We are focusing our gifts in two broad areas:
Transform Day-to-Day Treatments. Fund technologies that improve the ease and accuracy of care.
Develop A “Practical Cure”. Fund innovations offering a medium to long-term respite from insulin injections.
Our goal is to provide capital to exceptionally talented leaders who treat financial stakeholders as true partners, share openly about both progress and challenges, and have a clear vision of how their work will successfully improve the lives of Juvenile Diabetics.
Grant Strategy #2: Develop a “Practical Cure”.
A Practical Cure will be a Herculean task. Since the discovery of insulin in the early 1920’s, substantially all diabetes-related innovations have related to medical devices used to improve the standard of care (for example, blood glucose monitors and insulin infusion pumps) or to improve insulin formulations. After more than ninety years of research without a cure, some long-time supporters now doubt whether a cure can be found. Perhaps they have good reason to be doubtful; after all no autoimmune disease has ever been cured.
A complete cure for Juvenile Diabetes or, as we refer to it, a “Comprehensive Cure”, requires two innovations. First, the diabetic’s immune system must be “re-programmed” or otherwise stopped from killing insulin-producing beta cells. Second, new beta cells must be provided or must otherwise be regenerated. On the other hand, a Practical Cure, by our definition, is the elimination of insulin injections and regular blood glucose readings for at least 12 months. The more limited Practical Cure should be realized sooner than a Comprehensive Cure. Perhaps the knowledge gleaned from the Practical Cure could help with an eventual Comprehensive Cure. A Practical Cure must include the following elements:
- insulin independence for at least 12 months,
- a minimal day-to-day patient care during those 12 months (for example, no blood sugar readings, carb counting, restricted diet),
- must be accomplished through a simple physician office procedure,
- must exclude any immunosuppressive drugs, and
- must be cost effective so that it can be widely administered.
Specific examples of projects we are or will consider funding are outlined in summary form below:
A. Beta cell replacement.
The insulin producing beta cells in every Juvenile Diabetic are eventually depleted as a result of their autoimmune attack. In order to meet the first goal of a Practical Cure, a new supply of beta cells must be introduced and, if the autoimmunity is not first resolved, must be protected from attack by the patient’s immune system. There are at least two major challenges with beta cell replacement. First, there is a limited supply of beta cells (currently such cells are primarily available from organ donor derived isolations). Creating a high quality supply of beta cells will be a critical ingredient in the success of any Practical Cure. Second, a means of protecting the newly introduced beta cells must be developed so that they can survive for an extended duration.
Islet cell transplantation
Since the Edmonton Protocol was developed in 2000, researchers have tried to replace a diabetic’s beta cells. The Edmonton Protocol proved that it is medically possible to introduce new beta cells into a diabetic patient and provide some relief from insulin therapy. But the procedure has a number of important shortcomings including:
- the procedures expense ($140,000),
- the requirement of life-long immunosuppressive drugs with serious side effects and
- poor proof of efficacy (only 40% are insulin free for one year).
Beta cell regeneration
Beta cell regeneration will, we believe, ultimately involve human stem cells. Most of our understanding and utilization of human stem cells is remarkably recent. For example, the first human embryonic stem cells were isolated at University of Wisconsin in 1998. Embryonic stem cells are remarkably versatile and can become one of any of the body’s 200 tissue types. In January 2009, the FDA approved the first clinical trial of an embryonic stem cell based therapy for spinal cord injuries.
There are two basic approaches to creating new beta cells. The first approach uses the patient’s own cells that are transformed into stem-cells that then differentiate into new beta cells (these self-derived stem-cells are referred to as “induced pluripotent stem” cells or “iPS” cells). These cells would be grown in-vitro and then reintroduced. This approach has the benefit of a perfect genetic match with the patient. The second approach uses embryonic stem cells which are differentiated into beta cells. Because of the dramatic reproduction capabilities inherent in embryonic stems cells, a benefit of this approach is the ability to create massive volumes of beta cells. But the other side of such replication is that, if uncontrolled, such growth could stimulate tumors or other unwanted side effects. Once the beta cells can be reproduced it will be necessary to demonstrate that they can safely and effectively generate insulin in response to elevations in blood glucose levels. Animal testing followed by human clinical trials will be necessary.
