Christof Westenfelder, MD, FACP
Professor of Medicine and Physiology
University of Utah
Consulting Manager of SymbioCellTech, LLC
TSS: Welcome! We are really quite interested in what you have going on. Can you talk to us about the FDA’s interest in your system to make NEO-ISLETS that appear to rescue type 1 diabetes in dogs?
CW: Let me summarize what the main issues are in the treatment of T1D with cells:
1.-scarcity of suitable donors, the possibility of using autologous products does not exist.
2-all implantable islet therapies including Professor Doug Meltons’ elegant therapies still require anti-rejection drugs that are potentially nephrotoxic, and there exists therefore the possibility of having serious infections and developing a malignancy. It remains a real limitation of this type of therapy. The availability and success of Islet Allotransplants remain limited, although outcomes have improved by detailed donor screening systems. As an example, a recent study published in Lancet, from ~15 European centers showed that ~5 cadaveric donors are needed for the 1st therapy and within ~3 years a significant percentage of recipients need additional 5 plus cadaveric donors which may be a difficult to accomplish step.
3- the use of encapsulation devices containing insulin-producing cells and that are placed under the skin has only, because of foreign body reactions, a relatively short-term beneficial effect. The insulin that is released may help initially, then vascularization and cell oxygenation will fail because of induced fibrotic reactions. The subcutaneous administration of insulin via any modality (injections, encapsulation devices) is unfortunately not physiological. The most recent issue of Diabetes summarizes this accurately. The subcutaneous administration of insulin gradually increases insulin resistance. Physiologically, insulin that is released by the pancreas is delivered directly into the portal system of the liver. The insulin concentration in the portal system is reduced by up to 50 plus % before it is released into the general circulation. So normally, the peripheral tissue that has insulin receptors will never see the high concentration of insulin that a patient may generate by the subcutaneous administration of insulin or the release of insulin by the encapsulated insulin producing cells located in the subcutaneous space.
I have worked in the stem cell field for many years and have conducted several clinical trials. I am a Nephrologist and have seen and follow many diabetics on dialysis and on the transplant service. Significantly, up to 50% of diabetic patients develop End Stage Kidney Disease and depend on dialysis or a kidney transplant. I am very familiar with the biology, function and use in Regenerative Medicine of Mesenchymal Stem (MSC) or Stromal Cell, derived from bone marrow, adipose tissue and other tissues. This cell type is currently the most commonly used cell type in clinical trials.
Every capillary of all organs contains these cells (MSC) in a pericyte location, i.e., the “vascular stem cell niche”. They function as pericytes and monitor the health of capillaries and intervene if there is a problem that they can address (e.g. inflammation, infection, fibrosis, impaired endothelial cell function etc.). These cells do not express transplantation antigens (HLA-II, CD40, -80, -84), rendering them immune privileged in certain settings. In a patient who has Type I Diabetes mellitus (T1DM), the glucotoxicity and lipotoxicity that develops in such a patient gradually destroys the vasculoprotective functions of the MSC that reside in the highly vascularized pancreatic Islets. As a consequence, MSCs in the Islets can no longer provide adequate local immune protection, anti-inflammatory effects, anti-apoptotic effect and vasculoprotective effects, thereby facilitating the progressive auto-immune or stress-induced destruction of insulin producing cells. They also have an anti-viral effect. In fact, there is evidence that MSCs can be used to treat Hepatitis-C and we are doing work in this space to address Covid-19 disease that affects not only lungs but also kidneys and other organs.
We reasoned that the unique and complex immune-modulating, anti-inflammatory and organ-protective abilities of MSCs could be exploited when they are co-cultured with islet cells from a healthy donor. In this fashion, allogeneic islet cells are auto- and allo-immune isolated by the MSC component of the formed 3-D organoids named “Neo-Islets”. Both cell lines are co-cultured in an ultra-low adhesion system in which the 2 cell types attach with high efficiency to each other rather than to the plastic of the culture flasks or utilized culture system.
We reported that the intraperitoneal administration of allogeneic NIs to NOD mice with auto-immune T1DM permanently reestablishes normoglycemia and this without the need for anti-rejection drugs. NIs spontaneously engraft in the omentum, where they resume the glucose- sensitive production of insulin and other islet hormones, delivering them, as the pancreas does, directly into the portal system of the liver. The omentum becomes the permanent new endocrine pancreas.
