GTC Bio Diabetes Summit 2014

April 23-25, 2014; Cambridge, MA; Day #1; Highlights – Draft

Executive Highlights

Hello from the banks of the Charles River in Cambridge, MA, where GTC Bio’s Annual Diabetes Summit just began. The main event of the afternoon was a joint session between GTC’s Diabetes Summit and GTC’s concurrent Stem Cell Summit on the role of stem cell therapies in diabetes. This report contains in-depth coverage of our top 3 highlights from Day #1.

1. The usually tight-lipped BetaLogics (a J&J/Janssen venture) provided a detailed look into its stem cell-based islet transplant program – more detail than we have ever seen before from this company! Dr. Janet Davis, who led the presentation, shared convincing mouse data demonstrating that the pancreatic precursor cells developed through BetaLogics’ step-wise process were able to mature into functional beta cells after in vivo transplantation. Excitingly, she believes that the process that BetaLogics has developed to produce pancreatic precursor cells is ready to advance into clinical testing, although her presentation did not seem to suggest that BetaLogics has developed an encapsulation method yet.

2. Dr. Rohit Kulkarni of the Joslin Diabetes Center and Harvard Medical School touched upon a broader range of applications for pluripotent stem cells. In addition to their potential for helping produce beta cells for transplantation, Dr. Kulkarni noted that stem cell-derived tissue cultures from a given patient could also be used to predict responsiveness to therapies, thereby serving as a tool to individualize therapy. Switching gears, Dr. Kulkarni theorized (based on a type 1 diabetes study from his research group) that diabetes patients’ risk of developing complications from diabetes could depend on the relative presence or absence of DNA repair machinery. If this theory proves true, there are likely microRNA markers that could serve as a valuable predictive biomarker for diabetes complications.

3. Dr. Karen Segal (Mesoblast, Melbourne, Australia) provided a broad overview of the use of cell-based therapies in diabetes – Mesoblast’s mesenchymal progenitor cell therapy for type 2 diabetes and diabetic nephropathy is currently in phase 2. With an optimistic tone, Dr. Segal stated that cell-based therapies have the potential to be disease modifying for both diabetes and its complications. Others apparently share this belief – as of early April, there were 131 past or ongoing trials registered on investigating cell therapies for diabetes.

See below for our detailed coverage of the above presentations, and subsequent question and answer sessions. Stay tuned for our Day #2 coverage as well – the day promises to be packed! For an overview of what is to come, see our GTC Bio Diabetes Summit 2014 Preview.

Detailed Discussion & Commentary

Cell Therapy and Diabetes – Stem Cell Research in the Diabetes Space

BetaLogics: Cell Therapies for Diabetes

Janet Davis, PhD (Janssen Research & Development, Raritan, NJ)

Dr. Janet Davis presented on behalf of BetaLogics, a J&J venture focused on developing a stem cell-based islet transplant therapy to cure diabetes. This was the first significant update we have heard from the company, ever. BetaLogics has established a step-wise differentiation protocol to turn pluripotent cells (human embryonic stem cells or induced pluripotent stem cells) into pancreatic precursor cells. These cells are not fully mature beta cells, but they have the capability to develop into mature beta cells. Dr. Davis presented some convincing in vivo mouse data suggesting that these precursor cells were able to mature into beta cells after being implanted into mice. As such, Dr. Davis believes that the precursor cells are sufficient to advance to clinical testing. BetaLogics does not seem to have developed an a protocol for encapsulation (which would help the cells withstand immune system attack), but plans to do so. BetaLogics’ primary competitor is ViaCyte, which has a beta cell progenitor and encapsulation device poised to begin clinical testing.

