A truly groundbreaking diabetes trial is now underway: for the first time, a patient has received a transplant of lab-grown insulin-secreting islet cells that have been gene-edited to evade the immune system. The therapy is called VCTX210, and it raises hopes that people with diabetes could one day enjoy recovered insulin production without having to take immunosuppressive drugs.

The announcement was made by CRISPR Therapeutics, which developed the innovative gene-editing technique, and ViaCyte, a biotech firm devoted to finding a functional cure for diabetes using stem cell-derived pancreatic cells.

We were lucky enough to speak with Dr. James Shapiro, the clinical investigator in the new trial. Dr. Shapiro is a giant in the field—as a surgeon in the late 1990’s he performed the world’s first islet cell transplants for patients with type 1 diabetes, a technique that was dubbed “the Edmonton protocol.” He is now the director of the Clinical Islet and Liver Transplant Programs at the University of Alberta of Edmonton, Canada.

Pancreatic islet cell transplants have proven to be safe and effective, but they remain rare, partially due to the scarcity of organ donors. As a result, Dr. Shapiro says that such transplants are basically restricted to patients with a dire need—for example, those with extreme glucose management challenges, hypoglycemia unawareness, or advanced kidney disease. (They are also almost completely unavailable in the United States). ViaCyte, however, has developed a nearly “limitless” supply of pancreatic islet cells – by growing them in a laboratory from pluripotent stem cells.

A competitor, Vertex, has also devised a solution using stem cells, and the company recently made waves when it announced that the transplanted cells were successful in a clinical trial. That news was widely hailed as a breakthrough, but there was a catch—Vertex’s first patient requires anti-rejection drugs so that his own body doesn’t attack the new islet cells.

Dr. Shapiro told me that any islet cell transplant therapy that requires ongoing immunosuppression will necessarily be limited to a smaller number of patients, mostly those with “really impossible to control type 1 diabetes, patients facing dangerous lows in their blood sugar. And that’s about five percent, perhaps ten percent of the type 1 diabetes population today. And it doesn’t include children.”

“Immunosuppressive drugs are the big barrier for why we don’t do large numbers of cell transplants today.”

The reason is that immunosuppressive drugs can have serious side effects:

“The risks include increased risk of cancers, increased risk of life-threatening infections, side effects on the kidney, and they can also be toxic to the functioning of the transplanted cells and their ability to make insulin.”

“So being able to carry out a transplant with no anti-rejection drugs, if it’s successful, would be a milestone advance for cell therapy in this disease.”

Dr. Shapiro went on to explain that pancreatic cell transplants, if they effectively evade the immune system, could be used in a huge number of patients, potentially in “all forms of diabetes.”

“If we didn’t have that lifetime risk [from immunosuppressive therapy] ahead of us, we would be able to open the gates and include everybody. Not just adults but children and patients with type 2 diabetes. There’s no reason why this cell replacement therapy wouldn’t work in patients with insulin-requiring type 2 diabetes.”

“I think longer-term, if this is shown to be safe, and if it’s shown to be effective – that’s another big if – but if those two are achieved in a trial, then I think we’re going to be looking at much more use of cell therapies like this.”

Gene-editing is not the only proposed method of hiding transplanted islet cells from the immune system. ViaCyte has an alternative solution in the works, a porous pouch that would encapsulate the new islet cells, allowing glucose and insulin to filter across the barrier but barring the larger immune cells. Their competitor Vertex is reportedly working on a similar solution, which they compare to a “teabag.” And earlier this month we reported on a lab that has begun using nanocarriers to deliver small but precise doses of immunosuppressive drugs.

But Dr. Schapiro believes that precision gene-editing with CRISPR—a Nobel-winning technology frequently acclaimed as revolutionary—could ultimately prove to be the winning strategy.

“I think the ability to alter the immune signaling on the cell surface, to make a cell not recognized and not destroyed by the alloimmune system, is going to be a massive advance for all areas of transplantation. Since the 1950s people have been working on the idea of immune tolerance, and the holy grail is transplantation that wouldn’t need any of these immunosuppressive drugs. ViaCyte and CRISPR Therapeutics are really leading the way in that regard.”

The new breakthrough trial has begun with its first patient, the first in the world to have received a transplant of these gene-edited islet cells. The patient “tolerated the surgery without missing a beat.” The surgery doesn’t sound terribly invasive, requiring only “tiny little incisions on the abdominal wall.”

As many as ten patients may eventually receive this first round of transplants. Dr. Shapiro couldn’t have been more complimentary about the volunteers for this trial, or about the other patients that have offered themselves for ViaCyte trials in the past:

“These are amazing people, they have come forward voluntarily, not necessarily to help themselves, but to help mankind. To try for a better future for diabetes across the board. I’m immensely grateful for the bravery and the vision that these patients have to participate in trials like this.”

ViaCyte researcher thawing stem cells for expansion. Image courtesy of ViaCyte, Inc.

There’s no telling how much work it will take before the treatment is ready for primetime, and Dr. Shapiro was understandably hesitant to give me a timeline.

“Patients want to hear when it will be available, but they’re also sick of hearing ‘another five years to a cure,’ so we don’t talk about that. We talk about the immediate challenges ahead of us. It would be nice to have a crystal ball, but at the same time, I think the reality is that we work by facing challenges and fixing them.

“Maybe these first gene edits will get us a long way there, but maybe they won’t be perfect. I don’t know that yet. Maybe further edits and optimization will be required.”

Finally, I asked him a big question: would VCTX210, if all goes according to plan, be considered a “cure” for type 1 diabetes?

“We’re always careful about the word ‘cure.’ I think we can say very clearly that this could be far superior to insulin therapy, because it provides a potential biological solution to this biological disease. It could provide perfect day-to-day and moment-to-moment control of blood sugar that an injection of insulin from the outside cannot do. Even the closed-loop systems have so much lag when you deliver insulin under the skin, it’s really very inefficient compared to a normal pancreas or islet cell transplants.

“Cure is an emotive word. Could this be a potential cure for this disease? I think if you can transplant a limitless source of cells, not need anti-rejection drugs, and allow patients, for their lifetime, not to need insulin … I think we’d all be looking at that and saying, ‘Well, that’s as close to a cure as we can get.’

“Bottom line: this is an incredibly exciting and important trial. It’s the first-in-human trial, the first patient treated, and now we’re off to the races. For me, it’s been an immense privilege to be part of this, and I am really excited about the potential. There’s a lot happening right now in diabetes, but I think this could be big.”

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Read more about insulin, Intensive management, islet cell transplants, islet cells, low blood sugar (hypoglycemia), stem cells, viacyte.

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