They successfully treated mice with type 1 diabetes. They don't use the "cure" word.
Now Massimo Trucco and his collaborator Nick Giannoukakis, associate professor of pathology and also of immunology at the University of Pittsburgh School of Medicine, sit on the doorstep of one of the first major new treatments for type 1 diabetes since insulin was discovered in 1922. Other researchers are busy pursuing the same goal.
The big challenge for Dr. Trucco is funding.
Preparing for human clinical trials, the research pediatrician at Children's Hospital of UPMC of Pittsburgh needs $7 million to $10 million for a multi-site trial involving 105 people with a recent diagnosis of type 1 diabetes. He's considering beginning with 18-year-olds, and if the therapy succeeds, working backward in age to adolescents.
But federal budget cuts are making it difficult to land research grants through the National Institutes of Health. At age 65, and with dwindling finances for his research laboratory, Dr. Trucco said he would consider retiring if funding doesn't come through. That could put his potential treatment on the shelf without ever being tested.
"It would be the first trial in which live cells are used to treat a disease that is not cancer, and we would be dealing with children," Dr. Trucco said, discussing his desire to see results after decades of research.
Leading the pack
A study published last month in Diabetes describes the advantages in using one's own genetically engineered dendritic cells to stop the autoimmune cycle that destroys insulin-producing beta cells.
"It is our conviction that the age of personalized cell therapy ... has arrived and that type 1 diabetes could be the first autoimmune disorder to be successfully treated," the study states.
Dr. Trucco is leading the pack of researchers targeting dendritic cells as the focus of treatment for type 1. The Phase I human clinical trial already has proven the therapy to be safe while raising excitement for success.
"Massimo clearly is the leader in the field, and the only one, to my knowledge, to get approval for a Phase I trial. He has the correct equipment and facilities to do this," said C. Garrison Fathman, chief of the division of immunology and rheumatology at the Stanford University School of Medicine.
For proposed treatments, he's leading the research in using adoptive cellular therapy, or modifying the immune system's effect on certain cells, to treat a disease other than cancer.
But there are no guarantees in landing funding for a Phase II trial: "It's never been harder to receive NIH funding," Dr. Fathman said, noting that only about 6 percent of research proposals receive NIH funding.
It's not yet known if the Trucco team's procedure will work in humans. If it does, how long would it continue working? Dr. Trucco said it must be effective a year or longer to be cost-effective.
The study would be double-blind, which means neither researchers nor participants would know who's receiving treatment. But all participants would undergo blood work, which presented an initial concern.
The process known as leukapheresis requires a patient to sit for two hours while his or her blood is transferred from one arm, through a filter to capture dendritic cells, then into a blood vessel in the other arm. It raised ethical questions: Should participants who don't receive treatment be required to undergo a medical procedure?
In a conference call Wednesday, Dr. Trucco advised U.S. Food and Drug Administration officials that all participants' blood work would be saved. If the procedure works, those in the placebo groups immediately would undergo the treatment with their own genetically engineered dendritic cells.
"I am excited because FDA just gave us the green light to write our proposal," Dr. Trucco said after the meeting, adding that the approval was necessary for the study to proceed.
One in 400 children develop type 1 diabetes, the American Diabetes Association says, with as many as a million Americans having the disease. The majority of the nearly 26 million Americans with diabetes have type 2, which is thought to involve an insensitivity to one's own insulin.
Insulin turns blood glucose into cellular energy. With the pancreas no longer able to provide sufficient insulin in type 1 diabetes, the person must take daily injections of insulin or use an insulin pump, along with other dietary and testing requirements to keep blood-sugar levels in or near the normal range.
Even for those who take insulin, persistent elevations in blood sugar still can lead to multiple health problems, including heart disease, stroke, kidney disease, blindness, and circulatory problems that can lead to amputations of the extremities.
But as Dr. Trucco and others have determined, type 1 diabetes involves a biological conspiracy, beginning with a genetic predisposition activated by an environmental or epigenetic factor, such as a viral infection. The result is an errant immune response that kills the body's own insulin-producing beta cells.
Here's a highly simplified explanation of why type 1 diabetes occurs:
T-cells are the attack dogs of the immune system when they spot a foreign invader. In the case of diabetes, a vicious circle occurs, although it's unclear whether T-cells begin the process by attacking beta cells or the dendritic cells initiate it by teaching immature T-cells to target beta cells.
As it happens, the T-cells errantly attack beta cells located in the islets of Langerhans in the pancreas, which also contain other pancreatic cells with specific metabolic functions. The attack breaks beta cells apart, exposing hidden antigens that the immune system considers to be new targets to attack. The dendritic cells clean up the debris and return to a pancreatic lymph node to expose immature T-cells to the beta-cell debris, which teaches them what to target to attack.
The T-cells leave the lymph node and mount a new assault on beta cells.
Hope and potential
The body has a million beta cells. Diabetic symptoms occur when roughly 80 percent are destroyed, Dr. Trucco said. The destructive cycle continues until few if any surviving beta cells are available, leaving the person with marginal, if any, insulin production.
The Trucco team says dendritic cells are more easily obtained from the blood and genetically engineered in the laboratory than T-cells or other conspirators in the process. Engineering them to be tolerant to beta cells requires a newly created strand of RNA, which inactivates the RNA that encodes the molecules that cause dendritic cell to misidentify beta cells as dangerous. Returning to the pancreatic lymph nodes, the treated dendritic cells no longer are able to instruct T-cells to attack beta cells.
The therapy must be done within months of diagnosis so the highest percentage of beta cells can be saved. Twenty percent is enough for normal blood sugar to be maintained with dietary restrictions. The child might still require insulin injections, but the dose would be lower with less dangerous swings in blood sugar.
Immunosuppressant drugs would be unnecessary because the therapy involves one's own cells. Earlier therapy prompted by diabetes biomarkers indicating the onset of diabetes, but before symptoms arise, it could save a higher percentage of healthy beta cells.
Dr. Trucco said he faces a March 1 deadline to submit a draft funding proposal to the NIH, with a final proposal due in May. He expects to hear in September whether funding has been approved.
David Templeton: firstname.lastname@example.org or 412-263-1578.