  • The two major challenges for islet cell therapies for diabetes are (i) establishing a consistent and scalable cell source; and (ii) immunoprotection. Dr. Davis’ presentation focused on BetaLogics’ extensive work to address the former issue.
  • BetaLogics’ product concept (BL-808) is to develop a process that produces an implantable device that secretes insulin in a glucose-regulating manner, with the goal of providing users with an insulin-free lifestyle. The steps involved include (i) identifying a source of cells that are infinitely expandable (i.e., do not senesce); (ii) taking those cells through a series of differentiation steps to turn those cells into ones that mimic pancreatic beta cells; (iii) cryopreserving them in a bank; and (iv) thawing them and load them into an immunoisolation device that can be implanted into the patient.
  • Dr. Davis briefly summarized BetaLogics’ efforts to develop a cell source. They achieved the most success working with pluripotent stem cells (stem cells that have the flexibility to differentiate into any kind of mature cell found in the human body). BetaLogics did not have much success validating cell sources that already existed in the literature, and found that pluripotent cells were the only ones with enough plasticity to respond to in vitro cues well enough to differentiate into pancreatic endocrine cells.
  • BetaLogics has developed a step-wise differentiation protocol starting with human embryonic stem cells to generate pancreatic precursor cells in vitro in a manner that mimics pancreatic organogenesis during fetal development. Starting with pluripotent embryonic stem cells or induced pluripotent stem cells (iPS), the protocol advances the cells from pluripotency to a definitive endoderm stage to a foregut endoderm stage to a posterior foregut stage and finally to an endocrine precursor stage. The endocrine precursor cells BetaLogics has produced express key transcription factors that would then allow them to turn into mature beta cells. Although the pancreatic precursor cell that BetaLogics has developed in vitro is not a mature adult beta cell, Dr. Davis believes it is advanced enough to move into the clinic.
  • Dr. Davis presented in vivo animal data suggesting that when BetaLogics’ pancreatic precursor cells are implanted into mice, over time they mature into a cell population resembling mature adult beta cells that secrete insulin in a glucose-responsive manner. Studies were conducted in SCID immunocompromised mice. Lines of evidence suggesting that the implanted precursor cells matured into beta cells included the following findings:
    • Significant beta cell maturation occurs between one and three months post-transplant. One month after transplant, the progenitor cells secrete both glucagon and insulin (as visualized using fluorescent staining of these two hormones), but after three months, cells appear to differentiate into glucagon-expressing and insulin-expressing cells, indicating maturation.
    • Significant beta cell maturation also occurs between three and four months, as evidenced by the gradual appearance of key transcription factors. MafA is a critical transcription factor that characterizes a mature beta cell. At three months post-transplant, one sees very little MafA expression. In contrast, MafA expression begins to appear around four months, and only in insulin-secreting cells, which again suggests that the cells are maturing over time into beta cells.
    • Furthermore, between 16 and 21 weeks, one begins to see glucose-regulated expression of insulin. Using Mercodia’s ultra-sensitive C-peptide assay, BetaLogics looked at C-peptide expression in the fasting and fed state from weeks two to 20. Around weeks 16 and 21, levels of C-peptide begin to differ between the fasting and fed state, indicating that more insulin is secreted after being fed than when fasting.
    • Beta cells also secrete other hormones other than insulin, and between months three and eight, the implanted cells also begin secreting amylin.
  • As Dr. Davis mentioned, there are several limitations to preclinical models for such therapies. While the final product will be allogeneic (a transplant from the same species), the animal testing is xenogeneic (cross-species). The lifespan of immunocompromised mice is very short, precluding the collection of longer-term data. Finally, the animals’ small size limits dosing.
  • Dr. Davis described BetaLogics’ vision for how it could address the immunoprotection side of the equation now that they have identified a cell source. She did not disclose any work that has been done on this front, but simply suggested that they might pursue a pouch or “high tech tea bag” that allows nutrients, oxygen, hormones, etc. to flow through while blocking contact from immune cells – essentially an encapsulation technique.
  • Finally, Dr. Davis ended by describing diabetes as a core focus area for J&J: “We sell a variety of things, from Splenda to a new SGLT-2 inhibitor.” She sees cell therapy as another angle that could change the paradigm for diabetes treatments – “It’s a cure.”
  • BetaLogics is an internal venture inside of J&J, currently associated with Janssen in the J&J family of companies. After the landmark 2000 Edmonton study demonstrating proof of concept for islet cell therapy as a potential cure for diabetes, J&J formed the BetaLogics venture in 2002. The company is run like any small biotech would be on the outside except it is under the J&J umbrella – it is funded year-to-year and is expected to meet key milestones.

