For those with type 1 diabetes, the wait for a cell therapy to control blood glucose without systemicimmunosuppression has been long and disappointing. While recent commercial acquisitions for suchcell therapies offer hope that the field is finally advancing, there will be a need for numerous options,much like the approach to the COVID vaccine. Likarda holds multiple patents surrounding our novelmicroplates used for differentiation of induced pluripotent stem cells into insulin-producing cells andaround our unique encapsulation technology that allows us to use biocompatible hydrogels that are notavailable to traditional microencapsulation approaches. We have differentiated clinically-appropriatehuman pluripotent cells into insulin-producing cells (Insulin-Producing induced Pluripotent Stem Cells- IPiPSCs) using our 5-step protocol that incorporates few growth factors compared to publishedprotocols and can reverse diabetes in immune-compromised mice. We have encapsulated islets in aPEG-based hydrogel and reversed diabetes in immune-competent rats for their lifespan withoutimmunosuppression or exogenous insulin. However, the IPiPSCs did not function well in the PEG-based hydrogel. Preliminary data indicates that a new hydrogel formulation we have created based onthiolated hyaluronic acid (ThHA) is a better match for the IPiPSCs. The purpose of this project is toexamine the ability of ThHA to durably reverse diabetes in rats with a pilot trial in diabetic dogs. Thespecific aims are: 1) Identify genetic stability of the IPiPSCs after encapsulation and implantation intodiabetic rats; 2) Determine whether implantation of ThHA-encapsulated human IPiPSCs in diabeticrats and beagles arrests the clinical signs of diabetes; 3) Identify biomarkers of a possible foreign bodyreaction in the surrounding tissue at 2 wks, 3 and 9 mos post-transplant int diabetic rats and 6 mos indiabetic dogs. Once we confirm the optimal hydrogel formulation for the IPiPSCs, we will incorporatethem into our ribbon device, a retrievable device that maintains the large surface area and low diffusionbarrier characteristics of microspheres while delivering retrievability for regulatory requirements. At thecompletion of this Phase I feasibility study, we will undergo Phase II studies in spontaneously diabeticdogs, which are an optimal model for human T1D due to parallel clinical presentation, similarautoantibodies, pathology and complications. Promising long-term results in spontaneously-diabeticdogs would offer strong preclinical data for human clinical trials.
Public Health Relevance Statement: The key to a successful treatment of type 1 diabetes requires both insulin-producing cells and a
way to protect them from immune rejection by the recipient's body. We have both clinically
appropriate stem cells that we have differentiated into insulin-producing cells and a hydrogel to
coat the cells so that they are protected from the immune system. This proposal will test the
combination of the two in diabetic rats and dogs to determine whether they can reverse
hyperglycemia and the clinical signs of diabetes without insulin shots and without
immunosuppression.
Project Terms: Alginates ; Animals ; Autoantibodies ; autoimmune antibody ; autoreactive antibody ; self reactive antibody ; Blood Chemical Analysis ; Blood Chemical Analyses ; blood chemistry ; Blood Glucose ; Blood Sugar ; capsule ; Capsules ; Cartoons ; Cells ; Cell Body ; Chemistry ; Clinical Trials ; Collagen ; Cosmetics ; cosmetic product ; Diabetes Mellitus ; diabetes ; Insulin-Dependent Diabetes Mellitus ; Brittle Diabetes Mellitus ; IDDM ; Juvenile-Onset Diabetes Mellitus ; Ketosis-Prone Diabetes Mellitus ; Sudden-Onset Diabetes Mellitus ; T1 DM ; T1 diabetes ; T1D ; T1DM ; Type 1 Diabetes Mellitus ; Type 1 diabetes ; Type I Diabetes Mellitus ; insulin dependent diabetes ; juvenile diabetes ; juvenile diabetes mellitus ; ketosis prone diabetes ; type I diabetes ; type one diabetes ; Diffusion ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Feasibility Studies ; Fibrosis ; Foreign Bodies ; Foreign-Body Reaction ; Future ; Gel ; Glucose tolerance test ; IPGTT ; intraperitoneal glucose tolerance test ; Goals ; Grant ; Hematology ; Human ; Modern Man ; Hyaluronic Acid ; Hyperglycemia ; hyperglycemic ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Immunohistochemistry ; Immunohistochemistry Cell/Tissue ; Immunohistochemistry Staining Method ; Immunosuppression ; Immunosuppression Effect ; Immunosuppressive Effect ; immune suppression ; In Vitro ; Inflammation ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Islets of Langerhans ; B9 endocrine pancreas ; Endocrine Pancreas ; Islands of Langerhans ; Nesidioblasts ; Pancreatic Islets ; Pars endocrina pancreatis ; islet progenitor ; Joints ; Kidney ; Kidney Urinary System ; renal ; Laboratories ; Longevity ; Length of Life ; life span ; lifespan ; macrophage ; MÏ ; Methods ; Microencapsulations ; Microspheres ; Microbeads ; Mus ; Mice ; Mice Mammals ; Murine ; neutrophil ; Blood Neutrophil ; Blood Polymorphonuclear Neutrophil ; Marrow Neutrophil ; Neutrophilic Granulocyte ; Neutrophilic Leukocyte ; Polymorphonuclear Cell ; Polymorphonuclear Leukocytes ; Polymorphonuclear Neutrophils ; Omentum ; Omental Fat ; Legal patent ; Patents ; Pathology ; Pilot Projects ; pilot study ; Publishing ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Rodent ; Rodentia ; Rodents Mammals ; Vertebral column ; Spinal Column ; Spine ; backbone ; Stains ; Staining method ; stem cells ; Progenitor Cells ; Technology ; Testing ; Tissues ; Body Tissues ; Transplantation ; transplant ; Urinalysis ; Vaccines ; Work ; Glycocalyx ; Cell Coat ; base ; improved ; Area ; Surface ; Clinical ; Encapsulated ; Phase ; diabetic ; Lubricants ; cell mediated therapies ; cell-based therapeutic ; cell-based therapy ; cellular therapy ; Cell Therapy ; Genetic ; Immunes ; Immune ; Protocol ; Protocols documentation ; Source ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; biocompatibility ; biomaterial compatibility ; human data ; Hydrogels ; novel ; Human Cell Line ; Devices ; Filler ; Modeling ; response ; Insulin Cell ; Insulin Secreting Cell ; β-cell ; β-cells ; βCell ; Beta Cell ; Data ; immune competent ; Immunocompetent ; Quantitative RTPCR ; qRTPCR ; Quantitative Reverse Transcriptase PCR ; Stem Cell Research ; in vivo ; Rodent Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Monitor ; Characteristics ; Process ; Islet Cell ; pre-clinical ; preclinical ; pilot trial ; islet ; diabetic rat ; Rat model of diabetes ; diabetic rat model ; Implant ; implantation ; pluripotency ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; phase 2 study ; phase II study ; Formulation ; Growth Factor ; Growth Agents ; Growth Substances ; Proteins Growth Factors ; post-transplant ; post-transplantation ; posttransplant ; posttransplantation ; coronavirus disease ; COVID ; CoV disease ; corona virus disease ; differentiation protocol ;
