Sana Biotech's Hypoimmune Pancreatic Cells Control Type 1 Diabetes in Preclinical Model

13 April 2023 | Thursday | News

Sana Biotechnology Announces Preclinical Data Published in Science Translational Medicine Showing its Hypoimmune Pancreatic Islet Cells Evaded Allogeneic and Autoimmune Rejection and Controlled Type 1 Diabetes in Preclinical Model
Image Source : Public Domain

Image Source : Public Domain

Hypoimmune human islet cells normalized glucose in diabetic humanized immunocompetent mouse model and avoided allogeneic and autoimmune rejection by the immune system

Similar hypoimmune primary human islet cells to be tested in patients with type 1 diabetes as part of an investigator-sponsored trial expected to initiate with data readout later this year

Provides insight for SC451, Sana’s hypoimmune PSC-derived pancreatic islet cell therapy, in development for the treatment of type 1 diabetes

Goal to file IND for SC451 in 2024

 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on changing the possible for patients through engineered cells, today announced that Science Translational Medicinehas published a paper titled “Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice.” The paper details data from a series of ten in vivo experiments demonstrating the insulin-normalization activity, persistence, immune evasion, and lack of immunogenicity of human hypoimmune-modified islet cells, which cluster into effective endocrine organoids termed “pseudo islets.”

“The replacement of defective or missing cells has been the goal for many diseases; however, immune rejection results in either systemic immunosuppression or therapeutic failure. Sana’s proprietary hypoimmune platform was developed to solve this problem,” said Steve Harr, Sana’s President and CEO. “The Science Translational Medicine paper details data demonstrating that hypoimmune pseudo islets developed with our hypoimmune technology survived and were able to reverse diabetes without any immunosuppression in humanized mice. Eliminating the need for insulin administration and reversing diabetes with normalization of blood glucose levels, and doing this without immunosuppression, would be a transformational advance for patients. Insights from this research along with an expected investigator-sponsored trial this year will inform the development plan for our SC451 product candidate in type 1 diabetes as we move forward with our goal of submitting an IND in 2024.”

HIP Pancreatic Islet Cells Survive, Persist, and Escape Allogeneic Rejection
Sana generated human hypoimmune (HIP) pseudo islets (p-islets) and wild-type (wt) p-islets that were similar in size, cell type composition, and in vitro insulin secretion. The survival of the p-islets and their cell composition was assessed in immunocompetent, diabetic allogeneic humanized NSG-SGM3 mice. HIP or wt p-islet clusters were injected into the hindlimb muscle and were recovered on the same day or 7 or 28 days later. Wt p-islets could only be recovered on the same day and were fully rejected and dissolved at later time points. By contrast, the total cell count and cell composition of HIP islets did not change over time.

In another experiment, analyses were conducted a month following exposure to HIP and wt p-islets. There were no traces of wt p-islet grafts found in any animals after one month. Recovered splenocytes and serum from the wt p-islet treated animals showed markedly activated T cells (analyzed by ELISPOT) and donor-specific antibodies (analyzed by flow cytometry) against the grafts in the wt p-islet group, demonstrating a strong adaptive allogeneic immune response. By contrast, HIP p-islets showed the same morphology as before transplantation and contained alpha, beta, and delta cells. No immune cell infiltrate was observed in or around the HIP p-islet cells. Additionally, no adaptive allogeneic immune response was observed in humanized mice that received HIP p-islets and diabetes in these mice was alleviated. Confirmatory killing assays showed killing of wt p-islets and no killing of HIP p-islets.

HIP Islet Cells Control Insulin Similarly to Unedited Wild-Type Islet Cells in Immunodeficient Mice
The ability to control diabetes was assessed in immunodeficient NSG mice to remove the variable of immune rejection of allogeneic cells, enabling the comparison of wt and HIP p-islets. Diabetes was induced using streptozotocin (STZ) and all mice had fasting glucose concentrations >400 mg/dl on the day of p-islet graft transplantation. Wt and HIP p-islets both achieved glycemic control within approximately 2 weeks and generated similar c-peptide concentrations one months after transplantation. These functional data confirmed that HIP p-islet cells maintained endocrine function comparable to wt p-islets and showed unimpaired resilience toward the transplantation procedure.

HIP Islet Cells Ameliorate Diabetes in Models of Autoimmunity: NOD Mice as well as Humanized Autoimmune Mice
The ability of HIP islet cells to avoid autoimmunity was assessed in two different models. The first set of experiments were in the NOD mouse, which is the primary animal model for studying autoimmunity in diabetes due to the similarities to the human disease. These studies demonstrate that mouse HIP p-islets survive while syngeneic p-islets are rejected due to autoimmune killing. Additionally, the impact of autoimmunity was studied in a humanized, diabetic autoimmune mouse. To generate a humanized, autoimmune mouse, immune cells and iPSCs were generated from PBMCs collected from a person with type 1 diabetes (T1D). Mice were engrafted with the T1D immune cells and diabetes was induced. The iPSCs were then either hypoimmune-modified or mock-modified, differentiated into islet cells, and transplanted into these immunocompetent, diabetic humanized mice to study autoimmunity in vivo. All HIP iPSC-derived p-islets survived and glycemic control was achieved in all recipients of HIP iPSC-derived p-islets. In contrast, all autologous, mock-modified iPSC-derived p-islets were fully rejected within 10 days due to autoimmunity and showed no effect on blood glucose, even temporarily, and animals had no detectable c-peptide after one month.

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