We are currently conducting an FDA-Guided Clinical Pilot Study, using allogeneic canine “Neo-Islets” (cNIs), in insulin-dependent pet dogs in San Diego’s Veterinary Specialty Hospital and at the School of Veterinary Medicine at Washington State University. Similar to what we have shown in NOD mice, we reported that glycemic control and insulin needs in diabetic dogs can be significantly and durably (~ 3 years) improved with the intraperitoneal administration of allogeneic cNIs. The procedure in dogs takes 10-15 minutes. In comparison, highly invasive pancreas transplants in human recipients may take up to 16 hours, and an islet transplant takes 2-3 hours and may have significant side effects. We shave the abdomen of the diabetic dog, sterilize the skin, apply local anesthesia and give a tranquilizer and use ultrasound to guide the safe insertion of a small cannula ~ an inch above the belly button. Once in place, a slow infusion of cNIs (dose based on animal weight) into the peritoneal cavity is carried out. The cNIs are spontaneously taken up by the omentum where they engraft and gradually resume their endocrine functions. There have been no allo-immune responses to the cNIs, and no anti-rejection drugs are needed.
TSS: Why use dogs versus pigs?
CW: Approximately 40% of dogs are currently euthanized when they are diagnosed with insulin-dependent diabetes mellitus. We strongly oppose this approach for humanitarian reasons and also because dogs, rendered or spontaneously diabetic, have significantly contributed and continue to do so to our understanding of diabetes and its therapy.
The number of MSCs that are contained in NIs (murine, canine and human) are totally stable, in dogs for so far 3 years, they don’t proliferate, mal-differentiate or undergo oncogenic transformation.
Most importantly they provide immune isolation against auto- and allo-immune attacks that cause T1DM and rejection of an islet allograft. Accordingly, NI recipients are completely independent of the life-long use of anti-rejection drugs and not exposed to their side effects. And encapsulation devices are also unnecessary.
CW: Do you know the company Viacyte? Their newest encapsulation device, subcutaneously placed and containing insulin-producing cells, is open now, so that blood vessels can grow in to provide oxygenation for the beta-like cells. However, this requires that patients once again must be placed on immune-suppressants.
TSS: How long can the Neo-Islets function in dogs?
CW: The MSC in the neo islets provide dual immune protection. It is one treatment and they appear to remain in the omentum for the life of the dog. So far, the first pet dog with significantly improved diabetes control has reached 3 years following initial NI administration, and no deterioration in glycemic control, adverse effects or allo-immune responses have been observed.
CW: We recently had a successful Pre-IND meeting with the FDA and are now preparing, after we receive the needed IND, for a Phase 1-2 clinical trial in Utah and California. We have made human NIs from 33 non-diabetic individuals and tested them in diabetic NOD/SCID mice. They completely normalize blood sugar levels in these mice. These human NI data together with our dog observations were very positively judged by the FDA. Additional groups of tests need to be carried out with the “final human NI Product” in order for us to obtain an IND. This work is underway.
TSS: What about JDRF? Have they helped?
CW: We have contacted them multiple times and presented our data to them. The JDRF and Helmsley are currently focused on the use of encapsulation devices. Novo Nordisk, Eli Lilly and Jannssen (J and J) are not interested either. However, the FDA and the California Institute of Regenerative Medicine have indicated that they are very interested in our novel technology.
TSS: Regarding the seminal paper by Kevan Herold, “Beta cell death: murder or suicide?” What are your thoughts on this issue?
CW: I believe that there is evidence for both, murder and suicide of beta cells. Both genetics and epigenetics are very important players in the field. We exploit beta cell epigenetics in our potency assay. Accordingly, as we culture expand islet cells from an islet donor, we culture them up to a point where the epigenetic memory is still adequate for the cultured cells to “remember” to re-differentiate into their original cell type in vivo, i.e., into islet-specific endocrine cells.
We can now manufacture up to 600 therapeutic doses, using our technology, from one human donor, which has the capacity to directly and significantly improve world-wide scarcity of pancreas donors and thus has the potential, as we expect, to provide a much larger number of diabetic patients with a curative cell therapy.
TSS: So that’s very scalable then?
