Applying sophisticated science, a foursome from Northwestern University’s Feinberg School of Medicine and McCormick School of Engineering is well on their way to solving what has been an insurmountable problem ― controlling type 1 diabetes (T1D) without immunosuppressant drugs.
Like paratroopers jumping out of an airplane, mighty miniature foundations known as “scaffolds” are delivering targeted therapy that reverses the disease. Physicians and scientists are also loading small nanoparticles on these same scaffolds to transport proteins and bioactive chemicals that induce the body to accept healthy new cells.
Considerable investigation still needs to be conducted to find the right combination of scaffolds and nanoparticles that will work in humans, but success so far has researchers guardedly optimistic about defeating diabetes.
Two therapies currently dominate treatment for T1D, where the immune system destroys beta cells in the pancreas that make insulin. A third method has emerged over the last twelve years.
- Insulin Injection – In the most common method, patients must monitor their glucose levels every couple of hours and inject insulin to avoid high blood sugars, which increase their risk of diabetic complications, or low blood sugars which, if undetected, can lead to a diabetic coma.
- Pancreas Transplant - In the second approach, patients can undergo a pancreas transplant which is a serious operation. In addition, immunosuppressive drugs used to help prevent the immune system from fighting the new organ can cause problematic side effects. According to the American Diabetes Association, studies have shown that survival rates are better for patients who manage their diabetes with conventional therapy (insulin, diet, exercise, etc.).
- Transplanted Islets - Another method which has enjoyed some new successes over the last 12 years is transplanting donor islet cells from a healthy pancreas into a patient. New cells are inserted into blood vessels within the liver so they can naturally detect glucose levels in blood and adjust insulin secretion accordingly. Unfortunately, this organ isn’t the most hospitable host, so multiple transplants may be required.
“With transplanted islets, you often don’t get the number of viable cells to survive that you really want,” says Dr. Xunrong Luo, director of the Islet Cell Transplantation Program at Northwestern Memorial Hospital. “When you inject islets into the liver, often half of the islets die in a few hours because of an inflammatory reaction sparked by exposure to the blood, and more die over time due to immunosuppressant medications and other toxins.”
Because there is no long-term control for the disease and complications from inadequate treatment are all too frequent, Northwestern scientists started rethinking the entire approach.
Building a team that could outsmart the disease was like finding the right puzzle pieces. Back in 2003, William Lowe, MD, professor of medicine-endocrinology at the Feinberg School of Medicine, joined with Lonnie Shea, PhD, professor of chemical and biological engineering on the Evanston campus. Dr. Lowe wondered if scaffold technology could be applied to T1D and was delighted to find that Dr. Shea was already working on engineering the technology for medical uses.
Scaffolds, which are made of dissolvable surgical sutures, let physicians place cells in a strategic position in the body. As an alternative to the liver, the team decided to put islet cells in the omentum, the fat pad in the internal abdomen. With the scaffolds as an anchor, the transplanted cells could thrive there because of ample blood supply and welcoming tissues allowing cells to engraft into the body’s vasculature.
While this solved the problem of where to locate the cells, it did not address either the immune response that triggers the diabetes or that rejects transplanted cells. To tackle these issues , in 2008 they partnered with Stephen Miller, PhD, the Judy Gugenheim Research Professor of Microbiology-Immunology, and Xunrong Luo, MD, PhD, associate professor in medicine-nephrology, microbiology-immunology, and surgery-organ transplantation. Over several years, the scientists experimented with different approaches. Taking advantage of Dr. Shea’s engineering background they designed tiny nanoparticles to deliver proteins and bioactive chemicals which alter the body’s reactions. They also treated the donor tissues before and after transplant with the chemical EDCI, which tricks the body into thinking the transplanted tissues are not different.
Finally, they hit the right combination, using the newly created nanoparticles to achieve tolerance (cell acceptance) without immunosuppressants.
“We always knew that the immune system was a significant barrier to long-term function, and figuring it out has been like solving a puzzle, and with this collaborative team, all the pieces are beginning to fit,” explains Shea.
