Low immune islet transplantation is expected to cure type 1 diabetes

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Low immune islet transplantation is expected to cure type 1 diabetes

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 Low immune islet transplantation is expected to cure type 1 diabetes.

Insulin has been used to treat type 1 diabetes (T1DM) for more than 100 years, transforming this once fatal disease into a medically manageable chronic disease.

However, morbidity, mortality and quality of life in type 1 diabetes remain a concern, especially for the 25% of patients with impaired hypoglycemia perception (IAH) , who are at high risk of severe hypoglycemic events and associated morbidity .

However, current therapeutic drugs, as well as blood glucose monitoring devices, neither cure type 1 diabetes nor eliminate the uncertainty and burden of blood glucose levels.

Allogeneic islet transplantation, which replenishes the missing islet β-cell population, has been shown in clinical trials in IAH patients with a history of severe hypoglycemic events to control blood sugar, restore hypoglycemic perception, and protect patients with type 1 diabetes from severe hypoglycemic events Influence.

Previous clinical trial follow-up data showed that under immunosuppression, the average duration of function of allogeneic islet transplantation was 4.4 to 5.9 years.

However, after allogeneic islet suppression, the immediate blood-mediated inflammatory response leads to loss of the suppressed islets, requiring lifelong immunosuppressive drugs that lead to multiple side effects, including β-cell toxicity, nephrotoxicity, infection and cancer, etc., which greatly limits the widespread use of this strategy in type 1 diabetes.

On April 12, 2023, researchers from Sana Biotechnology published a research paper entitled: Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice in the journal Science Translational Medicine .

In this study, a research team at Sana Biotechnology reports proof-of-concept transplantation of human allogeneic, genetically engineered immune- hypoimmune islets that do not require immunosuppression , and in preclinical models, allo-hypoimmune islets protect against allogeneic and autoimmune response and provide glycemic control.

Allogeneic islet transplantation has been successfully used in diabetic patients with refractory insulin-dependent diabetes and impaired hypoglycemia perception (IAH) .

But this treatment requires lifelong use of immunosuppressive drugs, which has seriously hindered the widespread use of this cell replacement therapy in the wider population of diabetic patients.

In this study, the Sana Biotechnology research team used CRISPR-Cas9 gene editing technology to knock out the genes encoding class I and class II MHC in human primary islet cells, and overexpressed CD47 to prevent them from being killed by innate immune cells, These hypoimmune (HIP) cells were then repopulated into pseudoislets (p-islets) and transplanted into diabetic humanized mice.

The results showed that human hypoimmune pseudoislets were able to survive, colonize and improve diabetes in an immunocompetent, allogeneic humanized mouse model of diabetes, and avoid being killed by the autoimmune system.

The presence of unedited or partially edited hypoimmune pseudoislets did not impair the survival and endocrine function of successfully edited hypoimmune pseudoislets.

The research team also considered the potential out-of-control problems that may be caused by the overexpression of CD47.

They used the CD47-targeted fusion protein to inhibit the overexpression of CD47 as a safety switch, which can quickly and reliably eliminate low-immune pseudo-islet cells in vivo. This provides a safe strategy for future use of this therapy in the clinic .

Since no immunosuppression is required, this method can promote the application of islet transplantation in diabetes and help more diabetic patients with a history of IAH and severe hypoglycemia get rid of insulin injections.

It is worth mentioning that on April 10, 2023, researchers from Sana Biotechnology published a paper entitled: Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice in the journal Nature Communications, a sub -journal of Nature . Research Papers.

In this study, the TRAC , B2M and CIITA genes of T cells were knocked out by CRISPR-Cas9 gene editing , thereby constructing human hypoimmune (HIP) T cells .

Then, these HIP T cells were overexpressed with CD47 and CD19 CAR using lentiviral vectors to construct allogeneic HIP CD19 CAR-T cells .

This study further demonstrates that allogeneic HIP CD19 CAR-T cells are safe in immunocompetent humanized mouse tumor models and can achieve durable and effective tumor clearance.

This study shows that the “universal” CAR-T cell therapy based on low immune T cells can achieve the therapeutic effect that only autologous CAR-T cell therapy can achieve at present, which will help more cancer patients to obtain cell therapy in time.

Paper link :
1. https://www.science.org/doi/10.1126/scitranslmed.adg579
2. https://www.nature.com/articles/s41467-023-37785-2

Low immune islet transplantation is expected to cure type 1 diabetes

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