Human ES cell based cell replacement therapy for type I diabetes

Funding Type: 
Early Translational II
Grant Number: 
ICOC Funds Committed: 
Disease Focus: 
Spinal Muscular Atrophy
Neurological Disorders
Stem Cell Use: 
iPS Cell
Public Abstract: 
Diabetes significantly impacts the quality of life and the economy of California since it is estimated that more than 2.7 million people are afflicted with this disease, costing the State $24.5 billion annually. Since the rate of success- full insulin independence – using islet transplantation is less than 10% five years after treatment, and this even with persistent immune suppression, there is an urgent need for a new cell-based therapy especially for type 1 (T1D) or insulin dependent diabetes. In addition, other obstacles to this therapy include the shortage of organs available for islet isolation aggravated by the need for more than 1 donor per recipient, the destruction of the engrafted islets by allogeneic rejection and autoimmunity, and concerns about the risk/benefit ratio because the persistent immune suppression increases the risk of cancer and infection and other metabolic disturbances including high lipids and hypertension. Human ES cells (hESCs) could provide an unlimited source of endocrine β cells, and recent studies by biotech companies and academic labs have provided evidence that hESCs can be differentiated into pancreatic endocrine precursors and functional β cells. However, significant barriers remain. Thus there is a critical need to develop well-defined 'scalable' culture conditions that are free of animal products. The use of poorly defined animal products jeopardizes the safety and the utility of current protocols. In addition, current published protocols fail to offer strategies for the purification of β-cell precursor populations. In the absence of such a purification step, transplanted populations inevitably contain pluripotent cells that give rise to tumors in the transplant recipient. This is clearly unacceptable and urgently needs to be addressed. Another major challenge facing hESC-based therapy of T1D is the allogeneic rejection and autoimmune destruction of engrafted islets. While cell encapsulation technology offers a potential strategy to protect the graft from the recipient’s immune system, its feasibility in the clinic remains questionable despite decades of research and development. Therefore it is of the highest priority to develop novel hESC-derived endocrine precursors that can escape the recipient’s immune system and avoid tumor development in the graft. To resolve these critical issues, this grant encompasses a multi-disciplinary team to achieve the following four goals: To develop strategies to allow purification of hESC-derived endocrine precursors that could elude the recipient’s immune system; To establish chemical defined conditions to reproducibly differentiate hESCs into endocrine precursors; To validate in vivo that purified endocrine precursors can be used to treat diabetes in animal models without the risk of tumor development. Successful completion of the proposed research will greatly facilitate the clinic development of human ES based therapy for T1D.
Statement of Benefit to California: 
This research would benefit the State of California and its citizens on multiple fronts. First and foremost, positive results will create a new development candidate of a cell-based therapy for type 1 diabetes with the potential for avoiding the risk of tumor formation - a consequence that hinders the development of any human ES cell based therapy. Second, it may obviate the need for immune suppression therapy that today carries serious side effects including propensity to infections and cancer, abnormalities in lipid metabolism and hypertension, and even damage to the transplanted cells as it occurs following islet transplantation procedures, the only available therapy nowadays for insulin-dependent diabetes. Avoidance of these complications represents a significant positive step in the reduction of health care expenses directly attributed to diabetes and its complications. If successful, the approach involving the genetic modification proposed for the development of a cell product for diabetes in these investigations can also be utilized for the derivation of other therapeutically useful cells from human ES cells for human therapy, since the purification of cells of interest as well as avoiding teratomas risk and immune rejection are common bottlenecks for all human ES cell based therapy.
Progress Report: 
  • Spinal muscular atrophy (SMA) is the leading genetic cause of infant death in the U.S. This devastating disease affects 1 child in every 6,000-10,000 live births, with a North American prevalence of approximately 14,000 individuals. The disease is characterized by the death of spinal cord cells called motor neurons that connect the brain to muscle. Death of these cells causes muscle weakness and atrophy, which progresses to paralysis, respiratory failure and frequently death. The three different types of SMA differ in severity and prognosis, with Type I being the most severe. SMA is caused by a genetic defect that leads to reduced levels of a single protein called SMN. There are currently no approved therapies for the disease.
  • Existing treatments for SMA consist of supportive care for the respiratory and nutritional deficits, for example ventilation and feeding tubes. Previous attempts to develop drugs using conventional technologies, such as cultured cancer cells or cells derived from animals have been unsuccessful. These failures are likely due to the fact that previous attempts used cell types that do not reflect the disease or are not affected by low levels of the SMN protein. Our approach uses patient-derived motor neurons, the specific cell type that dies in SMA.
  • An added advantage to our approach is that we can test our drug candidates in motor neurons from many different patients and different disease subtypes. We have generated iPSCs from many patients with SMA and we will test compounds for effectiveness against this cohort. These studies will give us an indication of the effectiveness of our compounds across patients before moving into costly and lengthy clinical trials. It will increase the amount of SMN protein and prevent motor neuron death. Halting the death of spinal cord motor neurons prevents the progressive weakness and muscle atrophy. We anticipate that this would prevent disability in Type III patients. For Type I and II patients, we believe such a therapy would mitigate respiratory and feeding challenges and allow an increase in lifespan.
  • In the past year, we conducted drug discovery experiments using these motor neurons to find potential therapeutics that increase the levels of the SMN protein in these diseased cells. Induced pluripotent stem cell (iPSC) technology allows us to take skin cells from patients with SMA, grow them in a dish, and turn them into SMA motor neurons. We conducted high-throughput screens of potential drugs with these cells to identify drug candidates that increase SMN protein levels in motor neurons derived from SMA patients. Despite the high quality of these screens, no suitable drug candidate was identified. We have modified our strategy and developed a method to identify, in parallel, all targets in the “druggable” genome that regulate SMN protein levels. An exhaustive screen currently is being performed to identify such a target and will be completed by end April 2012. Once a target is identified, it will be developed into a lead and validated in animals.

© 2013 California Institute for Regenerative Medicine