Gene-Edited Stem Cell-Derived Therapies – A Functional Cure for T1D?

The incidence of diabetes is increasing globally at a concerning rate: an estimated 415 million people are living with the condition, and by 2040, cases are expected to increase to 642 million people. No cure exists, and current therapies are centered on lifetime management of the condition, through monitoring diet and the use of diabetes medications and insulin injections.  

ViaCyte, a clinical-stage regenerative medicine company, is striving to change this and develop a functional cure for type 1 diabetes (T1D). The company is partnering with CRISPR Therapeutics to create an allogeneic, gene-edited, immune-evasive and stem cell-derived therapy for the treatment of T1D. Technology Networks had the pleasure of speaking with Michael Yang, president and chief executive officer of ViaCyte, to learn more about the therapy and the technology behind it.

AM: ViaCyte’s stem cell-derived technologies, including VCTX210, are based on pancreatic-lineage cells. Can you tell us more about the cells and their intended effects?

MY: Pancreatic islet cells are responsible for insulin production, and they are destroyed by the body’s immune system in people with T1D. To overcome this challenge, we have developed our lead product candidate, PEC-Direct, which is comprised of stem-cell derived, pancreatic cells in a credit-card-size pouch with perforations in the membrane enabling vascularization. These cells are designed to differentiate into mature islet cells after implantation and produce both insulin and glucagon to regulate blood glucose.

PEC-Direct is undergoing first-in-human clinical trials in patients at high risk for severe complications of T1D, including hypoglycemia unawareness. These studies show early promising results, suggesting that these cells can offer a potential scalable, renewable source of pancreatic islet cells. The findings also provide the first reported evidence that differentiated stem cells implanted in patients can generate glucose-responsive insulin secretion and clinically meaningful improvements in glycemic control in a patient with T1D concurrent with decreased exogenous insulin requirements. It gives us enormous hope for the future potential of a functional cure for T1D.

We have demonstrated proof-of-concept that our pancreatic cells can produce insulin and control blood glucose. However, the PEC-Direct program requires concurrent immunosuppression. To address that challenge, we are working in collaboration with CRISPR Therapeutics on gene-edited cells designed to not only enable production of insulin and glycemic control but also evade the immune system and eliminate the need for immunosuppressants.

AM: What is the status of the program?

MY: We are excited that regulatory guidance from Health Canada is enabling us to move forward with a first-in-clinic Phase I safety trial of VCTX210. We’re breaking new ground with a next-generation approach that may eliminate the need for immunosuppression and, as a result, potentially broaden the number and types of diabetes patients who can be treated. We look forward to commencing the trial and providing updates on our progress.

AM: How will the cells be implanted into the patient?

MY: The cells will be contained in the same type of device that is used for PEC-Direct. They are implanted under the skin during an outpatient procedure and configured to enable direct vascularization of the engrafted cells.

AM: Why is immunosuppression required with some allogeneic implanted cell therapies?

MY: Implanted cells are allogeneic and, thus, can be recognized as foreign by the body’s immune system. Moreover, T1D is an autoimmune disease, in which a person’s own immune system attacks the pancreas’ functioning beta cells. When implanted allogeneic cells come into contact with cells of the immune system, immunosuppressants must be used to prevent immune rejection.  Alternatively, immunosuppression could be avoided if approaches are used to enable cells to evade the immune system.

AM: Do the gene-edited cells eliminate the need for patients to take immunosuppressive drugs? Can you explain how this may be achieved?

MY: The product is specifically engineered to avoid destruction by the patient’s immune system and potentially eliminate the need for immunosuppressants. At the European Association for the Study of Diabetes (EASD) meeting in 2019, CRISPR Therapeutics shared information on two of the gene edits, specifically the elimination of the β2-microglobulin (B2M) gene and expression of the pro-tolerance programmed death-ligand 1 (PD-L1) to inhibit T cell activation by the immune system. After gene-editing of the parent cell line, the cells will be differentiated into pancreatic endoderm cells, which will likely be housed in the same type of device used for ViaCyte’s PEC-Direct. This device would enable direct interaction between blood vessels and the implanted cells, but because the cells are designed to be immune-evasive, we would expect them not to be rejected by the immune system. Pre-clinical studies of the gene-edited cells show protection against activated T cells. With the initiation of a clinical trial of the VCTX210 candidate, we will gain additional data from patients on the immune evasiveness of the cells.

AM: How do gene-edited cells fit in with ViaCyte’s full portfolio of investigative, stem cell-derived therapies for T1D?

MY: We continue to advance a variety of product candidates to target a functional cure for all patients with T1D as well as those with insulin-requiring T2D. We’re manufacturing these products under quality-controlled conditions to provide a virtually unlimited supply of cells that can be optimally and safely administered to patients. By combining these products with new gene-editing approaches and device designs, we aim to eliminate the need for immunosuppressants, which would open up diabetes treatments to a much broader patient population. We’re pursuing encapsulation device approaches in collaboration with W.L. Gore & Associates to enclose our pancreatic cells and provide therapeutic potential without immunosuppression. Additionally, if our next-gen gene-editing immune-evasive technology successfully eliminates the need for immunosuppressants, it would free people from the associated risks of immunosuppression. We’re excited to introduce a first-in-class CRISPR-edited diabetes therapy to the clinic—a major step forward in transforming stem cell-derived treatments for diabetes.

AM: Where do you see the future of gene-edited stem-cell derived therapies heading?

MY: Gene-edited stem cell-derived therapies could very well be a game changer for the field. If we can successfully combine providing an unlimited source of insulin-secreting islet cells with eliminating the need for immune suppression, we could be well on our way toward developing a functional cure for T1D and insulin-requiring T2D. If that comes to pass, millions of people with diabetes across the world would be free from the daily burdens of managing their disease as well as from its many debilitating and life-threatening complications. It’s a goal we at ViaCyte work toward every day.

Michael Yang was speaking to Anna MacDonald, Science Writer for Technology Networks.