Interim report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using “Neo-Islets,” aggregates of adipose stem and pancreatic islet cells (INAD 012-776)

Abstract

We previously reported that allogeneic, intraperitoneally administered “Neo-Islets,” composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided pilot study (INAD 012–776) in insulin-dependent, spontaneously diabetic pet dogs by ultrasound-guided, intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) and sedated animals. We report here interim observations on the first 4 canine Neo-Islet-treated, insulin-dependent pet dogs that are now in the early to intermediate-term follow-up phase of the planned 3 year study (> 6 months post treatment). Current results from this translational study indicate that in dogs, Neo-Islets appear to engraft, redifferentiate and physiologically produce insulin, and are rejected by neither auto- nor allo-immune responses, as evidenced by (a) an absent IgG response to the allogeneic cells contained in the administered Neo-Islets, and (b) progressively improved glycemic control that achieves up to a 50% reduction in daily insulin needs paralleled by a statistically significant decrease in serum glucose concentrations. This is accomplished without the use of anti-rejection drugs or encapsulation devices. No adverse or serious adverse events related to the Neo-Islet administration have been observed to date. We conclude that this minimally invasive therapy has significant translational relevance to veterinary and clinical Type 1 diabetes mellitus by achieving complete and at this point partial glycemic control in two species, i.e., diabetic mice and dogs, respectively.

Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials

“…The current, preclinical study was undertaken in anticipation of a Phase 1 Clinical Trial with two objectives: to determine (a) whether human NIs (hNIs) can also restore euglycemia, and (b) whether redosing of suboptimally controlled diabetic animals could fully restore euglycemia in streptozotocin (STC)-diabetic Non-Obese Diabetic/Severe Combined Immunodeficiency mice (NOD/SCID, Harlan), as has been previously shown for mouse cell-derived NIs (mNIs), and to some extent for dog cell-derived NIs (cNIs) [ 13 , 14 ]. Since these NIs are composed of human cells, and since human MSCs do not maintain immune evasive abilities in a xenogeneic setting (unpublished results), the NOD/SCID model was used.…”

“…MSCs and Islet cells were co-cultured in DMEM (5mM glucose) + 10% hPL at a 1:1 ratio in ultra-low adhesion surface culture dishes (Corning), and NIs formed overnight as previously described [ 13 , 14 ] and as shown in Fig 1 .…”

“…Similarly, when canine NIs (cNIs), composed of Adipose-derived Stromal or Stem Cells (ASCs) and cultured islet cells were administered i.p. to Streptozotocin-diabetic NOD/SCID mice, such mice were rendered euglycemic long term through exclusive secretion of canine insulin as demonstrated both by ELISA and subsequent removal of omentally engrafted cNIs [ 13 , 14 ], resulting in prompt return of hyperglycemia. In order to test this promising biotherapeutic in a larger animal model and a more real-world setting, we are conducting an FDA-guided pilot study (INAD 012–776), treating spontaneously insulin-dependent pet dogs with allogeneic cNIs, using adapted protocols shown to be effective in NOD mice.…”

“…In order to test this promising biotherapeutic in a larger animal model and a more real-world setting, we are conducting an FDA-guided pilot study (INAD 012–776), treating spontaneously insulin-dependent pet dogs with allogeneic cNIs, using adapted protocols shown to be effective in NOD mice. Accordingly, canine NI (cNI)-treated dogs have shown a durable improvement in glycemic control, coupled with a reduction in the need for insulin, both achieved without the use of encapsulation devices or antirejection drugs [ 14 ]. So far, such effects have lasted greater than 3 years (unpublished observations from ongoing study), and without adverse events or allo-immune responses to NIs.…”

Stem Cells in Veterinary Medicine—Current State and Treatment Options

“…Moreover, the IP approach was used to inject Neoislets, aggregates of ADMSCs and pancreatic islet cells in an FDA guided pilot study in insulin-dependent diabetes mellitus in pet dogs. Neo-islets appear to engraft, redifferentiate, produce insulin, and do not trigger auto-or alloimmune response (152).…”