Questions and Answers

Q: I noticed you had glucagon-producing cells being produced using a protocol to derive beta cells. My question is, have you done long-term experiments to look at markers of ectoderm, mesoderm, endoderm in addition to insulin producing cells and glucagon producing cells?

A: You’re right that the characterization of these cells is key. Early in our endeavors it was difficult to get a very high efficient population of pancreatic endoderm. This beta cell organogenesis is one of hardest cells, in my opinion, to make. For this therapy you actually desire beta cells not alpha cells. The alpha cells appear to be default pathway. However the protocol we’ve developed tends to skew the population towards being the beta cell pathway when implanted in vivo.

Q: Related to immunogenesis, you talked about how you’ll look for markers of immunogenesis. In a type 1 patient who has already been exposed to some of these antigens, if you put cells back in, will you get re-activation of those autoimmune attacks?

A: Some of these questions won’t be addressed until a phase 1 trial. I’m hoping that the veil in our encapsulation will prevent cell-to-cell contact to prevent an autoimmune response.

Q: What do you do about the cells that are “contaminated”? I understand you’re saying you skew towards the beta cell, but you will always have some cells that are not beta cells. What happens to those in vitro and in therapy?

A: I showed you in vivo pictures where we do see endocrine cells that resemble what you would see in an islet. I’m not sure anyone really knows if there’s crosstalk between those populations that self regulates the final mature behavior of those populations. The efficiency by which you drive the population to express only those key markers is key.

Q: There was talk a couple years ago saying that it was transcription factors like FOXO that were controlling the switch from alpha to beta cell. Have you looked into this to modulate them and to get a better population of beta cells from your precursor?

A: We would not want to do that through the kind of research endeavors where you actually put genes into the cells. We would prefer to do that by touching specific pathways by some other mechanism that efficiently upregulates those key transcription factors. We believe our protocol tends to do that for key transcription factors. I mentioned MafA being one of the most critical transcription factors defining the beta cell. Our latest work suggests we’re driving towards having just beta cells.


The Use of Human-Induced Pluripotent Stem Cells to Treat Diabetes and its Complications

Rohit Kulkarni, MD, PhD (Joslin Diabetes Center, Boston, MA)

Dr. Rohit Kulkarni of the Joslin Diabetes Center and Harvard Medical School discussed how human-induced pluripotent stem cells (hiPSCs) could be used to treat diabetes and its complications. As opposed to other classes of stem cells (such as embryonic stem cells), hiPSCs can be derived from small skin or blood samples, and through a complex process (that is still being developed) they can then be re-differentiated into beta cells and potentially other cell classes that could be used to treat the vascular, renal, and retinal complications of diabetes. Dr. Kulkarni went on to point out that hiPSCs have utility beyond their potential direct therapeutic value. Researchers (and, perhaps in the future, clinicians) could derive hiPSCs from a small skin or blood sample, and differentiate them into any number of relevant specialized cells. Those cell cultures could be used (i) to test a variety of therapies for diabetes and its complications, (ii) to identify the ideal therapy for a given condition, or even (iii) to individualize therapy for a particular patient. Switching gears from hiPSCs, Dr. Kulkarni discussed potential predictive microRNA biomarkers for the complications of type 1 diabetes, based on the theory that the development of complications is due in part to a relative lack of DNA repair machinery.  

