Key Insights
A proof-of-concept trial in a single patient has shown that genetically engineered pancreas cells can survive transplantation without immunosuppression.
The results represent a watershed moment for both researchers and people with type 1 diabetes.
Hurdles remain in taking the technology through to approved treatment.
Four weeks after transplanting genetically modified insulin-producing cells into a patient with type 1 diabetes (T1D), Per-Ola Carlsson and his team at Uppsala University Hospital knew they’d achieved something extraordinary. Despite the patient not taking any immune-system-suppressive drugs, the transplanted cells were alive and functioning. “We were extremely happy when we saw that come true,” Carlsson recalls.
The full results of that single-participant trial were published in August (N. Engl. J. Med. 2025, DOI: 10.1056/NEJMoa2503822). For the first time, researchers had demonstrated that gene-edited cells could evade both transplant rejection and the autoimmune attack that defines T1D. “There are enormous numbers of studies showing that you could reverse type 1 diabetes in animal models,” Carlsson says. “Those have not come true in the human situation. But this time, we saw it work.”
The impact of this work could be huge for people with T1D, which occurs when the body’s own immune system destroys the pancreas cells that produce insulin. Without that hormone, the body doesn’t manage glucose levels in the blood, and people with the disease need to inject insulin multiple times a day. According to the World Health Organization, in 2017 there were 9 million people with T1D worldwide.
Sanjoy Dutta, chief scientific officer at US nonprofit Breakthrough T1D, calls T1D “a 24/7, 365-day disease that requires meticulous attendance.” Every carbohydrate in every morsel of food must be counted. Every insulin dose calculated.
One miscalculation triggers a vicious cycle lasting hours or days. Even with modern continuous glucose monitors and insulin pumps, people with T1D face a life expectancy 10 years shorter than that of their peers without T1D.
Improving on islet transplantation
James Shapiro, a surgeon in Canada, led a team that codeveloped the Edmonton protocol for islet transplantation. This approach transplants cadaveric donor islets into a person’s liver, requiring recipients to take immunosuppressants for life. Thousands of patients have received these transplants, and many live without needing insulin therapy for years.
“There just aren’t that many people for whom lifelong immunosuppression is better than lifelong insulin.”
Steve Harr, president and CEO, Sana Biotechnology
The Nordic countries have conducted the highest number of islet transplantations globally, with Uppsala University Hospital as the central hub. The hospital also boasts unique positron-emission tomography (PET) imaging capabilities crucial for monitoring transplanted cells. But the treatment has never scaled: supply of donor cells is limited and “there just aren’t that many people for whom lifelong immunosuppression is better than lifelong insulin,” says Steve Harr, president and CEO of Sana Biotechnology, the company developing the islet cells that Carlsson’s team transplanted successfully last year.
Sonja Schrepfer, one of Sana’s founding scientists who is now a research scientist at Cedars-Sinai, developed the science behind the company’s asset. Over 7 years, she identified three genetic modifications needed to create hypoimmune cells that evade immune detection.
The first step is to knock out human leukocyte antigen (HLA) class I and class II molecules, the major transplantation antigens triggering rejection. But cells lacking HLA normally fall victim to natural killer cells, which look for self-recognition signals as well as recognize signals that mark cells as nonself.
Schrepfer’s breakthrough came from further modifying cells to overexpress CD47, a “don’t eat me” protein signal that protects cells from destruction. These three genetic modifications combined mean that “cells escape from immune attack, both from allogeneic rejection and autoimmunity,” Carlsson explains.
For the recent Uppsala trial, Carlsson’s team used modified cadaveric islets for regulatory reasons. “In Europe, they are considered organ transplantation,” he says. “We only had to provide safety data for the genetic modifications.”
The team transplanted modified islets into the brachioradialis muscle in the arm. “If you place cells in muscle, you can monitor them by MRI, biopsy if necessary, and even retrieve them surgically,” Carlsson says. His team monitored the cells’ survival using gallium-68 exendin-4 and PET/magnetic resonance imaging (MRI).
Allogeneic rejection typically occurs within 2 weeks; autoimmune recurrence within 2 months. As months passed without immunosuppression, the evidence mounted: the cells were surviving and functioning. Even so, the proof-of-concept trial changes everything and nothing. The path forward requires making insulin-producing cells with the same genetic modifications but beginning with stem cells.
