Where Are the Cell Therapies for Type 1 Diabetes?

There is a team readily available to report 24/7 to a facility at the University of Chicago Medical Center to quickly receive and process a deceased donor’s pancreas into isolated islets for infusion into a patient with type 1 diabetes. The results have been astounding. Some patients who underwent allogeneic pancreatic islet transplants over a decade ago are still insulin-free today.

“People who were small children when they developed diabetes and had no idea what life was like without diabetes are overjoyed and having their minds blown that they can stop taking insulin,” said Piotr Witkowski, MD, PhD, professor of surgery and director of the Pancreatic and Islet Transplant Program at the University of Chicago Medicine.

However, for the approximately 2 million patients with type 1 diabetes in the U.S., a seemingly widely applicable, easy, and non-invasive treatment is only used a few times per year. And type 1 diabetes patients have not been blessed like their type 2 diabetes counterparts with semaglutide (Ozempic) and tirzepatide (Mounjaro). Instead, type 1 diabetes patients remain uncured and must continue a lifelong regimen of insulin administration via daily injections, an insulin pump, or an automated insulin delivery system. It has been this way for over a century (Box 1).

Are islet transplants a drug?

In the late 1980s and early 1990s, a team of researchers at the University of Alberta developed allogeneic pancreatic islet transplantation from deceased donors, which was published in the New England Journal of Medicine in 2000. It’s not the most complicated protocol: a donor pancreas is cut into small pieces, gently enzyme-dissociated into small cell clusters, centrifuged to isolate the cells, and then prepared for injection. This produces islet clusters in the transplant recipient that revascularize the portal vein.

From 2000 to 2014, clinical trials were conducted in the U.S. to demonstrate that deceased donor-derived islet transplantation is safe and effective. Toward the end of a 14-year effort, the FDA’s stance was that allogeneic pancreatic islet transplants required an accepted Biologics Licence Application (BLA) for approval.

As a result, Witkowski and others have suggested that the United Network for Organ Sharing, the Organ Procurement and Transplantation Network, and the Health Resources and Services Administration oversee a regulatory pathway for human islets that is similar to the one currently in place for other human organs in the U.S. However, the FDA has continued to reject the proposals, primarily due to a disagreement over whether the pancreatic islets made from deceased donors should be considered organs or manufacturable drugs.

Witkowski disagrees, and he’s not alone in believing that pancreatic islets from deceased donors qualify as organs.

Rita Bottino, PhD, who leads Imagine Pharma’s Islet Programs, agrees with Witkowski based on the fact that islets share many characteristics with transplanted organs, such as their natural existence in the human body, lack of manufacturing, preserved architecture, and integration into the recipient’s vasculature.

“If you culture single pancreatic beta islet cells alone, they do not even produce good insulin,” Bottino explained. “They must work in tandem with other cells to form a regulatory network. We take these micro-organs and give them to a patient, so we do not actually manufacture anything. They are distinct from drug entities such as vaccines, pills, and chemicals. They are micro-organs.”

Importantly, allogeneic islets from deceased donors behave similarly to any other transplanted organ in that they cannot withstand temperatures below zero and can only be kept at room temperature for a short period of time. Also, islets and organs for transplantation cannot be stored in commercial organ banks, require a potency certificate, and can only be assessed for effectiveness after transplantation based on successful clinical outcomes. As a result, organ transplant programs, and not manufacturers, are held responsible for the success of islet transplants. Furthermore, because human islets are inherently varied, like organs, they cannot be standardized as medications.

“Since 2014, we have been in limbo because we have the therapy that we can use, which is not approved as a drug by the FDA,” said Witkowski. “[Allogeneic pancreatic islet transplants are] working and insurance wants to pay, but they can’t for an unapproved drug.”

Next-generation type 1 diabetes therapies

Witkowski appears to be one of the last, if not the last, people standing in the U.S. doing islet transplants for type 1 diabetes. He has been able to get some funding to help the crawl towards a BLA, even if it enables him to do only about 20 procedures per year. But that does not mean that the development of therapies for type 1 diabetes by Witkowski and others has completely died out—on the contrary, it is beginning to blossom.

Last year, one team finally broke through the FDA’s requirements for allogeneic pancreatic islet cellular therapy. After heeding the FDA’s requirements, CellTrans was able to get approval for Lantidra™ for type 1 diabetes. However, Lantidra has not been without its share of problems. Its islet beta cells, extracted from donated pancreas tissue, are transplanted into the livers of adult patients who continue to experience dramatic blood sugar swings despite intensive insulin regimens. In clinical studies of 30 participants who received one to three infusions, 21 did not require additional insulin for at least a year, of whom 11 remained insulin-free for more than five years. However, it does not appear that Lantidra will monopolize the type 1 diabetes market anytime soon, especially as it is still unavailable to patients one year after the BLA approval.

A different approach is to drop the human donor and transplantation aspects entirely for a more tried-and-true cellular therapy. The creation of stem cell-derived, lab-grown islets has gained a lot of traction in recent years, despite being undoubtedly a much more costly, intricate, and possibly profitable procedure. The first FDA-approved CRISPR-based therapy provider, Vertex Pharmaceuticals, made headlines in October 2021 when it revealed that treatment of type 1 diabetes in one patient, in whom allogeneic stem cells (VX-880) had fully differentiated to insulin-producing islet cells.

“Vertex has effectively cracked the code on making fully differentiated islet producing cells on-demand, which have demonstrated efficacy in early clinical results and can be scaled up to meet demand,” a spokesperson for Vertex told Inside Precision Medicine.

