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Under the Microscope

Under the Microscope with...Giacomo Lanzoni, Ph.D.

The DRI has shown that islet cell transplantation can restore natural insulin production in those with type 1 diabetes. Almost all patients have been able to discontinue their use of insulin and maintain normal blood sugar levels, some for more than 10 years.
 
However, over time, most of these patients have had to resume insulin therapy. Researchers believe that many of the transplanted islet cells are lost at the time of infusion and in the days following the procedure due to several reasons, among them is a temporary lack of adequate oxygen immediately post-transplant within the infusion site; the harmful inflammation that occurs at the implant site; and the use of harsh anti-rejection drugs, among other reasons.
 
Currently, researchers do not have a means of locating and measuring how many insulin-producing cells remain alive and functioning in patients who have received islet transplants, or how many cells remain upon clinical diagnosis of type 1 diabetes.
 
Thanks to new advances in imaging and nanotechnology, DRI researchers are developing and testing a special class of manufactured molecules that can “hone in” on specific cell markers, including those that are unique to insulin-producing beta cells. This new “tool” presents a novel way to transport protective agents only to the desired target. These molecules, known as aptamers, are generated in our labs and designed to bind to the beta cells. Incorporating fluorescent “flags” to beta cell-specific aptamers could allow researchers to detect their location and acquire an accurate measurement of the number of functioning cells in vivo (within a living organism).
 
Researchers Luca Inverardi, M.D., Paolo Serafini, Ph.D., and Giacomo Lanzoni, Ph.D., are leading the effort. We spoke with Dr. Lanzoni about aptamers’ potential to target beta cells – not only for their imaging potential, but also for their ability to deliver anti-rejection drugs (immunosuppressants) locally, where the islets are placed, like within a DRI BioHub.
 
Q. What are aptamers?

A. Aptamers are very small molecules that can penetrate deeply into tissues. Think of them as very small programmable drones for delivery: they are revolutionary. We build them in the lab and they’re designed to target something of interest, such as a specific component of a living cell - and they will bind to that. This unique characteristic makes them very useful for beta cell imaging and targeting. We are testing aptamers designed to visualize functioning beta cells within the body in order to quantify their numbers and location.  

In the future, we would like to use these aptamers for the delivery of protective agents directly to the beta cells themselves. Aptamers are easy and relatively cheap to produce. Plus, the way we modify them makes them very robust. Moreover, they are non-immunogenic - which means they will not cause an immune reaction. That’s very important. We do not want an immune reaction against the beta cells.
 
Q. Why do you consider aptamers to be revolutionary?

A. In addition to the characteristics mentioned above, aptamers can also be developed with amazing speed. Doing the same thing with antibodies would take several years. For example, we developed aptamers for mouse islets in just a few months, and we are now seeing the binding of these aptamers in vivo in just one year within these experimental models. It’s truly remarkable.
 
Q. How can aptamers be used? 

A. We believe we can use them to see beta cells in vivo. As of today, there is no way to visualize insulin-producing cells, nor to know their numbers and location, for example, when transplanted into a recipient. If we could see them, we could understand a lot more about what is going on during disease progression and after a treatment. We could also follow them at various time points after islet transplantation and treatment. 

Currently, the way researchers estimate cell function is to measure the levels of C-peptide, a by-product of natural insulin release. However, these levels do not indicate the number of cells doing the job. In order to see them, to measure the beta cell mass in vivo, we are tagging the aptamers so they emit light. If they bind to beta cells, we’ll be able to scan the body and see how many and where they are.

Q. How safe are they?

A. Aptamers are already used in the clinical setting for other diseases, so, they have been shown to be safe. But since every single aptamer is different, further research will be needed in order to obtain regulatory approval for this purpose. 

Q. How do we know they will bind to the correct cells – the ones we’re targeting?

A. We select beta cell-specific aptamers out of literally millions of random aptamers.  We identify those aptamers that bind with a very high affinity to beta cells, the cell type we actually want to target.  During that same selection process, aptamers that bind to other cells and tissues are eliminated. 

Q. What’s the current state of this research?

A. We have developed aptamers that bind to these cells in mice. In preliminary studies, we saw the specific binding in the pancreas in vivo. We have sequenced these aptamers, which means we know how to build them. Now we can build up large quantities of them, and for a relatively low price because of the technique we use.
 
We know that rodent islets are different from human islets, so we have to design different aptamers for humans. We are developing them right now, and we have already been successful in developing aptamers that bind to human islets in laboratory experiments. 

Q. What are the next steps?

A. We have selected aptamers that bind to islets. But islets are clusters of several types of cells. So, now we need to identify which aptamers bind specifically to beta cells (the cells that produce insulin), which aptamers bind specifically to alpha cells (the cells that produce glucagon), and so on. 

Q. How could this help patients who receive islet cell transplants? 

A. We would be able to see and track the transplanted cells.  Today, we know how many cells we infuse into a patient, but it’s not possible to see them and follow what happens to them – where they end up and how many survive. Currently, we assess only the function of islet cell transplants by measuring C-peptide levels in blood samples, but we really do not know if that level is being produced by just a few, over-worked cells trying to keep up with the glucose demands, or if that measurement reflects many cells working efficiently.

Recent studies by groups here at the DRI reported that, despite the use of chronic anti-rejection drugs, autoimmunity can again be triggered, resulting in the return of type 1 diabetes.  So, we believe that this technology will allow us to assess the number of viable beta cells in patients, and evaluate changes over time in the same individual. Also, it could help assess the effectiveness of immunosuppressive drugs or other methods to protect these cells. 






The DRI's Giacomo Lanzoni, Ph.D.


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