Regenerative Medicine in Type 1 Diabetes: Opportunities and Obstacles

Stem cell transplantation holds ever greater potential for improving glucose control in patients with type 1 diabetes; however, these same patients also face increased morbidity and mortality for cardiovascular disease, an ongoing hurdle.

with Juan Dominguez-Bendala, PhD, Atta Behfar, MD, PhD, and Jeffrey Halter, MD

Regenerative medicine, driven by developments in stem cell research, is moving ever closer to functional use in the clinical setting. The opportunity to employ the advances in regenerative medicine in type 1 diabetes is introduced by Juan Dominguez-Bendala, PhD, director of stem cell development for translational research and an associate professor of surgery at the Diabetes Research Institute at the University of Miami Miller School of Medicine in Florida.

This discussion was enhanced by exploration of the application of regenerative medicine in improving cardiovascular disease (CVD) outcomes in individuals with diabetes, offered by Atta Behfar, MD, PhD, deputy director of translation for the Center for Regenerative Medicine and director of the Van Cleve Cardiac Regenerative Medicine Program at Mayo Clinic in Rochester, Minnesota. These presentations were featured during a webinar hosted by Science, the journal of the American Association for the Advancement of Science.

Use of stem cells is poised to change current care for patients with type 1 diabetes.

Aim to Tackle Autoimmune Response Arising in Type 1 Diabetes

In cases of type 1 diabetes (T1D), the autoimmune process turns on the pancreas, destroying the beta cells within the islets of Langerhans. While insulin is the mainstay of treatment for type 1 diabetes, it is not a cure, so patients are often faced with chronic glucose imbalances, leading to hypoglycemia and diabetes related complications.

At present, a pancreas transplant presents one alternative to insulin treatment for patients with poorly controlled type 1 diabetes.However, it is challenging as patients must contend with anti-rejection drugs and other issues that typically arise due to organ transplantion. With islet transplantation, on the other hand, the islets are isolated from a donor pancreas and transplanted into the recipient's liver. This process leads to normalization of blood glucose levels, supporting a lower risk of hypoglycemia, and even improved quality of life.2

“We don’t have enough islets to transplant,” said Dr. Dominguez-Bendala. “There are more than three million people in the United States with type 1 diabetes, so the demand is much too great to be able to meet at present.Thus, researchers are turning to other sources, including stem cells, to develop insulin-producing cells."

While patients remain at risk for adverse effects from immune-suppressing drugs, 60% of this cohort achieve insulin independance,"1 Dr. Dominguwz-Bendala told EndocrineWeb. "However, because the rate of pancreatic donation is so low, this approach remain very limited and preliminary."

Introducing Stem Cell Transplantation to Jumpstart Functional Beta Cells

In describing the potential for stem cell applications in patients with type 1 diabetes, Dr. Dominguez-Bendala focuses on therapies aimed to replace pancreatic beta cells that have been destroyed by this autoimmune disease. These emerging therapies rely on human pluripotent stem cells, which have the advantage of growing in unlimited fashion. Although researchers have been able to coax stem cells into becoming insulin-producing beta cells, the process remains inefficient, relying on conditions that are vastly different from those seen during normal embryonic development.

“Understandably, a plastic dish simply cannot mimic the complexity of a living organism,” he said. “As a result, when we perform directed differentiation in vitro, the desired cell type is often only a fraction of the total cells that are derived.”

A research team in Canada, led by Timothy Kieffer, PhD, professor of cellular and physiological sciences at the University of British Columbia in Vancouver, has succeeded in perfecting the differentiation of stem cells into functional beta cells, such that these new cells have produced insulin after transplantation.Other researchers are combating the differentiation problem by using pancreatic beta-cell precursors, which have already committed to becoming beta cells.

As a great example of unusual collaboration, ViaCyte, a company focused on regenerative medicine for diabetes, has partnered with Gore-Tex, a manufacturer of outdoor wear, to develop devices that deliver pancreatic beta cell precursors to patients.One technology under development is a membrane-based encapsulation device that can be implanted under the patient’s skin by the clinician. The device works by protecting pancreatic progenitor cells from attack by the immune system while allowing glucose and insulin to enter and exit the cells unimpeded.   

Reports from early clinical trials of this technology have offered evidence that progenitor cells have the capacity to become differentiated and vascularized, but not to a sufficient enough level to alleviate glucose needs occurring in people with type 1 diabetes. However, a second device, which does not focus on immunoprotective activity, does permit progenitor cells to become vascularized directly. This device is currently being tested in two ongoing patient cohort trials, so outcomes data are not yet available, and so should be anticipated.

