Monday, June 24th, 2019

Time	Event
11:00a	A better way to encapsulate islet cells for diabetes treatment When medical devices are implanted in the body, the immune system often attacks them, producing scar tissue around the device. This buildup of tissue, known as fibrosis, can interfere with the device’s function. MIT researchers have now come up with a novel way to prevent fibrosis from occurring, by incorporating a crystallized immunosuppressant drug into devices. After implantation, the drug is slowly secreted to dampen the immune response in the area immediately surrounding the device. “We developed a crystallized drug formulation that can target the key players involved in the implant rejection, suppressing them locally and allowing the device to function for more than a year,” says Shady Farah, an MIT and Boston Children’s Hospital postdoc and co-first author of the study, who is soon starting a new position as an assistant professor of the Wolfson Faculty of Chemical Engineering and the Russell Berrie Nanotechnology Institute at Technion-Israel Institute of Technology. The researchers showed that these crystals could dramatically improve the performance of encapsulated islet cells, which they are developing as a possible treatment for patients with type 1 diabetes. Such crystals could also be applied to a variety of other implantable medical devices, such as pacemakers, stents, or sensors. Former MIT postdoc Joshua Doloff, now an assistant professor of Biomedical and Materials Science Engineering and member of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine, is also a lead author of the paper, which appears in the June 24 issue of Nature Materials. Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), is the senior author of the paper. Crystalline drug Anderson’s lab is one of many research groups working on ways to encapsulate islet cells and transplant them into diabetic patients, in hopes that such cells could replace the patients’ nonfunctioning pancreatic cells and eliminate the need for daily insulin injections. Fibrosis is a major obstacle to this approach, because scar tissue can block the islet cells’ access to the oxygen and nutrients. In a 2017 study, Anderson and his colleagues showed that systemic administration of a drug that blocks cell receptors for a protein called CSF-1 can prevent fibrosis by suppressing the immune response to implanted devices. This drug targets immune cells called macrophages, which are the primary cells responsible for initiating the inflammation that leads to fibrosis. “That work was focused on identifying next-generation drug targets, namely which cell and cytokine players were essential for fibrotic response,” says Doloff, who was the lead author on that study, which also involved Farah. He adds, “After knowing what we had to target to block fibrosis, and screening drug candidates needed to do so, we still had to find a sophisticated way of achieving local delivery and release for as long as possible.” In the new study, the researchers set out to find a way to load the drug directly into an implantable device, to avoid giving patients drugs that would suppress their entire immune system. “If you have a small device implanted in your body, you don’t want to have your whole body exposed to drugs that are affecting the immune system, and that’s why we’ve been interested in creating ways to release drugs from the device itself,” Anderson says. To achieve that, the researchers decided to try crystallizing the drugs and then incorporating them into the device. This allows the drug molecules to be very tightly packed, allowing the drug-releasing device to be miniaturized. Another advantage is that crystals take a long time to dissolve, allowing for long-term drug delivery. Not every drug can be easily crystallized, but the researchers found that the CSF-1 receptor inhibitor they were using can form crystals and that they could control the size and shape of the crystals, which determines how long it takes for the drug to break down once in the body. “We showed that the drugs released very slowly and in a controlled fashion,” says Farah. “We took those crystals and put them in different types of devices and showed that with the help of those crystals, we can allow the medical device to be protected for a long time, allowing the device to keep functioning.” Encapsulated islet cells To test whether these drug crystalline formulations could boost the effectiveness of encapsulated islet cells, the researchers incorporated the drug crystals into 0.5-millimeter-diameter spheres of alginate, which they used to encapsulate the cells. When these spheres were transplanted into the abdomen or under the skin of diabetic mice, they remained fibrosis-free for more than a year. During this time, the mice did not need any insulin injections, as the islet cells were able to control their blood sugar levels just as the pancreas normally would. “In the past three-plus years, our team has published seven papers in Nature journals — this being the seventh — elucidating the mechanisms of biocompatibility,” says Robert Langer, the David H. Koch Institute Professor at MIT and an author of the paper. “These include an understanding of the key cells and receptors involved, optimal implant geometries and physical locations in the body, and now, in this paper, specific molecules that can confer biocompatibility. Taken together, we hope these papers will open the door to a new generation of biomedical implants to treat diabetes and other diseases.” The researchers believe that it should be possible to create crystals that last longer than those they studied in these experiments, by altering the structure and composition of the drug crystals. Such formulations could also be used to prevent fibrosis of other types of implantable devices. In this study, the researchers showed that crystalline drug could be incorporated into PDMS, a polymer frequently used for medical devices, and could also be used to coat components of a glucose sensor and an electrical muscle stimulation device, which include materials such as plastic and metal. “It wasn’t just useful for our islet cell therapy, but could also be useful to help get a number of different devices to work long-term,” Anderson says. The research was funded by JDRF, the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust Foundation, and the Tayebati Family Foundation. Other authors of the paper include MIT Principal Research Scientist Peter Muller; MIT grad students Atieh Sadraei and Malia McAvoy; MIT research affiliate Hye Jung Han; former MIT postdoc Katy Olafson; MIT technical associate Keval Vyas; former MIT grad student Hok Hei Tam; MIT postdoc Piotr Kowalski; former MIT undergraduates Marissa Griffin and Ashley Meng; Jennifer Hollister-Locke and Gordon Weir of the Joslin Diabetes Center; Adam Graham of Harvard University; James McGarrigle and Jose Oberholzer of the University of Illinois at Chicago; and Dale Greiner of the University of Massachusetts Medical School. (Comment on this)
