Transcript of Interview with Luca Inverardi, M.D.

Narrator:
The Diabetes Research Institute presents a series of reports on the latest progress in cure-focused research – promising discoveries aimed at restoring natural insulin production in those living with diabetes.

Reporter:
Scientists have observed that when women become pregnant, their bodies create more of the cells that produce insulin -- called beta cells. Beta cells live inside clusters of cells called islets.

But just how does the body produce those additional beta cells? What causes them to proliferate?

Scientists at the Diabetes Research Institute are trying to answer those questions. Because if they can figure out how to make beta cells proliferate, researchers could make many more cells available for those suffering from type 1 diabetes.

Right now, there’s a shortage of those cells.

Dr. Luca Inverardi directs a group of researchers working to understand the pregnancy phenomenon.

Inverardi:
“So if we have a pregnant mouse, the pregnant mouse will undergo a wave of proliferation of the beta cells in the pancreas at a certain stage of pregnancy that allows us to study what’s the mechanism of proliferation.”

Reporter:
Once researchers identify how this happens naturally, they would try to make that happen in the lab.

Inverardi:
“If, for example, we unveiled all the mechanisms that lead to beta cell proliferation, we identified all the cues that are necessary, and all the growth factors that are needed, then we might concede that we would harvest a human pancreas, isolate the islets from the human pancreas, put them in culture, increase their mass by tenfold and transplant 10 patients, starting with one donor. That would be already a very major achievement.”

Reporter:
That’s just one area of focus for Inverardi and his team.

Another: a different possible source of beta cells – animals, such as the pig.

The term for transplanting from one species to another is “xenotransplantation.”

Inverardi:
“It’s a great potential, in my opinion, and that would be a complement, not necessarily an alternative, to what we’re trying to accomplish by the use of proliferation of beta cells and generation of beta cells.”

Reporter:
Pig and human insulin are nearly identical. For decades, pig insulin was used by humans with diabetes.

But there are serious concerns. It’s possible that unknown viruses could be transmitted to the recipient along with the pig islets.

And, the recipient’s body would rapidly try to reject the cells from a different species.

Inverardi:
“It is a sizeable risk that we have to take into account in our equation when we try to balance advantages and disadvantages.”

Reporter:
Still, he says, if scientists could overcome these safety issues…

Inverardi:
“We would be immediately capable of utilizing a non-exhaustible source of transplantable tissue. If you think about how many pigs we have available, it would be an instant, enormous leap forward.

"One might argue that that is already available, while everything that we are doing with stem cells and precursor cells might require a much longer time than we think; so I would not dismiss xenotransplantation as something that we shouldn’t look into, but in fact quite the opposite. I think it’s still a very promising field of investigation.”

Reporter:
Another promising field is stem cells – taking a cell in its earliest stages of development, and guiding so it becomes an insulin-producing beta cell.

Not only is the DRI looking at embryonic stem cells, but also cells from human umbilical cord blood.

Inverardi:
“It’s easy to get. It’s in plentiful supply and we hope that the cord blood will have also additional types of stem cells that will be able to give rise to adult beta cells that produce insulin and there are some encouraging initial data that would suggest that that is indeed the case.”

Reporter:
Inverardi says the DRI is also looking at the potential of another kind of stem cell – called a “mesenchymal” cell – harvested from bone marrow and other parts of the body. Increasing the supply of insulin-producing cells is one goal of Inverardi and his team.

Another is to get the body of the patient to accept these cells – without the need for powerful anti-rejection drugs.

Inverardi:
“Right now what we do is we transplant islets and we put patients under an umbrella of chronic immunosuppression to prevent the rejection of islets and this works for quite awhile and well, but as we prevent the rejection of the transplant, we also make the whole immune system much less capable of reacting in a normal fashion to viruses and fungi and other microorganisms.

"So yes, we have an advantage and we achieve our goal of making the transplant survive long term, but we pay a big price.”

Reporter:
The goal is to induce what scientists call “tolerance.”

Inverardi:
“Defining tolerance is not easy, but simply we can say that if we treat shortly the patient so that we teach the immune system not to reject the graft, then we take the patient off any kind of immunosuppressive or immunomodulatory treatment and the graft survives long term, but the immune system works otherwise perfectly normally, that’s tolerance.”

Reporter:
And tolerance, Inverardi says, is the “holy grail.” One approach – in search of the holy grail -- is to re-educate the patient’s immune system so it does not see the new islets as “foreign,” and would therefore accept the cells.

Researchers have been testing strategies using bone marrow.

They transplant bone marrow cells into a recipient. The body can accept bone marrow without the long term need for anti-rejection drugs.

After the patient accepts the foreign bone marrow, it would be conditioned to accept islet cells – and other tissue -- from the same donor.

This is what scientists call “chimerism.”

Inverardi:
“So let’s say that if you have a white and a black mouse and you manage to put some of the black bone marrow into the white mouse, the white mouse now can accept the skin and other organs from the black mouse in the absence of any immunosuppression.

“If you manage to induce a state of chimerism in an animal, you achieve tolerance.”

Reporter:
The challenge, he says, is that before transplanting bone marrow, the recipient must undergo a harsh pre-conditioning regimen. This was designed for those fighting a potentially fatal disease such as leukemia, but it’s not desirable for a potentially widespread treatment for diabetes.

Inverardi:
“So now we’re trying to understand whether the same end result, which is chimerism and tolerance, can be achieved via much milder and clinically acceptable regimen that is clearly not necessary to clear leukemia or lymphoma, but could be utilized in patients that are going to receive a transplant to make them tolerant.”

Reporter:
Inverardi is quick to point out that this is just one strategy to achieve tolerance. The DRI is working on many others.

Inverardi:
“Every single possibility that we have, we’re exploring in terms of its applicability to a safe procedure that can be transferred to the clinical setting for patients that are about to receive an islet transplant.”

Reporter:
He says the ability to move promising ideas quickly – from the lab to the patient, in clinical trials – is one of the great strengths of the DRI.

Inverardi:
“We have a translational approach to research that I think is not equaled anywhere else in the world. We screen promising ideas at the basic level. We select the ones that pass the first set of tests. They go into pre-clinical level, and the ones that still hold promise at the end of this second step are moved to clinical pilot trials. And all of this occurs under the same roof. This is unique.”

Narrator:
This has been a production of the Diabetes Research Institute Foundation.

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