Curing type one diabetes -- a work in progress.

    Type one Diabetes is an immunologic disease.  It occurs when the body, for some reason, destroys the beta cells.  Beta cells make insulin. They are hormone producing cells.  They are found in islets of cells that are scattered in the pancreas.  

    Humans and other creatures of the earth survive, in part, because they have evolved an immune system that protects them from a universe of pathogenic microbes that are themselves constantly. evolving.  There are two kinds of lymphocytes that destroy invading pathogens.  

 B lymphocytes are a cadre of cells each of which recognize a different pathogen, toxin, or allergen.  when a B lymphocyte encounters a potential invader, it proliferates, divides rapidly, and creates an army of identical cells.  They in turn mount an effective response against the microbe or the toxin.  Some of the new cells are long-lived.  They persist in an apparently dormant state, but can grow into a large number of cells rapidly when and if they again encounter the same antigen, even if the next invader is encountered  decades after the initial sensitizing event.  

T lymphocytes can't identify foreign tissue until it has been recognized and processed as an invader by antigen presenting cells: macrophages, B cells, and dendritic cells.  These cells recognize, process, and display the foreign antigen on something called the "major histocompatibility complex" Then they present the invader to the T cell receptor, and the T cell goes to work. 

When surgeons transplant a liver, kidney or heart the transplanted organ must come from a person with the same blood type.  That’s the easy part of the match.  It is, however, virtually impossible to find a transplant donor who has the same HLA as the recipient.  And that's the rub.  

Much as every citizen has a unique social security number, every individual is born with a unique immunologic identity, a special tissue type or HLA.  (like all genes, HLA genes make proteins and they coat cells.)  

said another way--  "Human leukocyte antigens (HLA) are proteins found on most cells in the human body. Your immune system uses HLA to identify which cells belong in your body and which do not. Doctors use HLA typing to match blood stem cell donors with patients, but it’s not as simple as it sounds. Your body has 12 unique HLA markers (proteins), creating millions of possible combinations for doctors to consider when searching for a match."

The blue print for identity HLA proteins are present in every body cell that has a nucleus. Nucleotides from the father and the mother’s HLA genes combine and form a new, different HLA gene. each cell has the same 22,300 or so genes.  Genes make up about two percent of the 3 billion pairs of nucleotides.)  Each nucleated human cell has 23 chromosomes and the HLA genes are located on the 6^th Chromosome.  There are more than 200 HLA genes.  Most of them play a role in many of the immunologic problems people suffer from.  Six (or 12) are identity genes. 

Type one diabetes is an auto immune disease.  For some, as yet, argued about reason, it occurs when a person’s immunologic mechanism starts destroying the beta--insulin producing cells.  scientists understand the mechanism of the destruction but we don’t know why it happens. 

Proof a concept--curing diabetes

When a person dies it has long been possible to isolate beta cells and transplant them.  When transplanted beta cells are soon recognized as the other and the body quickly destroys the cells. “For many years, islet transplantation was considered experimental and was only performed in clinical trials.  In 2023, the U.S. Food and Drug Administration (FDA) approved the first cell therapy made from islets of deceased donors for use in islet transplantation. This cell therapy is approved for adults with type 1 diabetes who have a hard time managing their blood glucose levels and continue to have repeated severely low blood glucose, also called severe hypoglycemia, despite intensive diabetes management and education.

After an islet transplant, recipients must take immunosuppressants for as long as the transplanted islets are working. These medicines help prevent the body from rejecting the transplanted islets. Rejection occurs when the body’s immune system sees the islets as “foreign” and tries to destroy them. If the recipient stops taking immunosuppressants, the recipient’s body will reject the transplanted islets, and the islets will stop working.”

Question:  if the HLA genes in a beta cell are destroyed, if a beta cell no longer has an identity—thus it is NOT an invader or foreigner, will the immune system destroy these cells??  

Proof of concept from Sweden and the New England Journal of Medicine

Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression

Authors: Per-Ola Carlsson, M.D., Ph.D., Xiaomeng Hu, Ph.D., Hanne Scholz, Ph.D., Sofie Ingvast, B.Sc., Torbjörn Lundgren, M.D., Ph.D., Tim Scholz, M.D., Ph.D., Olof Eriksson, Ph.D., Per Liss, M.D., Ph.D., Di Yu, Ph.D., Tobias Deuse, M.D., Olle Korsgren, M.D., Ph.D. https://orcid.org/0000-0002-8524-9547, and Sonja Schrepfer, M.D., Ph.D.Author Info & Affiliations

Published August 4, 2025

DOI: 10.1056/NEJMoa2503822

"Exogenous insulin has been used in the treatment of type 1 diabetes mellitus for more than 100 years. Intensive insulin therapy delays the onset and slows the progression of long-term complications and improves life expectancy. However, insulin remains a treatment and is not a cure; persons with early-onset type 1 diabetes continue to have a reduced quality of life, an elevated risk of serious cardiovascular outcomes, and a shortened life span."

The need to suppress a patient’s immune system after the transplantation of allogeneic cells is associated with wide-ranging side effects. 

We report the outcomes of transplantation of genetically modified allogeneic donor islet cells into a man with long-standing type 1 diabetes. 

The research team destroyed two of the HLA identity genes, using the technique known as CRISPR.  We also used a virus to introduce a protein.   a

 The altered cells were then transplanted into the participant’s forearm muscle and he did not receive any immunosuppressive drugs. 12 weeks after transplantation, he showed no immune response against the gene-edited cells. 