11:00a	Chemists discover structure of glucagon fibrils Patients with type 1 diabetes have to regularly inject themselves with insulin, a hormone that helps their cells absorb glucose from the bloodstream. Another hormone called glucagon, which has the opposite effect, is given to diabetic patients to revive them if they become unconscious due to severe hypoglycemia. The form of glucagon given to patients is powdered and has to be dissolved in liquid immediately before being injected, because if stored as a liquid, the protein tends to form clumps, also called amyloid fibrils. A new study from MIT reveals the structure of these glucagon fibrils and suggests possible strategies for altering the amino acid sequence so that the protein is less likely to become clumped. “Insulin in solution is stable for many weeks, and the goal is to achieve the same solution stability with glucagon,” says Mei Hong, an MIT professor of chemistry and one of the senior authors of the study. “Peptide fibrillization is a problem that the pharmaceutical industry has been working for many years to solve.” Using nuclear magnetic resonance (NMR) spectroscopy, the researchers found that the structure of glucagon fibrils is unlike any other amyloid fibrils whose structures are known. Yongchao Su, an associate principal scientist at Merck and Co., is also a senior author of the study, which appears in the June 24 issue of Nature Structural and Molecular Biology. MIT graduate student Martin Gelenter is the lead author of the paper. Fibril formation Amyloid fibrils form when proteins fold into a shape that allows them to clump together. These proteins are often associated with disease. For example, the amyloid beta protein forms plaques associated with Alzheimer’s disease, and alpha synuclein forms Lewy bodies in the neurons of Parkinson’s disease patients. Hong has previously studied the structures of other amyloid peptides, including one that binds to metals such as zinc. After giving a talk on her research at Merck, she teamed up with scientists there to figure out the structure of the fibrillized form of glucagon. Inside the human body, glucagon exists as an “alpha helix” that binds tightly with a receptor found on liver cells, setting off a cascade of reactions that releases glucose into the bloodstream. However, when glucagon is dissolved in a solution at high concentrations, it begins transforming into a fibril within hours, which is why it has to be stored as a powder and mixed with liquid just before injecting it. The MIT team used NMR, a technique that analyzes the magnetic properties of atomic nuclei to reveal the structures of the molecules containing those nuclei, to determine the structure of the glucagon fibrils. They found that the glucagon fibril consists of many layers of flat sheets known as beta sheets stacked on top of one another. Each sheet is made up of rows of identical peptides. However, the researchers discovered that, unlike any other amyloid fibril whose structure is known, the peptides run antiparallel to each other. That is, each strand runs in the opposite direction from the two on either side of it. “All thermodynamically stable amyloid fibrils known so far are parallel packed beta sheets,” Hong says. “A stable antiparallel beta strand amyloid structure has never been seen before.” In addition, the researchers found that the glucagon beta strand has no disordered segments. Each of the tens of thousands of peptide strands that make up the fibril is held tight in the antiparallel beta sheet conformation. This allows each peptide to form a 10-nanometer-long beta strand. “This is an extremely stable strand, and is the longest beta strand known so far among any proteins,” Hong says. Stable structure One major reason that glucagon fibrils are so stable is that side chains extending from the amino acids making up the glucagon peptides interact strongly with side chains of the peptides above and below them, creating very secure attachment points, also called steric zippers, that help to maintain the overall structure. Courtesy of the researchers. While all previously studied amyloid fibrils have a fixed set of residues that form the steric zippers, in glucagon fibrils, even-numbered residues from one strand and odd-numbered residues from the neighboring strand alternately form the steric zipper interface between two beta sheet layers. This conformational duality is another novel feature of the glucagon fibril structure.   “We can see from this structure why the fibril is so stable, and why it’s so hard to prevent it from forming,” Hong says. “To block it, you really have to change the identity of the amino acid residues. I’m now working with a colleague here to come up with ways to modify the sequence and break those stabilizing interactions, so that the peptide won’t self-assemble to form this fibril.” Such alternative peptide sequences could remain shelf-stable for a longer period of time in solution, eliminating the need to mix glucagon with liquid before using it. “Considering the crucial physiological role of glucagon, it is encouraging that new structural data on this polypeptide hormone continue to be collected,” says Kurt Wuthrich, a professor of biophysics at ETH Zurich, who was not involved in the research. “Although the structural data reported here characterize an ‘unwanted’ form of glucagon, the authors point out that it promises to provide novel leads for engineering glucagon analogs which would have improved physico-chemical properties for its administration as a drug, specifically a reduced tendency to form amyloid fibers.” The research was funded by Merck Sharp and Dohme Corp., a subsidiary of Merck and Co., and the National Institutes of Health. 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