  • Dr. Kulkarni suggested that a microRNA (whose expression is associated with a lack of DNA repair machinery) might have utility as a predictive biomarker for complications in patients with type 1 diabetes. He cited a study from his research group that compared gene expression from type 1 diabetes patients with complications, patients without complications, and non-diabetic individuals. The data showed (rather strikingly) that gene expression was largely similar between people with type 1 diabetes without complications and people without diabetes. In contrast, gene expression was very different in type 1 diabetes patients with complications. Dr. Kulkarni theorized that a type 1 diabetes patient’s risk for complications might be the product of a relative lack of DNA repair machinery that would prevent cells from effectively repairing tissues, subsequently leading to complications. A lack of DNA repair machinery is believed to be associated with abnormally high expression of a specific microRNA strand. This microRNA (which might be measurable in the blood) could potentially serve as a predictive biomarker for complications, should Dr. Kulkarni’s theory be confirmed by further study.
  • Much of Dr. Kulkarni’s work in hiPSCs and diabetes has focused on the relatively rare maturity onset diabetes of the young (MODY), which he characterized as a form of diabetes that is a particular opportunity for gene therapy. As opposed to type 1 and type 2 diabetes, which almost certainly have a multifactorial set of contributors, MODY can generally be linked to a change in a single gene. Correcting this defect and using differentiated stem cells to introduce healthy beta cells back into the body is an application that Dr. Kulkarni sees as a nearer-term target area for stem cell therapy in diabetes.  
  • The derivation of insulin-producing beta cells from hiPSCs is a challenging process that has yet to be perfected. Dr. Kulkarni highlighted that there are at least five discrete stages of growth that a hiPSC must pass through before it matures into a beta cell; at each stage, there is room for the cell to differentiate incorrectly, and there are a number of transcription factors required to guide differentiation in the right direction. Dr. Kulkarni’s team has been able to produce beta cells, but these cells do not release insulin in vitro, indicating that there might be additional unknown signaling mechanisms in vivo that are required for the full maturation of beta cells.

Questions and Answers:

Q: How are you able to study these cells in healthy volunteers?

A: We take skin biopsies form healthy volunteers, and we do not see that as an issue. All we need is a 3 mm biopsy of the skin. Now, the technology is improving so fast that we don’t need a skin biopsy; we only need blood samples to create iPS cells.

Q: What therapeutic approach could you use to get to a lower microRNA level, if the microRNA theory you discussed is true? Is there microRNA circulating in the blood?

A: That microRNA is circulating in the blood for sure. The question is: what is regulating that microRNA? We’re doing experiments where we take normal human cells, knock out microRNA expression in some cells, overexpress the microRNA in other cells, and compare the two cell populations. The number of DNA repair errors is higher in the cells that express the microRNA.

Q: Can you use small molecules to modulate the microRNA levels?

A: We’re working in that area. It has to be done with pharmaceutical companies, given the large number of screening tools and libraries you need. We’re screening small molecules to see if a small molecule would dissimulate any microRNAs.

Q: Have you had challenges finding funding for these studies?

A: Funding is a huge issue for us. Nearly all the data I presented has been from two grants from JDRF, which we are very grateful for. We will go to the NIH with this data, and hope to get support for work in patients themselves.


Cell Therapy for Diabetes and Its Complications

Karen Segal, PhD (Senior Vice President, Diabetes and Metabolic Diseases, Mesoblast, Melbourne, Australia)

Mesoblast’s Dr. Karen Segal opened the first session of the meeting and moderated the rest of the day’s proceedings. She provided a broad overview of how cell therapy could be applied to diabetes and its complications. As background, Mesoblast is developing a mesenchymal precursor cell (MPC) therapy for type 2 diabetes and diabetic kidney disease (currently in phase 2; Dr. Segal noted in Q&A that Dr. Jay Skyler would present phase 2 results in June). Dr. Segal set the stage for her presentation by noting that existing treatments for type 2 diabetes do not halt the progression of renal, retinal, and other categories of diabetes complications. Stem cell therapy could address the unmet need for therapies for diabetes complications due to its disease-modifying potential and ability to halt or reverse microvascular and macrovascular complications. Cell therapy is believed to have anti-inflammatory, anti-fibrotic, angiogenic, anti-scarring, and chemoattractive effects. Encouragingly, as of April 9, 131 clinical stem cell trials in diabetes have been/are being conducted worldwide according to, of which 40 were interventional treatment-related studies. Of these 40 studies, 58% were conducted in type 1 diabetes patients, and mesenchymal cells were the most common cell type used.