"We had previously shown previously that transplantation of islet cells obtained from a deceased human donor or from a rhesus monkey and edited to be hypo-immune cured diabetes in allogeneic, diabetic, humanized mice and in an allogeneic, diabetic cynomolgus monkey, respectively, WITHOUT the use of immunosuppression. 

Here, we report the results of a proof-of-concept study of the transplantation of gene-edited, hypoimmune platform (HIP) islet cells in a patient with long-term type 1 diabetes, without the use of immunosuppression.  

(There are multiple patents that have to be negotiated before Crispr is used commercially.  A few biotech organizations in the U.S. and Japan sell the CRISPR related biotechnical tools that researchers use to destroy genes.)  

Case Report of the treated patient.

"A 42-year-old man with a 37-year history of type 1 diabetes provided written informed consent to participate in the study. He had a glycated hemoglobin level of 10.9% (96 mmol per mole), undetectable endogenous insulin production and was receiving a daily insulin dose of 32 units.

A blood type O–matched pancreas from a 60-year-old donor with a glycated hemoglobin level of 6.0% (42 mmol per mole) became available, and islets were isolated after 5 hours 11 minutes of cold ischemia at Uppsala University Hospital. These islets had a glucose-stimulated insulin secretion index of 16.7 and a purity of 87%. (The cells made insulin.)

"The islets were shipped to Oslo University Hospital for gene editing. At the manufacturing facility of the hospital, the islets were dissociated into single cells, and 2 HLA genes were destroyed.

one of the genes is called B2M 

The other gene CIITA that was inactivated encodes a master regulator of class II HLA transcription.

CRISPR uses an enzyme that destroys the gene. it is called CAS 9.  A segment of RNA that mirrors the gene is used to find and identify it. gene.

AI Overview

The B2M gene encodes a protein that plays a crucial role in the immune system.  it destroys a complex that is essential for presenting antigens to cytotoxic T cells, cytotoxic T cells are key players in the body's defense against infections and cancer.

CIITA plays a critical role in immune responses.

CD47 is not an HLA gene.  A virus carries this gene into the cell and once inside it causes cells to produce a “don’t eat me” protein that is found on the surface of cells.  It keeps macrophages from destroying healthy cells. 

 first the cells were modified by CRISPR.  Then they were allowed to re-cluster and rest before they were attacked by a lentiviral vector that contained  CD47 complementary DNA. 

it worked.  

"Of the edited islet cells, 85.8% were negative for HLA class I, 

100% were negative for HLA class II. 

46.4% had high CD47 expression.

"The final cellular product contained fully edited HLA-depleted islet cells with high CD47 expression.

The injection also contained some cells that were not edited

These so called wild type cells had: HLA class I and II double-knockout cells with endogenous CD47 levels, and they retained HLA expression and varying CD47 levels.  

Gene editing did not change the composition of the islets. Approximately 66% of the islet cells in the study were beta cells .

The engineered islet cells were then shipped to Uppsala University Hospital for implantation. With the participant under general anesthesia, a small (3.8m) skin incision was made over the participant’s left brachioradialis muscle. A total of 79.6 million engineered HIP islet cells were prepared into 17 syringes and delivered through 17 injections into the muscle. In each injection, the islets were distributed in a linear pearl-on-string pattern while the syringe was slowly pulled back. The participant remained hospitalized overnight to monitor for immediate complications and was discharged the following day. The participant did not receive any glucocorticoids or anti-inflammatory or immunosuppressive medications.

they monitored the participant’s immune response against each of the islet-cell subpopulations.  

 the wild-type isle cells that remained in the graft induced strong T-cell activation and WERE DESTROYED by the body's immune system.

In spite of the ongoing immune responses against wild-type and double-knockout cells, 

Islet cells that lacked the HLA genes were not killed by the participant’s immune cells, did not induce antibodies. 

the researchers did not detect any immune response targeting the HIP islet cells over the course of the study.  After 12 weeks, the participant continued to do well.  their findings are encouraging.

 https://www.nmdp.org/patients/understanding-transplant/finding-a-donor/hla-typing-matching

  https://www.nejm.org/doi/full/10.1056/NEJMoa2503822

ANOTHER APPROACH:  in June 2025 the pharmaceutical company Vertex told those at the American Diabetes Association 85th Scientific Sessions about 12 patients who were infused with stem cells that were converted to islet cells and followed for a year.  The cells are called product was called limislecel.

– All12 patients achieved ADA-recommended target HbA1c levels <7% and >70% time-in-range (70-180 mg/dL), and 10/12 patients were insulin free. 

The 12 participants: Demonstrated engraftment with glucose-responsive endogenous C-peptide production, which was durable through one year of follow-up.  They Achieved the ADA targets of HbA1c <7% and time in range of >70% and ha a reduction in exogenous insulin use (mean reduction daily insulin dose: 92%)

10/12 (83%) no longer required exogenous insulin at Month 12.

Two patient deaths occurred.  Both were believed to be unrelated to treatment with zimislecel.

One death occurred approximately 19.5 months after zimislecel infusion and was due to serious cryptococcal meningitis caused by an extensive sinus surgery. The person had been taking high-dose systemic glucocorticoids and was also receiving immunosuppressive therapy.

 The other death occurred approximately 30 months after zimislecel infusion and was due to severe dementia with agitation owing to the progression of preexisting neurocognitive impairment. This participant had had a history of severe traumatic brain injury due to a motor vehicle accident that was caused by a severe hypoglycemic event

So Vertex modified stem cells that controlled diabetes in many. 

Nejm June 20, 2025