By S.I. Rosenbaum
The patient had a full life: She held a demanding academic post, and was raising young children. She took shots of insulin regularly to manage her Type 1 diabetes. Even so, she couldn’t always tell when her blood sugar dipped dangerously low. Without realizing it, she’d find herself in hypoglycemic shock — her thinking impaired, her movements clumsy. If she didn’t recognize what was happening in time, she could even pass out or experience a seizure.
“It was so disruptive at every level of her life,” recalled Ali Naji, MD, PhD’81. “It’s a life-threatening situation.”
In 2009, the woman became a participant in a trial Naji led to transplant islet cells isolated from a donor’s pancreas to her own liver. A narrow catheter delivered the donor cells to the portal vein leading to her liver, where they began to thrive.
Today, 14 years later, Naji’s patient no longer experiences hypoglycemia. What’s more, she no longer needs to take insulin — a result that held true for more than half of the other patients in the trial.
It’s an outcome that may someday be common in the U.S., and is part of a global project to find better treatments for Type 1 diabetes — a project to which Naji has dedicated decades of his career at Penn.
Intelligent Control
Naji first started working on diabetes as an immunology PhD student at Penn in the 1970s. Naji was already a medical school graduate, but, he says, “When I finished my training as a general surgeon, I really thought that I needed to acquire in-depth basic science if I wanted to compete in an academic setting.” His studies led him to work beside the pioneering transplant surgeon and founder of Penn’s transplant program, Clyde F. Barker, MD.
Barker knew first-hand how devastating diabetes could be from performing amputations on patients after the disease had caused neuropathy and blood vessel loss in their limbs, and from performing kidney transplants for people whose diabetes had damaged their own. “Both Barker and I knew that diabetes is a really disastrous disease,” Naji said.
At the time, it had been about 60 years since the advent of insulin therapy had changed diabetes from a fatal disease to a chronic one — “one of the miracles of the 20th century,” Naji says.
But even modern insulin therapy can’t replicate the way the body naturally regulates its insulin levels to control blood glucose concentrations in the normal range. That takes place in tiny clumps of cells scattered throughout the pancreas like so many islands — which are therefore known as “islet cells.”
Some of the cells in these clumps, beta cells, produce insulin, the hormone that helps all the body’s cells take in the glucose they need to function. “It’s an amazing metabolic control, very precise,” said Naji. Governed by the enzyme glucokinase, discovered at Penn by the late Franz Matschinsky, MD, beta cells are capable of sensing and responding to minute changes in the amount of glucose in the bloodstream, making more or less insulin accordingly.
“They are really intelligent,” Naji said. “They have the best radar system that God almighty has ever put in our cells.”
In Type 1 diabetes, these cells are attacked and destroyed by the body’s own immune system, a paradigm that Naji helped to establish. Regular injections or continuous infusion of insulin compensate enough to keep a patient alive — but compared to the precisely calibrated, real-time responses of islet cells, dumping a set amount of insulin under the skin that must make its way into the bloodstream is a blunt method. That’s why patients may still experience severe long-term effects of diabetes even with insulin treatment: blindness, circulation problems, nerve damage, kidney failure, stroke, seizures — and, of course, hypoglycemic attacks.
Ali Naji, MD, PhD
‘Simple but Practical’
Transplanting an entire healthy pancreas can help patients produce and precisely regulate insulin on their own, but the surgery is dangerous, invasive, and complicated. Barker wondered whether transplanting just the islet cells could be just as effective. “He always believed in simple but practical approaches,” Naji recalled.
When Naji began studying with him, Barker was working on animal studies. “It was really amazing as a graduate student to cure an animal [of diabetes] with a simple injection of islet cells,” Naji recalled.
It took decades for Barker and other medical scientists pursuing the idea to learn how best to successfully isolate human islet cells, and to determine how best to transplant them into people.
Over the years there were sporadic, experimental islet cell transplants around the world, but in 2000 a Canadian team successfully performed seven such procedures in a row.
Naji wanted to replicate that success. “I went to Barker and said, ‘It’s time to expand this novel therapy for human clinical trials,’” he recalled.
To isolate islet cells for human transplantation, Naji needed a special, million-dollar facility. Barker found space for him at Stemmler Hall, and philanthropic contributions helped him create a “small but efficient” lab in 2000 where he could process donor pancreases into islet cells ready for transplant.
In 2004, the National Institutes of Health formed the Clinical Islet Transplantation Consortium, a network comprising investigators from across the country as well as Canada and Sweden. Naji and Penn were among them. Over the years, Naji and Penn colleagues including Michael Rickels, MD‘99, now the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases, worked to improve and standardize methods for islet isolation and transplantation, with techniques that include manipulating the immune system to prevent rejection and designing therapies to prevent the islet cells from being damaged or stressed after transplant. A Penn endocrinology fellow at the time, Naji conducted the first islet cell transplant in a patient at the Hospital of the University of Pennsylvania. Rickels investigated how the transplanted islets functioned in their new home of the liver, both to release insulin as well as the islet hormone glucagon that is impaired in type 1 diabetes and critical to the counterregulatory defense against the development of hypoglycemia.
Recently, Rickels led the Consortium’s follow up of the patients who received islet cell transplants as part of the National Institutes of Health–sponsored phase III clinical trials, including those isolated in Naji’s lab. Eight years later, Rickels wrote, over 90% remained cured of their hypoglycemia, and 74% achieved a period of insulin-independence, with more than half no longer requiring insulin.
Building a Better Drug
While islet transplantation has become a standard treatment in the U.K., Canada, Europe, and Australia, in the U.S., federal regulations classify isolated islet cells as a drug, not an organ transplant. This makes the procedure of isolating islet cells prohibitively expensive to perform for commercial production under biologic licensure required by the FDA. So the procedure is in limbo: Despite successful phase III clinical trials, only very limited research support is available in the U.S. But without an industry partner, none of the academic medical centers that manufactured islets for the trials has achieved the FDA licensure required to offer islet cell transplantation in clinical practice.
Meanwhile, research has continued. In addition to his ongoing practice as a transplant surgeon, Naji, together with Rickels, is now leading trials based on discoveries by a researcher at Harvard University, Douglas Melton, PhD, who aims to make islet transplantation even more effective. Instead of isolating islet cells from donor organs, Melton has been growing them from stem cells. These stem cell–derived islets are now being transplanted in a phase I/II clinical trial using the liver as a transplant site and immunosuppression as established by Naji and Rickels as part of the NIH Consortium for deceased donor islet transplantation. Other investigators in the lab are using the gene-editing technology of CRISPR to make these stem cell–derived islets invisible to the recipient’s immune system. This may eliminate the need for future islet cell transplant recipients to take immunosuppressant anti-rejection drugs.
Melton is also developing a procedure for implanting the cells just beneath the skin, rather than in the liver — a less invasive approach.
“I am delighted by the progress of science,” Naji said. “It is a really exciting time — I really believe we will have enormous opportunity to cure Type 1 diabetes.”