Researchers have demonstrated that some patients with long duration diabetes still have insulin-producing beta cells. longstanding feasibility of forming new beta cells, even in patients who have had diabetic for more than 50 years.Several investigative teams are now trying to harness this functionality to promote active beta cell regeneration. One group, for example, has trialed a  treatment that combined inhibitors of dual-specificity tyrosine-regulated kinase 1A and TGF-beta receptor signaling that resulted in beta cells proliferation both in vitro and in vivo.6 

In Dr. Dominguez-Bendala’s laboratory,7 his team has found a subset of pancreatic progenitor cells in the exocrine ductal tree that proliferate and become functional beta cells in response to bone morphogenetic protein 7. These cells may be employed to screen for compounds that could then be developed into drugs capable of stimulating beta cell regeneration, he said.

A Turning Point Attained in Stem Cell Applications in Type 1 Diabetes

During the webinar, Dr. Dominguez-Bendala reported that Vertex Pharmaceuticals recently acquired Semma Therapeutics, marking an inflection point in accelerating the adoption of stem cell therapies for use in patient care. In addition to the clinical trials, he discussed a lineup of clinical trials to ensue.

“The application of human pluripotent stem cells for type 1 diabetes is no longer wishful thinking, but a reality happening right now,” he told EndocrineWeb. “If it works as intended and patients can be freed of insulin injections for months, it will be a drastic improvement in their quality of life.” Patients who struggle with hypoglycemic unawareness or with maintaining stable glucose levels would most certainly gain immense benefit from stem cell therapies.

While promising, Dr. Dominguez-Bendala acknowledged that stem cell therapies remain early in clinical development with a need for phase 3 studies, and still ahead, regulatory and reimbursement hurdles that will have to be navigated before a regenerative medicine approach is ready as a standard of care.

Jeffrey Halter, MD, an endocrinologist and professor emeritus of Internal Medicine at the University of Michigan in Ann Arbor, echoed these comments, and highlighted the need to understand the safety of these therapies.

“The idea of replacing or regenerating beta cells in patients with type 1 diabetes has been around for a long time,” Dr. Halter told EndocrineWeb. “New approaches will require proof of both efficacy and long-term safety. Patients with type 1 diabetes who have a severe metabolic disorder still live for many, many years with their current therapy. Thus, defining safety parameters for any new treatment requiring life-long use are critical.”

One safety issue identified by Dr. Dominguez-Bendala involves stem cells that do not differentiate but remain pluripotent and keep dividing. Transplanting this type of cell might lead to the formation of tumors, especially in patients who are already immunosuppressed. This remains a major concern coming from the federal regulatory agencies and reflects the highest barrier to the introduction of stem cell therapies in the clinic.

He and other researchers have addressed this challenge by engineering stem cells with suicide genes that are activated in any cells that still divide after transplantation or do not become beta cells. In mouse studies, this approach has proven effective not only in preventing the formation of tumors, but also in eliminating tumors that have formed.8

Prevention Remains the Ultimate Goal for Type 1 Diabetes

Although regenerative medicine holds much promise, Dr. Halter emphasized the need for more research aimed toward prevention of this autoimmune disease.

“Gaining a better understanding of the causes of beta cell death and damage that occurs in type 1 diabetes will lead to more effective prevention measures against destruction of pancreatic function, and this is the surest way to ultimately obviate the need for replacement or regeneration of beta cells,” he said.

Stem cell therapies do not represent a cure for diabetes. While alternative transplantation approaches may fill an urgent therapeutic void, he said, the goal must remain finding the means to stop the autoimmune reaction that gives rise to type 1 diabetes at the outset. Ultimately, if we are to offer the most benefit to patients, we will need successful, endogenous regeneration approaches that can be combined with a targeted immunotherapy that addresses the autoimmune behavior, said Dr. Dominguez-Bendala.

Toward that end, a study by Castella and colleagues has made inroads by demonstrating that interleukin 2 (IL-2) has the ability to promote the regulatory T-cell response and thus restore the balance between Th1 cells and regulatory T cells in patients with autoimmune alopecia.9

Looking ahead, according to Dr. Dominguez-Bendala, the Diabetes Islet Preservation Immune Treatment (DIPIT) trial, a Diabetes Research Institute trial authorized by the U.S. Food and Drug Administration (FDA), will use a combination of agents to target various components of the immune system and restore beta-cell health.10

The Institute also has FDA authorization to proceed with a trial to use low-dose IL-2 to rebalance the immune system and preserve remaining insulin-producing cells to sustain their survival and possibly increase insulin production.

Cardiovascular Disease Imposes Greater Needs for Regenerative Medicine

Dr. Behfar said that efforts to use stem cells for CVD have given rise to two paradigms: the introduction of stem cells to form new blood vessels or cardiac tissue, and cell-based therapies that trigger an endogenous response to build, protect, or replenish chronically injured cardiac tissue.11  

With traditional cell-based approaches in cardiology, the research has focused on deriving unselected stem cells from a patient’s bone marrow, then introducing these cells into the diseased myocardium. Although some clinical trials have shown some promise with this approach, many large scale studies have yielded neutral results given differences in the regenerative potency of individual patient’s stem cells.