For Miller, the nanoparticle technology to induce tolerance is the most encouraging approach he has seen in his 30 years studying autoimmune diseases at Feinberg. “We are really committed to carrying this forward,” Miller says. “I still want to be cautious about it. There is a lot of good stuff that still has to be proven, but in my many, many years of trying many, many ways to intervene, this is by far the most robust approach.”
“We are highly hopeful this will work in humans,” says Dr. Luo.
Fortunately, NIH has supported their research to find new therapies to the tune of several million dollars. All four investigators have received NIH and RO1 grants together and individually that fuel the collaboration. The Juvenile Diabetes Research Foundation and the Myelin Repair Foundation have also funded their work.
From Mice to Men
Lengthy, painstaking research has solved the vexing problems of locating the islet cell transplants outside the liver and inducing tolerance to the new cells ― at least for mice.
“We have been able to get the scaffolds to function in a ‘small-scale operation,’ now we must move to a larger scale,” says Dr. Lowe.
Several challenges lie ahead. Five millimeters in diameter in mice, larger scaffolds need to be constructed for testing in large animals.
In addition, the team is working on how to deliver a peptide through the scaffold that helps islets more easily take root in the fat pad and integrate into the body’s vasculature.
To complement the nanoparticle work, Shea and Luo also sought ways to use the scaffolds to impact the immune response. To protect the donor islets, they co-located regulatory T cells on the scaffolds. (Their study will be published in Tissue Engineering later this year.)
“These regulatory T cells prevented other T cells from attacking the islets and induced long-term function and systemic tolerance, which was both surprising and promising,” says Shea.
If regulatory T cells can help disarm the immune system and, in the long term, be used in combination with nanoparticles, it may mean immunosuppressant drugs will be unnecessary or can be significantly reduced. That would be a huge advantage because immunosuppressants reduce the body’s natural defenses, leaving patients more susceptible to other diseases.
Luo adds it’s possible that primates and later on, patients, may need immunosuppressants after transplant but could gradually be weaned off the drugs as islet cells grow stronger. Following her approach of “safety first, then innovation,” immunosuppressants will be used initially in further animal studies.
Go the Distance
The team knows how eager patients and their families are for improved treatments. In severe cases of diabetes, patients inject insulin up to seven times a day. Since T1D often afflicts young people, some parents may need to get up several times during the night to test their children, living in constant fear that their son or daughter will slip into a coma.
If all goes well, patient trials will be at least three years away. The team does not expect everything leading up to phase 1 testing to go smoothly, but they believe that between the four of them and their unique individual expertise, they can solve just about any problem.
Following primate testing, the therapy will need to be refined for humans. The team is already anticipating possible challenges: human islet cells are not as pure as mouse islets which can be collected from a controlled environment; scaffolds need to be re-sized for humans; to further optimize transplant success, scaffolds need to be re-engineered to hold peptides and/or DNA. However, the team is encouraged by their success in transplanting human islets on scaffolds into mice.
FDA scrutiny will be intense, but Dr. Lowe notes that a few hurdles have already been cleared. Islet transplants and the materials used to make the scaffolds are already FDA-approved.
Lowe predicts scaffold transplant technology will enable more islets to survive post-transplant, making more of these precious cells available to more patients. Currently, islet transplant is limited mainly to people with severe hypoglycemia. However, Lowe notes, “If we succeed and an endless supply of cells becomes available, you could potentially treat everyone with type 1 and type 2 diabetes, but I have to add that that’s not going to happen tomorrow.”
Even more importantly, if the nanoparticles are successful in specifically curtailing the immune response underlying type1 diabetes, transplants may not be necessary in the long term.
“Right now, our hope is to get patients with type 1 diabetes treated soon after diagnosis,” says Miller. “We are striving to provide life-long protection.”
Since diabetes has a strong genetic component, Miller also foresees using nanoparticles to treat high-risk patients before the disease develops.
But Dr. Miller won’t stop there. He envisions “switching out” the therapies on the nanoparticles to treat patients with other autoimmune diseases. Multiple sclerosis is next on his list.
Indeed, if the team succeeds, the potential global health impact of the nanoparticles on the full range of autoimmune disorders could be enormous because nearly 350 million people are living with different types of the disease, according to the World Health Organization.
If Northwestern scientists knock out T1D first, it would be a monumental victory.