Orgenesis Receives New Patent for Potential T1D Cure

Orgenesis is a company that is committed to curing type 1 diabetes with a breakthrough technology that combines cellular therapy and regenerative medicine – “Cellular Transdifferentiation.” Forget the pancreas! Professor Sarah Ferber and the research team at Orgenesis have successfully reprogrammed liver cells into fully functional Insulin Producing Cells (IPCs). They’ve had success curing diabetes in mice, and they are planning to begin Phase 1 clinical trials to see if the same will be true for people like you and me.

What’s really exciting is that Orgenesis was recently granted a new patent that will help further their mission. I was lucky enough to interview Scott Carmer, CEO of Orgenesis North America, about what lies ahead for their company. Here he gives us a fascinating behind-the-scenes-tour.

You recently joined Orgenesis in August, 2014. What drew you to the company? What is the most exciting part about your new role?

After a four month review of published literature (pre-clinical and clinical data), I found Orgenesis through their science – Cellular Transdifferentiation. It was my opinion that the technology they were developing held great promise as a potential cure for type 1 diabetes. The most exciting part of my job – by far – is having the opportunity to work with some of the most dedicated, passionate and intelligent scientists on the planet as we bring this technology to the clinic (Phase 1 trials).

Many people who work in the diabetes world have a personal connection to the disease. I read that you have a child with type 1 diabetes. When was he or she diagnosed? When and why did you decide that you would dedicate your work to curing this disease?

My daughter, Ana, was diagnosed in 2008 – when she was 5 years old. . . so we’ve been living with Type 1 diabetes (as a family) for the last six years.

Professionally, I’ve been in the biopharmaceutical business for the past 26 years – working for some of the most inspiring and successful companies in the industry. . . companies like Genentech, Amgen and MedImmune/AstraZeneca. I’ve benefited enormously from working with many of the world’s leading scientists, drug developers and corporate leadership teams. After Ana’s diagnosis, I felt like I’d been given the chance – perhaps the obligation – to take all that experience and apply it an area that means such a great deal to me, personally. If there’s a possibility – no matter big or small – that I might have a role to play in getting a potential cure to patients. . . I wanted to make sure I was in a position to do so.

Transforming liver cells into beta cells… that’s amazing! It’s like something you’d see in a sci-fi movie. Are there any similar therapies (where one part of a body is being altered to work like another part of the body) being used in other areas of medical research?

Yes – it does sound like a sci-fi movie. But, if you think about it, sci-fi movies have been the source of ideas and technologies that have ultimately found a way to reality (space travel, computers, cell phones, etc). I see this as NO different.

And, yes! There are other approaches currently being investigated that use one cell type to grow other types of tissues – like using olfactory cells to generate neuronal growth in patients with severe spinal chord injuries. Specific to type 1 diabetes, there has been a lot of work done with different types of stem cells. . . efforts to direct their differentiation toward insulin-producing beta-like cells.

I read that Orgenesis chose to use liver cells to mimic insulin-producing beta cells because of the similarities between the liver and the pancreas. I understand that the liver is the best bet. Are there any other organs that Professor Ferber and the research team would consider if the liver cells don’t work out?

We do believe that the liver is the best source of cells to trans-differentiate into fully functional and physiologically glucose-sensitive insulin-producing cells (IPCs). We believe this not only because of their developmental similarities, but also because these cells originate from the patient (autologous) and will not be subject to rejection by the body.

The Orgenesis Team is also exploring alternative cell sources that may have potential to deliver IPCs of the same quality and viability as liver cells.

Orgenesis recently received a new patent. How will it help your research?

Our new patent is a “Methods of Use” patent, and covers all intellectual property associated with the generation of insulin-producing cells from any other non-pancreatic adult cell. This patent is a testament to how innovative and ground-breaking the technology developed by Professor Sarah Ferber really is. The patent will help protect our current and future investments in bringing this very promising technology through all phases of clinical development, regulatory review and hopeful approval. It is our goal to make this therapy available to every patient living with type 1 diabetes.

Recently there’s been breaking news about stem cell research from Harvard Stem Cell Institute (HSCI) and an imminent cure for type 1 diabetes. What are the advantages of Orgenesis’s approach over that of using stem cells?

We feel there are three fundamental areas where using a patient’s own liver cells to produce physiologically glucose sensitive insulin producing cells (IPCs) is different from using stem cells:

Autologous IPCs cells do not require encapsulation
Patients will not require concomitant immunosuppressive therapy
Because we’re turning one adult cell into another adult cell through the use of genetic transcription factors, our trans-differentiation process is very rapid (3-5 days) and does not require an intermediary stage where cells exist in a pluripotent state

(Pluripotency is a state where cells can differentiate into any cell type in the body. Embryonic stem cells are an example of pluripotent cells. Pluripotency has been associated with unwanted proliferative disorders like teratoma formation within encapsulated iPSCs.)

Because liver cells are so closely related to pancreatic cells, we believe they are at a fundamentally different / later starting point in the cellular differentiation process. The liver and pancreas originate from the same embryonic lineage – the endoderm. In fact, both organs develop from the same original group of cells in the embryo. Because of this, they also share many genetic transcription factors and – perhaps most importantly – they each have a built-in glucose sensing system.

