Nanotherapy offers new hope for the treatment of type 1 diabetes


People with type 1 diabetes must carefully follow prescribed insulin regimens each day, receiving injections of the hormone through a syringe, insulin pump or other device. And without viable long-term treatments, this treatment is a life sentence.

Pancreatic islets control insulin production when blood sugar levels change, and in type 1 diabetes, the body’s immune system attacks and destroys these insulin-producing cells. Islet transplantation has emerged over the past few decades as a potential treatment for type 1 diabetes. With healthy islets transplanted, type 1 diabetic patients may no longer need insulin injections, but transplant efforts have suffered setbacks as the immune system continues to reject new islets. Current immunosuppressive drugs provide inadequate protection for transplanted cells and tissues and are plagued with undesirable side effects.

Now, a team of researchers from Northwestern University has discovered a technique to help make immunomodulation more effective. The method uses nanocarriers to redesign the commonly used immunosuppressive rapamycin. Using these rapamycin-loaded nanocarriers, the researchers generated a novel form of immunosuppression capable of targeting specific transplant-related cells without suppressing broader immune responses.

The article was published today (January 17) in the journal Nature Nanotechnology. The Northwestern team is led by Evan Scott, Kay Davis Professor and Associate Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering and Microbiology-Immunology at Northwestern University Feinberg School of Medicine, and Guillermo Ameer, Daniel Hale Williams Professor of biomedical engineering at McCormick and Surgery at Feinberg. Ameer is also director of the Center for Advanced Regenerative Engineering (CARE).

Body Attack Specification

Ameer has worked on improving the outcome of islet transplantation by providing islets with an engineered environment, using biomaterials to optimize their survival and function. However, issues associated with traditional systemic immunosuppression remain a barrier to the clinical management of patients and also need to be addressed to have any real impact on their care, Ameer said.

“This was an opportunity to partner with Evan Scott, a leader in immunoengineering, and engage in a convergence research collaboration that was well executed with great attention to detail by Jacqueline Burke, a National Science Foundation graduate researcher,” Ameer said.

Rapamycin is well studied and commonly used to suppress immune responses during other types of treatment and transplants, notable for its wide range of effects on many cell types throughout the body. Generally administered orally, the dosage of rapamycin should be carefully monitored to avoid toxic effects. Yet, at lower doses, it has low efficacy in cases such as islet transplantation.

Scott, also a CARE member, said he wanted to see how the drug could be improved by putting it in a nanoparticle and “controlling where it goes in the body.”

“To avoid the broad effects of rapamycin during treatment, the drug is usually given in low doses and via specific routes of administration, primarily orally,” Scott said. “But in the case of a transplant, you need to give enough rapamycin to consistently suppress T-cells, which can have significant side effects like hair loss, mouth sores, and an overall weakened immune system.”

Following a transplant, immune cells, called T cells, reject the newly introduced foreign cells and tissues. Immunosuppressants are used to inhibit this effect, but can also impact the body’s ability to fight other infections by shutting down T cells throughout the body. But the team formulated the nanocarrier and the drug mix to have a more specific effect. Instead of directly modulating T cells – rapamycin’s most common therapeutic target – the nanoparticle would be engineered to target and modify antigen-presenting cells (APCs) that allow for more targeted and controlled immunosuppression.

The use of nanoparticles also allowed the team to administer rapamycin by subcutaneous injection, which uses a different metabolic pathway to avoid significant drug loss that occurs in the liver after oral administration. This route of administration requires much less rapamycin to be effective – about half the standard dose.

“We wondered if rapamycin could be redesigned to avoid non-specific T-cell suppression and instead stimulate a tolerogenic pathway by delivering the drug to different types of immune cells?” said Scott. “By changing the cell types targeted, we actually changed how immunosuppression was achieved.”

A ‘chimerical dream’ come true in diabetes research

The team tested the hypothesis in mice, introducing diabetes to the population before treating them with a combination of islet transplantation and rapamycin, administered via the standard oral Rapamune® regimen and their nanocarrier formulation. Starting the day before transplantation, the mice received injections of the modified drug and continuous injections every three days for two weeks.

The team observed minimal side effects in the mice and found that diabetes was eradicated for the duration of their 100-day trial; but the treatment must last for the life of the graft. The team also demonstrated that the population of mice treated with the nano-delivered drug had a “robust immune response” compared to mice receiving standard treatments of the drug.

The concept of improving and controlling drug side effects via nano-delivery is not new, Scott said. “But here, we’re not enhancing an effect, we’re changing it – by reorienting the biochemical pathway of a drug, in this case mTOR inhibition by rapamycin, we’re generating an entirely different cellular response.”

The team’s discovery could have far-reaching implications. “This approach can be applied to other transplanted tissues and organs, opening up new areas of research and new options for patients,” Ameer said. “We are now working to bring these very exciting results closer to clinical use.”

Jacqueline Burke, the study’s first author and National Science Foundation graduate researcher and researcher working with Scott and Ameer at CARE, said she could hardly believe her readings when she saw the mice’s blood sugar levels drop by highly diabetic levels to an even number. . She kept double-checking to make sure it wasn’t a fluke, but saw the number sustained over the months.

Search hits near you

For Burke, a doctoral student in biomedical engineering, the research touches closer to home. Burke is one of those people for whom daily shooting is an integral part of his life. She was diagnosed with type 1 diabetes at the age of nine and had known for a long time that she wanted to contribute in some way to the field.

“In my previous program, I worked on healing diabetic foot ulcers, which are a complication of type 1 diabetes,” Burke said. “As a 26 year old, I never really wanted to get there, so I thought a better strategy would be to focus on how we can treat diabetes now in a more summary that mimics the natural occurrences of the pancreas in a non-diabetic person.”

The all-Northwest research team has been working on experiments and publishing islet transplantation studies for three years, and Burke and Scott say the work they just published could have been split into two or three items. What they have published now, however, they consider a breakthrough and say could have major implications for the future of diabetes research.

Scott began the process of patenting the method and working with industry partners to eventually advance it to clinical trials. Commercialization of his work would solve the remaining problems that have arisen for new technologies such as Vertex stem cell-derived pancreatic islets for the treatment of diabetes.


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