exosome research at XOStem is expected to significantly contribute to the development of this proprietary technology, which was conceived and developed over the past two-decades by members of our Scientific Research Team.

The insulin producing cells will be human or xenograft islets from swine, immunologically isolated from attack with a proprietary hydrogel protective barrier. Other possible candidate insulin-producing cells include mesenchymal stem cells induced to produce insulin, and even to clump into what is termed “organoids”, morphologically similar to how islet cells exist in clusters in vivo.

In studies, exosomes have already proven of value as adjuvants that enhance vascularization and tissue growth of implanted biocompatible devices, and as a contributing element to hydrogel composition that contributes to promoting a beneficial local anti-inflammatory milieu for transplanted cells and islets.

Selected References Co-Authored by XOStem Scientific Board Members

Smink AM, de Haan BJ, Lakey JRT, de Vos P. Polymer scaffolds for pancreatic islet transplantation - Progress and challenges. Am J Transplant. 2018 Sep;18(9):2113-2119. doi: 10.1111/ajt.14942. Epub 2018 Jun 13. https://pubmed.ncbi.nlm.nih.gov/29790274/

Mohammadi M, Luong JC, Rodriguez SM, Cao R, Wheeler AE, Lau H, Li S, Shabestari SK, Chadarevian JP, Alexander M, de Vos P, Zhao W, Lakey JRT. Controlled Release of Stem Cell Secretome Attenuates Inflammatory Response against Implanted Biomaterials. Adv Healthc Mater. 2020 Jun;9(12):e1901874. doi: 10.1002/adhm.201901874. Epub 2020 May 18. https://pubmed.ncbi.nlm.nih.gov/32419390/

Najdahmadi A, Smink AM, de Vos P, Lakey JRT, Botvinick E. Non-Invasive Monitoring of Oxygen Tension and Oxygen Transport Inside Subcutaneous Devices After H2S Treatment. Cell Transplant. 2020 Jan-Dec;29:963689719893936. doi: 10.1177/0963689719893936.

Hu S, Kuwabara R, Navarro Chica CE, Smink AM, Koster T, Medina JD, de Haan BJ, Beukema M, Lakey JRT, García AJ, de Vos P. Toll-like receptor 2-modulating pectin-polymers in alginate-based microcapsules attenuate immune responses and support islet-xenograft survival.
Biomaterials. 2021 Jan;266:120460. doi: 10.1016/j.biomaterials.2020.120460. Epub 2020 Oct 19.

Lau H, Corrales N, Rodriguez S, Luong C, Mohammadi M, Khosrawipour V, Li S, Alexander M, de Vos P, Lakey JRT. Dose-dependent effects of necrostatin-1 supplementation to tissue culture media of young porcine islets. PLoS One. 2020 Dec 7;15(12):e0243506. Doi: 10.1371/journal.pone.0243506. eCollections 2020.

Medina JD, Alexander M, Hunckler MD, Fernández-Yagüe MA, Coronel MM, Smink AM, Lakey JR, de Vos P, García AJ. Functionalization of Alginate with Extracellular Matrix Peptides Enhances Viability and Function of Encapsulated Porcine Islets.
Adv Healthc Mater. 2020 May;9(9):e2000102. doi: 10.1002/adhm.202000102. Epub 2020 Apr 7. https://pubmed.ncbi.nlm.nih.gov/32255552/

Krishnan R, Ko D, Foster CE 3rd, Liu W, Smink AM, de Haan B, De Vos P, Lakey JR. Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials. Methods Mol Biol. 2017;1479:305-333. doi: 10.1007/978-1-4939-6364-5_24.

Kuwabara R, Hu S, Smink AM, Orive G, Lakey JRT, de Vos P. Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts. Tissue Eng Part B Rev. 2021 Feb 24. doi: 10.1089/ten.TEB.2020.0326. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33397201/

Smink AM, Najdahmadi A, Alexander M, Li S, Rodriquez S, van Goor H, Hillebrands JL, Botvinick E, Lakey JRT, Vos P. The Effect of a Fast-Releasing Hydrogen Sulfide Donor on Vascularization of Subcutaneous Scaffolds in Immunocompetent and Immunocompromised Mice. Biomolecules. 2020 May 6;10(5):722. doi: 10.3390/biom100507 https://pubmed.ncbi.nlm.nih.gov/32384680/