When the FDA placed a clinical hold on the Phase I/II VX-880 study in May 2022 after two patient deaths, the initial promise appeared to have been too good to be true. However, the FDA lifted the regulatory pause in July 2022 after a review showed that the study pause was “protocol-specified” and that the deaths were “unrelated” to the treatment being studied.

Suppress graft rejection or immunoprotect islets

Regardless of the allogenic approach, whether from deceased patients or stem cells, the problem of graft rejection remains, and two main approaches have emerged: immunoprotective encapsulation and immunosuppression.

With VX264, Vertex is protecting its fully differentiated pancreatic islet cells derived from stem cells from the immune system in a capsule-like device that is surgically implanted into the body. The idea for the immunoprotective device used by Vertex (and pioneered by Viacyte) is not entirely new and has been explored by several biopharma companies and researchers, including Canadian biotechnology company Sernova, which is developing an immune-protected “Cell Pouch System” to treat a variety of chronic diseases, like type 1 diabetes. One year ago, Sernova presented data for their first cohort of the ongoing Phase 1/2 clinical trial, in which the first five patients to complete protocol-defined islet transplants achieved insulin independence for ongoing periods of six to 38 months.

Eledon Pharmaceuticals has taken the more traditional approach to host-graft rejection by using immunosuppression. While Eledon’s primary focus is on kidney transplants, the company announced in January 2024 that the first participant in an investigator-led clinical trial has received an islet cell transplant and is being treated with their novel immunosuppression regimen, which includes tegoprubart, the company’s novel anti-CD40L antibody. 

Eledon CEO David-Alexandre C. Gros, MD, said that tegoprubart is designed to prevent transplant rejection by disrupting the CD40-CD40L co-stimulatory pathway, a primary mechanism through which immune cells are activated and mediate organ rejection. Human clinical trials and non-human primate pre-clinical studies have demonstrated the potential for tegoprubart to offer better efficacy and improved safety, including a reduction in the diabetogenic side effects associated with standard immunosuppressants like calcineurin inhibitors. Tegoprubart is currently in a Phase II clinical trial for islet cell transplantation using human cadaveric cells.

“Tegoprubart has potential applications as an adjunct therapy across islet cell transplantation technologies, including cells sourced from pigs (xenotransplantation), manufactured cells both with and without cloaking technologies, and in combination with delivery devices such as encapsulation pouches,” Gros told Inside Precision Medicine. “As such, we believe tegoprubart is the key to fully unlocking the potential of islet cell transplantation as a functional cure for Type 1 diabetes.”

A scarcity of genome-editing angles

The development of type 1 diabetes therapies based on gene editing, whether an edited autologous approach or an in vivo editing approach, has generated little to no hype.

For the latter, no research has gone much further than testing in mice. The biggest wave was made in 2022 by the Garvan Institute of Medical Research in Australia, which announced that an in vivo gene therapy program using adeno-associated viruses (AAVs) had received funding and approval to begin clinical trials. The treatment, called GARV-AAV2-A20, is based on work done by Shane Grey, PhD, head of the Transplantation Immunology Lab at Garvan. His team identified a key protein known as A20, which is involved in inflammation and autoimmune disorders. The protein could be used to genetically engineer insulin-producing islet cells, slowing or stopping damage from the immune system. The last update on GARV-AAV2-A20 stated that “patients will be recruited through the Royal Adelaide Hospital in mid-2024.”

The most recent development in gene-edited cell therapy occurred earlier this year, when Vertex parted ways with CRISPR Therapeutics on a gene-edited, stem cell-derived cell therapy for type 1 diabetes. A next-generation prospect and VCTX210, the initial drug candidate, both began clinical trials in 2022. CRISPR, which will fully own the assets once the opt-out is completed, intends to continue running a Phase I clinical trial of the next-generation candidate, now known as CTX211, without the assistance of Vertex. The clinical trial is scheduled to be completed in 2025. 

Vertex hasn’t put all of its gene-editing efforts in this field to rest, but it doesn’t have to do that with a genomic engineering strategy that treats type 1 diabetes directly. Vertex does have a hypoimmune cell program, which involves using CRISPR-Cas9 to gene edit the same stem cell-derived, fully differentiated islets used in the VX-880 and VX-264 programs to cloak the cells from the immune system. This program is progressing through the research stage. When asked whether Vertex has any gene therapy approaches for type 1 diabetes, the spokesperson stated, “Vertex is currently developing cell therapies for type 1 diabetes.”

The search for the right gene therapies for type 1 diabetes continues, starting with how certain cells in the body can be reprogrammed to make insulin and not experience an immune system response. But right now, it looks like the next approval in the type 1 diabetes space is most likely not going to be based on gene-editing but rather on unmodified allogenic stem cell-derived islets.

Whoever strikes first, Witkowski, who is a consultant for Vertex, Sernova, and Eledon, will be involved. While he may not get approval for allogeneic islet transplants from deceased donors, Witkowski is doing everything he can to move all clinical trials of islet cell transplantation forward to make sure that type 1 diabetes patients get a treatment, and maybe even a cure, that can save and change their lives.

Jonathan D. Grinstein’s wonder for the human mind and body led him to an undergraduate education in Neural Science and Philosophy and a doctorate in Biomedical science. He has 10 years of experience in experimental and computational research, during which he was a co-author on research articles in journals such as Nature and Cell. Since then, Jonathan hung up his lab coat and has explored positions in science writing and editing. Jonathan’s science writing work has been featured in Scientific American, Genetic Engineering and Biotechnology News (GEN), and NEO.LIFE.