Harr describes the challenge candidly: “It’s still a science project.” Manufacturing involves creating a master cell bank that can be used to produce enough cells for anybody with T1D who wants a transplant. But genomic instability after gene editing can cause tumor-forming mutations. Creating a stable, gene-modified master cell bank has taken Sana years of work.
Next comes differentiation: coaxing stem cells to turn into functional islets. “You’re going from a stem cell to an islet,” Harr says. “What you don’t want is [that] along the way you make a little bit of stomach, a little bit of [gastrointestinal] tract.”
Sana has achieved sufficient purity and yield for a Phase I trial, “but barely,” Harr says. The company hopes to file an investigational new drug (IND) application to start a trial in 2026.
At the most recent JPMorgan Healthcare Conference, Sana updated 1-year public data to show that the gene-modified primary islet cells continue to survive, function, avoid immune detection, and be visible via PET/MRI scan. The company has observed no adverse events or severe adverse events related to the treatment. The patient in the study is still alive and doing well.
A parallel cell editing path
While Sana pursues gene-edited hypoimmune cells, Vertex Pharmaceuticals has taken a different route into the clinic.
For zimislecel, Vertex has developed proprietary methods to differentiate pluripotent stem cells into functional pancreatic s, scaling production to billions of cells in bioreactors. These cells are delivered via intravenous infusion into the hepatic portal vein, where they engraft in the liver and aim to sense and respond to blood glucose levels.
But Vertex’s cells will still trigger an immune response, requiring patients to take antirejection medication to protect the transplanted cells. “The immunosuppressive regimen being used is well established and developed specifically for islet transplant, and is required to make sure the cells are protected from the immune system and ensure they are able to function,” according to a Vertex spokesperson.
For patients who experience severe, unpredictable hypoglycemia, the trade-off may be worthwhile. The company points to the profound burden of T1D as justification for moving forward with immunosuppression while better solutions develop.
But Vertex isn’t betting solely on this approach. The company is also working on its own hypoimmune cell program, using gene-editing to cloak its fully differentiated stems from immune detection. That program is currently progressing through the research stage. The company’s dual strategy (advancing zimislecel through clinical trials while developing an immunosuppression-free alternative) reflects the broader tension in the field between getting effective therapies to patients now versus waiting for the ideal solution.
What patients want
Even if the gene-editing science succeeds and manufacturing scales, health-care systems face a challenge: expense. “The whole reimbursement model around the world is set up for chronic therapies,” Harr says. “There isn’t yet a mechanism to pay for these.”
A one-time curative therapy with high upfront costs (but decades of savings) doesn’t fit into existing reimbursement frameworks. In the US, patient co-payments can be prohibitive, and hospitals may be disincentivized from offering one-time cures that generate less revenue than chronic disease management.
Scale compounds the problem. Even if 100,000 people are treated annually, it would take 20 years to reach everyone currently with T1D in the US alone.
Despite such challenges, a market is out there.
Back in Uppsala, Carlsson is planning the next trial with stem-cell-derived, gene-modified islets. “All components are there with regard to knowledge,” he says. “It’s mainly a time-and-effort perspective.” Given the unmet need, he expects that regulatory authorities will be interested and supportive of future studies.
The organization Breakthrough T1D recently convened global experts to define patient-reported outcomes for cell therapy trials. The framework, scheduled to be published in the first half of 2026, identifies what matters most to people with T1D who opt for islet transplantation.
Freedom tops the list. “It’s the first time my daughter allowed me to be alone with my grandchild,” one grandmother told Breakthrough T1D’s Dutta after transplantation. Another woman, diagnosed at age 3, wept while describing traveling alone for the first time in 44 years.
For people with T1D, mental well-being, sleep quality, and work productivity matter as much as stable blood glucose levels. Current islet transplantation may require lifelong immunosuppression with serious side effects, yet when offered the choice, patients overwhelmingly accept the trade-off. Dutta told C&EN that recent data from the Canadian Edmonton protocol program showed that of 373 patients offered transplantation, only two declined.
Jo Shorthouse is a freelance science writer from the UK.
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