  • The disease-modifying potential of stem cell therapies, in Dr. Segal’s view, has the potential to fill a number of treatment gaps in type 2 diabetes. The predominant effects of mesenchymal lineage cells include immunomodulation, inhibition of apoptosis, angiogenesis, support of stem and progenitor cell growth, anti-scarring, and chemoattraction. This range of effects could halt or reverse microvascular complications, provide a macrovascular benefit, and improve beta cell mass and function. The need to treat the complications of diabetes is, of course, enormous: diabetic retinopathy is the leading cause of blindness in adults; diabetic nephropathy costs an estimated$28 billion in the US; stroke and cardiovascular disease account for 65% of deaths in type 2 diabetes patients; and diabetic neuropathy is a leading cause of lower extremity amputations. Dr. Segal characterized mesenchymal precursor cell (MPC) therapy as a major key player in the future of diabetes therapy.
  • There are still a number of challenges that must be addressed to bring cell therapy products to the market. As Dr. Segal noted, “These therapies are not technically drugs, so everything about drug development goes out the window.” In the transition from pre-clinical to clinical stages, researchers must address challenges in “dosing calculations” for such a therapy, decide upon suitable models for disease, select appropriate cells for therapy, and manufacture cells under the correct conditions. Encouragingly, Dr. Segal commented that the FDA has an office of cell therapy and gene therapy that has been a fairly enthusiastic supporter of ongoing research and clinical development efforts.
  • For context on the extent to which stem cells are being used in diabetes clinical trials, Dr. Segal showed that inputting a “stem cells and diabetes” query on resulted in 131 trials worldwide (as of April 9, 2014). The highest distribution of these were in the US (n=45), with Europe a close second (n=32), and China following (n=29). Of these 131 cell therapy studies, 40 were interventional treatment-related trials. Of these 40: 58% were conducted in type 1 diabetes patients; 38% used autologous cells; 43% were conducted in China; 15% were based in the US; the most common cell type used was mesenchymal cells; and the most common cell source was bone marrow.
  • Before 2006, almost all mesenchymal stem cells were bone marrow-derived, but more recently there has been a shift towards adipose and embryonic stem cells. During Q&A Dr. Segal shared that there are no ongoing clinical trials that compare the superiority of one stem cell source versus another. However, Dr. Segal noted that some preclinical trials suggest that adipose derived stem cells may be particularly potent.

Questions and Answers

Q: Do you know of any ongoing studies with stem cell therapy in diabetic neuropathy?

A: There is a tremendous amount of work being done on ischemia and neuroischemia with diabetic foot ulcers that have the etiology of diabetic neuropathy.

Comment: Major studies are being conducted in Japan that use adipose tissue, which could potentially move into clinical studies. They used undifferentiated stem cells that were administered systemically.

Q: Can you share any promising outcomes of any trials?

A: I know a number of cardiovascular studies have been published; are there any audience members that want to share their work in this area? [There were no volunteers] For diabetes, there have been a couple of papers in Stem Cell Educator conducted in China. Those used a very different approach in which patients were connected to dialysis and their blood was run through machines that exposed the blood to stem cells. Also, Mesoblast is conducting two phase 2 studies for diabetes patients, one of which is specifically for diabetic kidney disease. Dr. Jay Skyler will present the diabetic kidney disease results in June, so I will not discuss those results. The other study is still ongoing and no results have been released yet.

Q: You noted that there were eight to ten sources for obtaining stem cells and 25 different markers. How transferrable is that information for people working with bone marrow to those working with mesenchymal adipose? It doesn’t appear that there is much homogeneity that is being considered.

A: From what I understand and from FDA guidance, the markers need to be established for every cell type individually. You can’t just assume that one cell will be like another. Thus the potency markers and all of the different assays need to be established on an individual basis.

Q: Are there difference being found in the bone marrow mesenchymal and adipose derived stem cells? Has anyone looked at which is superior in one application versus another?

A: I’m not aware of any ongoing clinical trials that compare one source against another. However, some preclinical trials may suggest that adipose derived stem cells may be more potent.

--by Jessica Dong, Jenny Tan, Manu Venkat, and Kelly Close