There is a lot of evidence to show that inflammation accompanies damage in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The nervous system has its own unique immune cell type, call microglia. Microglia provide the first line of defense against infection, tumors and injury in the central nervous system (CNS: brain, spinal cord and optic nerve). These cells become activated in response to any of these insults, producing inflammatory substances called enzymes, cytokines and chemokines. It is also clear that microglia are activated when any cell is transplanted into the CNS such as would occur in stem cell transplant. Although microglia activation is a normal response to injury or disease, it is thought to have a negative effect on the transplants in the brain.
We plan to study the involvement of microglia in the survival of stem cell transplants into the CNS of mice with a disease similar to Parkinson’s disease. We want to see if stopping activation of microglia will allow long-term survival of stem cells transplanted into the CNS. Three approaches will be used, the first will involve a type of mouse that lacks the ability to activate microglia, while the second will involve treatment of diseased mice with two drugs that are currently FDA approved to treat other conditions, but which are known to also stop microglial activation. We will follow mice that are treated with these drugs and see how much longer transplanted cells survive compared to mice that did not receive any treatment. We will also see if the transplanted cells are still able to function normally in the treated mice and see if they are now able to help repair the damaged brain.
The use of the two drugs that are already used in humans to treat other symptoms will allow us to easily translate the results of these experiments to patients with neurodegenerative disease. Thus, this project is not only unique, but is especially relevant to the treatment of human disease in the CNS.
Statement of Benefit to California:
The State of California has made a critical investment in the future of medicine by pioneering efforts to support and conduct stem cell research for repair and regeneration in many human diseases. The first funding initiatives were directed to invest in training of scientists for stem cell research, defining basic science priorities and establishing core facilities to support stem cell research efforts. Recently, CIRM has focused on translational approaches to move research into the clinic, a move that will benefit patients in California as well as the financial future of the state.
We have concentrated on regenerative medicine in the nervous system, developing techniques to create reliable progenitor neural cells that can be used as transplants to promote repair in neurological diseases. Because all neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, Huntington’s disease and multiple sclerosis involve inflammation and changes in immune responsiveness in the nervous system, we have focused on developing an understanding of the interaction of the immune response and neural stem cells.
In order to use stem cells in the treatment of these diseases one has to address the possibility that stem cell transplants in the central nervous system are likely to be rejected. Our team has experience in degenerative diseases of the nervous system, stem cell biology, transplantation, and of particular importance expertise in the study of immune responses in the CNS.
The number of individuals with neurodegenerative diseases in the United States and the State of California is staggering. In addition, our population is aging, which means that the incidence of neurodegenerative diseases is likely to increase ten-fold over the next ten years. The human suffering and the financial burden associated with these diseases is also staggering. Costs to both the state and federal government are likely to run into the billions. The state of California, as the most populous state with an enormously high indigent population, is now, and will continue to be disproportionately affected by both the human and financial burden of neurological disease. Efforts to reduce this burden by developing viable strategies for stem cell transplants in the nervous systems are greatly needed.