Doug Melton, the Director of the Harvard Stem Cell Institute’s diabetes research efforts, is working on both approaches. Dr. Melton has two children with Juvenile Diabetes. He is a tenured professor at Harvard where he has the largest stem cell bank in the world. Doug is working to develop a massive supply of beta cells that he plans to “create” from his stem cell bank by “programming” these embryonic stem cells to develop or differentiate into human beta cells. Dr. Melton’s group is also working to perfect the techniques to manipulate the patient’s own stem cells or iPS cells – his lab demonstrated the scientific ability to do this in 2008.
Dr. Melton is the Thomas Dudley Cabot Professor in Natural Sciences at Harvard University and is co-Director of the Harvard Stem Cell Institute. Doug earned his PhD in molecular biology at Cambridge University where he studied under Sir John Gurdon, the first to clone a frog. Dr. Melton began working on diabetes research twenty years ago when his son was diagnosed with Juvenile Diabetes. In 2008 in Doug’s lab, a colleague created the first human embryonic stem cell directly from an adult’s own tissue (this could lead to a patient’s own cells being used to “create” another organ for transplantation without rejection because it would be genetically identical).
Beta cell encapsulation and implantation
One of the greatest challenges to any beta cell replacement strategy is that the newly implanted beta cells will are likely to be attacked and killed by the diabetic’s dysfunctional immune system. There are a variety of approaches to solving this problem. One solution is to encapsulate the beta cells in a protective “bubble” to protect them from autoimmune attack. Considerable research has been funded here but has not yet proven successful. An alternative approach is to build a microscopic mesh “basket” or “tea bag” that could hold a large supply of beta cells. The mesh would allow insulin secreted by the beta cells to flow through as needed but would not allow the beta cells to be attacked by the immune system.
The Diabetes Research Institute at the University of Miami is working to perfect an approach they refer to as the “Bio-Hub”. DRI has done extensive work on islet cell transplantation and is repurposing its experience towards a “Practical Cure” in the form of its Bio-Hub project. The basic Bio-Hub design incorporates the following elements:
Beta Cell Generation
In order to provide sufficient beta cells for a Practical Cure, DRI researchers will use insulin-responsive beta cells from stem cell lines. DRI believes they can produce beta cells in sufficient volumes and quality to meet the needs for animal and human clinical testing. With some laboratory proof of concept, DRI must now demonstrate clinical efficacy and safety of their beta cells, first in animals and then in humans.
Beta Cell Protection
DRI is also creating a synthetic mesh “basket” capable of holding enough beta cells to provide a one to two year respite from insulin injections. Their researchers are working to perfect an oxygen coating to provide the beta cells with enough oxygen to survive until the patient’s own vascular system can feed the new beta cells. DRI scientists are also working on a topical immunosuppressive coating that would protect the beta cells for during the formative stages after their insertion into the patient.
Beta Cell Implantation
DRI physicians have extensive experience with islet cell transplantations. They believe that their specially coated beta cell basket can be surgically inserted into the patient’s adipose tissue in the belly. This should be accomplished in an outpatient surgery in a physician’s office.
B. Eliminate or repair the autoimmune response.
In order to extend the life of a Practical Cure and, eventually, a comprehensive cure, the diabetic’s immune response to his beta cells must be stopped. This part of a cure may be more complicated than creating the beta cell bank. There are a number of approaches to solving the problem. One approach is to “reprogram” the defective parts of the immune system to stop these attacks – one technique referred to as immunoablation is described below. Another approach is to identify those T-cells that are attacking the beta cells and then develop an antigen to knock down the offending T-cells.
Autoimmune reprogramming – immunoablation
Immunoablation is a medical procedure used to “reset” the immune system. The technique has been used in some MS and cancer patients with very high rates of success and moderate risks. The procedure is challenging for the patient. The basic technique is to extract the patient’s stem cells from his bone marrow. Then the patient’s entire immune system is chemically eliminated. During this period the patient must be carefully isolated from any infections. Finally the stem cells are reintroduced into the patient, which rebuilds his immune system (apparently with no memory of the prior autoimmune response to MS and, hopefully, diabetes). One drawback to this approach is that it does require the use of large doses of immunosuppressive drugs and total immune recovery can take from few months to as long as a couple years.
Experimental procedures were conducted in Brazil and Poland with encouraging results, but no such tests have been conducted in the U.S. Researchers at Northwestern University, which wrote the protocol for the Brazil experiments, are working follow up studies in the U.S. but the procedures are expensive and hard to recruit patients. Researchers at the University of Florida are working on a “Brazil-lite” technique that is less radical than the complete immunoablation.