DRWF Research: Researchers achieve first transplant of insulin-producing cells without immunosuppressive drugs
Study represents a major advance in the treatment of type 1 diabetes.
One of the main problems for scientists aiming to achieve a successful transplantation is the wide range of side-effects.
A recent study has looked at the need to suppress a patient’s immune system after the transplantation of allogeneic cells is associated with wide-ranging side effects. The process of an allogeneic stem cell transplant involves using healthy blood stem cells from a donor to replace bone marrow that is not producing enough healthy blood cells
The results of the study, published in the New England Journal of Medicine, report on the outcomes of transplantation of genetically modified allogeneic donor islet cells into a man with long-standing type 1 diabetes.
Researchers said: “We used clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 12b (Cas12b) editing and lentiviral transduction to genetically edit the cells to avoid rejection; the cells were then transplanted into the participant’s forearm muscle. He did not receive any immunosuppressive drugs and, at 12 weeks after transplantation, showed no immune response against the gene-edited cells. C-peptide measurements showed stable and glucose-responsive insulin secretion. A total of four adverse events occurred, none of which were serious or related to the study drug.”
Study lead Per-Ola Carlsson is a Professor at Department of Medical Sciences at Uppsala University in Sweden, whose previous research was funded by our sister organisation Diabetes Wellness Sverige.
Professor Carlsson highlighted the significance of the discovery: “This is the first time that someone has managed to transplant insulin-producing cells to another individual without immunosuppressive drugs.”
Insulin therapy has been the main treatment available for type 1 diabetes since its discovery in the 1920s, and this latest research offers a development of the evolution of treatment and the wider options potentially available for people living with type 1 diabetes and its related complications.
Professor Carlsson said: "Over the years, the treatment has improved. Fast-acting, long-acting insulin and even sensor-controlled insulin pumps have been obtained. But we have not been able to offer a cure. Hopefully, with this new concept we are working on, we can offer a cure in the future.”
For this study, researchers achieved transplantation of insulin-producing cells from a donor to a recipient with type 1 diabetes, without using immunosuppressive drugs in the recipient.
Professor Carlsson explained the process by which the results were achieved: “By genetically modifying the insulin-producing cells in three different ways before we have transplanted the cells. Through these genetic modifications, the cells are not detected by the immune system, but they go under the radar of the immune system.”
So far, the study has shown positive results and now the researchers are moving on to the next step on the road to treating type 1 diabetes. They will produce insulin-producing cells from stem cells with the aim to produce a genetically-modified drug product that could be used for a large number of individuals.
On what inspired his move to pursue a career in diabetes research, Professor Carlsson said: “It was probably mostly a coincidence, where I was offered the opportunity to start research as a summer job after two semesters of medical school. The research project concerned experimental studies with insulin-producing cells and quite quickly I got the opportunity to work with transplantation of islets of Langerhans.”
Addressing current challenges faced by diabetes researchers, Professor Carlsson said: “The challenges differ quite a lot between type 1 and type 2 diabetes. For type 2 diabetes, a challenge for clinical studies is that patients are spread over a large number of health centres, which makes it difficult to recruit and conduct clinical studies. For type 1 diabetes, one difficulty in understanding the causes is that the mechanism of what causes type 1 diabetes can be several years before symptoms (high blood glucose) of the condition appear. In addition, most of all cells have been destroyed, which makes it difficult to treat blood glucose levels. It is not enough to save the cells that are left.”
The research found a way for cells to survive without immune attack when no immunosuppressive drugs were given.
Professor Carlsson said: “The cells we transplanted are islet cells of Langerhans including insulin-producing cells from a deceased organ donor. The cells were transplanted to an individual with long-standing type 1 diabetes who had no measurable insulin production of their own.
“To make it easier to study and monitor the cells after transplantation, we transplanted them to forearm muscles. It is a simple procedure, where an incision was made in the skin and the muscle was exposed. The cells were then spread by injection with a cannula in different places in the musculature.
“To get the cells to avoid detection by the immune system, they were modified in three different ways. We removed two genes, which code for the proteins HLA genes (Human Leukocyte Antigens – genes strongly linked to type 1 diabetes) class I and class II, on the cell surfaces. By removing the HLA molecules from the cell surfaces, the immune cells called lymphocytes do not detect the islet cells as foreign.
“We then also overexpressed a gene that codes for the protein CD47 (also known as integrin-associated protein, or IAP) on the cell surface. By increasing CD47 on the cell surfaces, the cell is protected even though they are foreign from attack by so-called natural killer (NK) cells. The concept itself had already worked in test studies, so we had good hopes that it would also work in the current first-in-human study, which was also the case.
“Normally, the immune system kills foreign cells within a week or so after transplantation, so when we were able to measure completely stable insulin production during the first four weeks after transplantation, we knew we had succeeded.”
Researchers needed to produce a large number of insulin-producing cells for the tests to succeed.
Professor Carlsson said: “The biggest challenge was the technical one, whether we could produce enough triple-genetically modified insulin-producing cells (80 million cells) for transplantation. In retrospect, we are very pleased with how it went and believe that we would not have done anything differently.”
However, more research is required to find a potential cure for some people living with type 1 diabetes.
Professor Carlsson said: “To be able to cure type 1 diabetes, two things are required: access to a large number of insulin-producing cells and the ability to transplant them without immunosuppression.
“Our study has created the possibility of the latter, but we will not be able to use insulin-producing cells from deceased organ donors, because then we would quickly have an organ shortage and very few could be treated.
“In order to treat many people with type 1 diabetes, it is estimated that there are about 10 million people diagnosed with the condition, stem cell-produced insulin-producing cells that are genetically modified in the same way are needed instead. In theory, you can produce infinite amounts of insulin-producing cells from stem cells, and it is necessary because at least one billion cells are needed to cure an individual.
“One advantage, however, is that you only need to genetically modify at the immature cell level and then when you expand the cell number, all daughter cells will have the same genetic modifications.
“We expect it to take a couple of years before we have established a cell production of insulin-producing cells for treatment from genetically modified stem cells. Then it will take several years to carry out the clinical trials required to get the cell drug approved. Only then can the treatment become available, which therefore takes 10 years.”
While it may take several years for the treatment to be available, there was no age restriction suggested as a barrier to treatment.
Professor Carlsson said: “In principle, everyone with type 1 diabetes could be treated because it is a simple surgical procedure. However, because it is surgery, there is a limit to how many people can be transplanted. But in principle, this could be a cure for type 1 diabetes.”
Professor Carlsson outlined his future research project plans: “I am now working on achieving a production of stem cells that can be genomically identified to develop into insulin-producing cells.”
Professor Carlsson described how Diabetes Wellness Sverige funding had driven the latest research project: “Diabetes Wellness Sverige has funded another of my research projects where we have worked to stop continued cell death in the development of type 1 diabetes with mesenchymal stromal cells, a type of connective tissue stem cell.
“That trial has also been very successful and those who have received treatment have been able to keep insulin-producing cells for more than five years after treatment, with more easily regulated blood sugar as a result.
“The hope is that this therapy can be given even before diagnosis and prevent individuals who show signs of autoimmunity from developing the disease.”
For young researchers starting out in the field of diabetes, Professor Carlsson proffered: “Something to consider is the clinical relevance of the research being conducted. A lot of basic research can be extremely relevant for understanding basic cell function and ultimately contributing to the treatment of diseases. However, it is wise to always keep in mind how your research can contribute to improving the lives of our patients.”
Read the report in the New England Journal of Medicine
Read more about DRWF Research
Interview reproduced with thanks to our colleagues at Diabetes Wellness Sverige
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