Wu C, Pan LL, Luo Y, Niu W, Fang X, Liang W, Li J, Li H, Pan X, Yang G, Chen W, Zhang H, Lakey JRT, Agerberth B, de Vos P. Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction. Sun J.Mol Nutr Food Res. 2019 Nov;63(21):e1900307. doi: 10.1002/mnfr.201900307. Epub 2019 Sep 5. https://pubmed.ncbi.nlm.nih.gov/31423661/

Lau H, Corrales N, Alexander M, Mohammadi MR, Li S, Smink AM, de Vos P, Lakey JRT. Necrostatin-1 supplementation enhances young porcine islet maturation and in vitro function.
Xenotransplantation. 2020 Jan;27(1):e12555. doi: 10.1111/xen.12555. Epub 2019 Sep 18.

Cao R, Avgoustiniatos E, Papas K, de Vos P, Lakey JRT. Mathematical predictions of oxygen availability in micro- and macro-encapsulated human and porcine pancreatic islets.
J Biomed Mater Res B Appl Biomater. 2020 Feb;108(2):343-352. doi: 10.1002/jbm.b.34393. Epub https://pubmed.ncbi.nlm.nih.gov/31013399/

Wu C, Pan LL, Niu W, Fang X, Liang W, Li J, Li H, Pan X, Chen W, Zhang H, Lakey JRT, Agerberth B, de Vos P. Modulation of Gut Microbiota by Low Methoxyl Pectin Attenuates Type 1 Diabetes in Non-obese Diabetic Mice. Sun J.Front Immunol. 2019 Jul 30;10:1733. doi: 10.3389/fimmu.2019.01733. eCollection 2019.

Sremac M, Lei J, Penson MFE, Schuetz C, Lakey JRT, Papas KK, Varde PS, Hering B, de Vos P, Brauns T, Markmann J, Poznansky MC. Preliminary Studies of the Impact of CXCL12 on the Foreign Body Reaction to Pancreatic Islets Microencapsulated in Alginate in Nonhuman Primates.
Transplant Direct. 2019 Apr 15;5(5):e447. doi: 10.1097/TXD.0000000000000890. eCollection 2019

Smink AM, Li S, Hertsig DT, de Haan BJ, Schwab L, van Apeldoorn AA, de Koning E, Faas MM, Lakey JR, de Vos P. The Efficacy of a Prevascularized, Retrievable Poly(D,L,-lactide-co-ε-caprolactone) Subcutaneous Scaffold as Transplantation Site for Pancreatic Islets.
Transplantation. 2017 Apr;101(4):e112-e119. doi: 10.1097/TP.0000000000001663.

Mohammadi MR, Rodriguez SM, Luong JC, Li S, Cao R, Alshetaiwi H, Lau H, Davtyan H, Jones MB, Jafari M, Kessenbrock K, Villalta SA, de Vos P, Zhao W, Lakey JRT. Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation.
Commun Biol. 2021 Jun 3;4(1):685. doi: 10.1038/s42003-021-02229-4. https://pubmed.ncbi.nlm.nih.gov/34083739/

Smink AM, Li S, Swart DH, Hertsig DT, de Haan BJ, Kamps JAAM, Schwab L, van Apeldoorn AA, de Koning E, Faas MM, Lakey JRT, de Vos P. Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet-transplantation enhances immediate post-transplant islet graft function but not long-term normoglycemia. J Biomed Mater Res A. 2017 Sep;105(9):2533-2542. doi: 10.1002/jbm.a.36101. Epub 2017 Jun 15. https://pubmed.ncbi.nlm.nih.gov/28470672/

de Vos P, Smink AM, Paredes G, Lakey JR, Kuipers J, Giepmans BN, de Haan BJ, Faas MM. Enzymes for Pancreatic Islet Isolation Impact Chemokine-Production and Polarization of Insulin-Producing β-Cells with Reduced Functional Survival of Immunoisolated Rat Islet-Allografts as a Consequence.
PLoS One. 2016 Jan 29;11(1):e0147992. doi: 10.1371/journal.pone.0147992. eCollection 2016. https://pubmed.ncbi.nlm.nih.gov/26824526/