CW: Yes, instead of using culture flasks, we use a hollow-fiber culture cell expansion system. You may have seen dialysis machines that utilize hollow-fiber cartridges with a large surface area and relatively small intracapillary volume, which saves expensive culture medium. These hollow-fiber cartridges can be modified to facilitate attachment of cultured cells for economical and large-scale cell expansion (e.g., MSCs, Islet Cells). Formation of Neo-Islets in such a system is currently being optimized. We collaborate in this work with TERUMOBct (Colorado and Japan). The system is called QUANTUM. It is a fully computerized closed system, functions as an FDA approved clean room, the size of a refrigerator.
We also produce in the QUANTUM Exosomes (nano-particles) that are released by MSCs that are cultured in this hollow-fiber system. The Exosomes are 40-100 nm in diameter. Being so small, they can be introduced into perfusion-compromised micro-circulations, as for example seen in patients with myocardial infarctions, diabetic retinopathy, stroke, renal disease etc.). Exosomes are endocytosed by the affected endothelial and other cells and release their therapeutic cargo into the target cells: miRNA, RNA, DNA, lipids and proteins with therapeutic functions that they acquire from their parent cells. Changes in the culture conditions of the parent cells can be used to program the exosome cargo for a particular indication, such as capillary repair, anti-inflammatory activity, immune modulation etc..
The MSC and Exosome technologies complement each other
In one arm of our planned Phase 1-2 Clinical Trial patients in early stage T1D, i.e., without significant end organ damage that generally occurs after 7-10 years on insulin, an IV dose of allogeneic MSCs is administered in parallel with intraperitoneally infused NIs. The injected MSCs spontaneously home to the pancreas and islet microenvironment where they engraft and protect still functioning islets and potentially support neogenesis of beta cells. In patients in later stages of diabetes and significant end organ damage, only NIs are administered and their ability to halt or reverse end organ damage is monitored.
TSS: What is the timeline for these studies?
CW: It depends on adequate funding. CROs are charging $6-7M to do the work that is required to obtain the IND, which puts us in a major funding raising phase. Once we have adequate funding, and a qualified CRO finishes the mandated studies and they are successful, we will be able to obtain the IND for our Phase 1-2 Clinical trial.
If we obtain adequate funding we can begin the Phase 1-2 trial in Q2 of 2021.
TSS: We are trying to host round table events with people like you and other bioengineering focused scientists. Are you interested?
CW: Yes indeed!
An example for discussion and collaborations: We have previously proposed to colleagues in the field that we could co-culture others’ islet-like cells with our MSCs, utilizing the latters’ immune-isolating and other capabilities, in order to allow in vitro and in vivo testing of such novel organoids and confirming that anti-rejection drugs or encapsulation devices are not required.
CW: We also have developed clear concepts as to how we plan to control Type 2 diabetes.
We have 2 detailed papers that document that and how our NI technology works. (See citations below)
TSS: This has been fascinating. One last question, what do you think is going on in the honeymoon?
CW: The still functioning beta cells get more stressed as insulin demand increases while they are functioning in a hostile environment (auto-immune attack, growing gluco- and lipotoxicity, inflammation, pericytopathy, capillary damage). The protective MSCs in the vascular niches of islets become dysfunctional and without them beta and other islet cells lose a major protective principle.
TSS: If you have a diabetic patient with kidney failure and they are up for a kidney transplant, and you infuse MSCs while the patient is receiving the kidney transplant, is the patient’s diabetes cured or affected?
CW: For a while a patient’s diabetes control may be better. It depends on the stage of diabetes a patient is in (early, late), the dose of MSCs, and the use of potentially harmful anti-rejection drugs.
TSS: Why doesn’t the MSC maintain the protection of the islets?
CW: Because in later stages of diabetes the local protection is inadequate, even if aided by recruited MSCs.
CW: One last thing. Patients with T1D are particularly susceptible to Covid-19. They have a 40% mortality rate. It’s imperative that a patient’s blood sugar is optimally controlled for as long as the Covid-19 disease is active. Diabetics have very vulnerable kidneys. Covid-19 can cause kidney failure due to the high renal ACE2 levels. Better glycemic control translates into higher resistance to Covid-19. This will be eventually accomplished by effective vaccines, medications but also optimal blood glucose control with our NI technology.
TSS: Thank you so much Christof for explaining your fascinating approach. We wish you the best of luck with ongoing studies in type 1 diabetes!