To gain a clearer understanding of the variability of individual stem cell response, Dr. Behfar and others at the Mayo Clinic have compared the molecular profiles of cells having high regenerative potential with those of cells with low regenerative ability, using a systems biology approach. This work has advanced the ability of researchers to identify and segregate highly reparative cells, which get reintroduced into heart tissue that has been preconditioned to receive them.11 Similar to the process used in beta cell applications, researchers in cardiology are exploring the transplantation of stem cells that are preprogrammed for the myocardium.

Next Step in Disease Management—Aligning Regenerative Medicine with Standard of Care

Regenerative medicine introduces risks as well as offering potential solutions to cardiovascular disease management.

“Regenerative technologies implemented to date have often required additional tools and enhanced skill sets that seem positioned to disrupt the current standards of care, in some ways,” Dr. Behfar said. “People are getting evidence-based, guidelines-directed care, but seek the advantages of regenerative medicine. The adoption and successful implementation of these stem cell technologies can be cumbersome.” In addition, intravenous or intracoronary routes of delivery have been highly inefficient or unsuccessful so more effective methods must be developed.

The challenge has already been addressed; researchers at Mayo Clinic are creating regenerative medicine platforms that align with current standards of care. Dr. Behfar described approaches that rely on percutaneous delivery, which is the same mode of delivery used for angiography or right heart catheterization.

“A physician that can put in a stent will also be able to introduce a biologic using a similar procedure,” he said. “The equipment we’re using and how we’re packaging and developing these biologics are made to conform with routine procedures in cardiovascular surgery, such that the adoption rate will follow suit, matched with the therapeutic potential.”

This approach has been tested in the CHART-1 trial,12 where patients experiencing class III heart failure symptoms with an ejection fraction lower than 25% had their bone marrow harvested. For the treatment group, mesenchymal bone marrow cells were expanded, conditioned in medium to preprogram them to form cardiac tissue, then delivered percutaneously, through a curved needle and catheter, into the myocardium around the scar tissue.12

Dr. Behfar reported that patients with baseline left ventricular end-diastolic volumes of 200 to 370 mL showed a significant response to stem cell therapy based on the primary outcome of a composite mortality rate of worsening heart failure, Minnesota Living with Heart Failure Questionnaire Score, 6-minute walk test, left-ventricular end-systolic volume, and left ventricular ejection fraction at nine months. Survival was also better among these patients.12

Introducing Acellular Therapies Aimed at Improving Cardiovascular Outcomes

Dr. Behfar indicated that even with carefully selected and preconditioned cells, responses varied overall in the CHART-1 trial.13  further analysis showed that highly reparative cells shed exosomes that were highly potent, suggesting that the active ingredient was not the cell but the cell secretions. Researchers at Mayo Clinic have developed a process to purify high concentrations of these exosomes, which enter cells efficiently and interact with different biologic materials.14

In preclinical studies, purified exosomes have shown antioxidant and vasculogenic properties and provided a shield against scar formation by protecting against inflammation arising during a myocardial infarction (MI).

The cells used in cardiovascular regeneration do not last long, he said, which is another reason for the need to move toward cell-free technologies. To this end, there is a clinical trial underway to evaluate patient response and receptiveness to purified exosomes when simultaneously experiencing an acute MI as they undergo procedures to restore blood flow to the heart, according to Dr. Behfar.

“Acute MI is a life-threatening disorder,” said Dr. Halter. “Thus, efforts to minimize heart damage and replace damaged cells has great potential for immediate impact.” However exciting, studies are still needed to establish the safety and efficacy of these treatments beyond experimental use.

A Realistic Expectation of Regenerative Medicine Applications Going Forward

Dr. Behfar noted that the ability to modulate the immune system marks an advance not only in other fields such as cancer but is also advancing the applications in regenerative medicine.

“There are trillions of progenitor cells in almost every single tissue of the body,” he said. “If we can understand the mechanistic basis for activation of these progenitors in the resident tissue and deliver that effectively to damaged tissue while modulating the inflammatory signal, we should be able to achieve effective endogenous repair.”

Dr. Behfar envisions a time when regenerative medicine will likely be accessible to everyone, with affordable costs, and more regenerative platforms offered as “off-the-shelf,” universal donor delivery.

While it’s easy to be enthusiastic about the potential of stem cell approaches, Dr. Halter suggested that the promise of regenerative medicine should not eclipse the importance of keeping prevention as the ultimate goal in chronic disease management.

“Effective prevention measures have led to a reduction in MIs over time,” he told EndocrineWeb. “Thus, reliance on stem cell therapies and acellular therapies to fix damaged heart tissue, even if effective, will be reactive rather than advancing preventive measures.”

What might be anticipated as this emerging therapeutic approach enters the clinical realm?  “If patients had to come to the doctor’s office once every six months for a new subcutaneous stem cell implant, when compared to the current insulin injections and pump therapy, the positive impact in the management of their diabetes would be tremendous,” Dr. Dominguez-Bendala said.

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