In terms of the trans-differentiation process, we treat these liver cells with some of the same pancreatic transcription factors that fetal cells are exposed to during embryonic development. Transcription factors are proteins in the cell nucleus that help determine which genetic material (DNA) is expressed and determine the cell’s final designation. We believe the use of these very specific transcription factors closely mimics the process of pancreatic formation during embryogenesis, and therefore, the resulting insulin-producing cells very closely resemble naturally occurring insulin-producing beta-cells. We are very confident that the IPCs generated from liver-to-pancreas trans-differentiation will result in fully functional and physiologically glucose-sensitive cells.

It’s always been my understanding that if a cure for type 1 diabetes came from stem cells, it would involve the use of encapsulation and immunosuppressive drugs. Are you saying that with Orgenesis’s technology, those things wouldn’t be necessary?

That’s right. Because these cells are autologous (from the patient), they will not need to be encapsulated, nor will a patient need to take chronic immunosuppressive therapy to avoid host rejection. In fact, our pre-clinical data suggest that these cells may even ameliorate some of the adverse immune reactions that occur in type 1 diabetes.

What about the autoimmunity? What’s to stop the body from attacking the new Insulin Producing Cells (the ones that came from the liver), just like it did to the original pancreatic beta cells?

This is a very important question. . . and one that can only be answered once we get into Phase 1 clinical trials. Having said that, we have conducted a pre-clinical experiment (in mice) to address this specific question. In a model specifically designed to mimic auto-immune mediated (type 1) diabetes, we found that liver-to-pancreas differentiated IPCs were NOT subject to auto-immune attack. In fact, the investigators found that when introduced back into these severely hyperglycemic mice, the IPCs not only cured diabetes, but also induced a state of ‘immune tolerance’. This means that the immune system within these mice had been ‘re-set’. In other words, it appears the immune response to the transplanted IPCs shifted from one of “attack” to that of “tolerate”.

This gives us reason to believe / hope that these cells will NOT be subject to auto-immune attack once introduced to a type 1 diabetes patient . . . but as I said, we’ll only know the definitive answer once we’re in Phase 1 trials.

What other obstacles does Orgenesis need to overcome for the technology to become a viable cure?

I think we’ve conducted every pre-clinical experiment conceivable . . . all with very consistent, complimentary and conclusive outcomes. The only thing keeping us from the clinic is the final validation of our GMP (Good Manufacturing Practice) systems and process. And we plan to accomplish this in the very near future.

Once we initiate our clinical development program, issues may arise that we don’t yet foresee . . . this is why clinical trials are so important. Additionally, the process to regulatory approval is long and expensive, and everything has to go well at every stage. As a small company, Orgenesis will need a lot of resources to bring our technology through the approval process and then to make it available to treating physicians and the type 1 diabetes patients they serve.

When do you plan to begin clinical trials? Where will they take place?

We plan to be in Phase 1 trials within the next 12-15 months. We plan to conduct these trials concurrently in the US and Europe.

What would the Orgenesis Cure look like? Talk me through the process (transplantation, etc.) Are there any risks?

Our therapeutic approach would involve three basic steps:

Patient schedules a liver biopsy at an accredited Hospital facility. The biopsy removes 1-2g of liver tissue. In terms of overall mass of the liver, this represents a very small fraction, and would not impact normal liver function or health.
The liver tissue taken from biopsy is sent to a central (Orgenesis) facility where it is put into a special culture to isolate specific hepatocytes – about 2 million cells. These cells are then expanded (multiplied) to a volume of more than a billion cells. They are then exposed to three very specific pancreatic transcript factors. The result is our final product – fully functional, glucose-sensitive Insulin Producing Cells (IPCs)
These cells are put into solution, and shipped back to the patient’s original hospital for transplant back into the patient. This procedure is very similar to the Islet Cell Transplantation procedure that is already used clinically. The IPCs are infused back into the patient’s liver, where they take up residence, and start producing insulin in response to glucose within 3-5 days. It is our goal that patients will be completely insulin-independent within one month of implantation

Risks associated are similar to those associated with the procedures involved (liver biopsy and Cellular Transplantation).

Is there any fear the cells could become deregulated once inside the body? Could they produce too much insulin, or produce it erratically?

This is another important question. In each of our pre-clinical studies conducted to-date, the trans-differentiated IPCs have demonstrated a ‘physiological’ glucose-sensitivity to insulin secretion. This means, that when stimulated with physiologic levels of glucose (5mM-10mM), the IPCs demonstrated an insulin-production response similar to that of normal islet cells.

If the Orgenesis Cure comes to fruition, and I hope it does, are there any other diseases besides type 1 diabetes that could benefit?

If our current approach proves to be safe and effective in type 1 diabetes, we would pursue developing it for other insulin-dependent conditions, like Insulin-dependent type 2 Diabetes

A similar approach using other tissue specific transcription factors may lead to a regenerative cell therapy for other degenerative diseases (neurologic, hematologic, cardiac).

Is there anything else on the horizon for Orgenesis and its mission to cure type 1 diabetes?

We plan to establish centers for autologous therapy worldwide in order to serve the global type 1 diabetes market. These centers will be state-of-the-art cell therapy manufacturing centers and will have the capability to manufacture a number of autologous cell therapies. We hope and believe that our technology will represent a major step forward for every patient currently living with type 1 diabetes.

This sounds promising! When can I sign up?

I like your enthusiasm!!

For more about Orgenesis see here.

*Artwork by Jen Jacobs