Stem cell therapy is offering new hope to patients currently suffering serious or even lethal medical conditions. One such condition is called pulmonary arterial hypertension (PAH) which affects thousands in the U.S. every year and for which there is no cure. PAH mainly affects young to middle aged women and is often the result of systemic inflammation (called autoimmunity) which attacks the blood vessels in the lungs. The injury to the blood vessels leads to very high blood pressures in the patient's right heart causing early death. A prevailing theory for why systemic inflammation occurs in autoimmune diseases is that key cells in the immune system, called 'regulatory T cells' or 'Tregs', are not working properly or are too few in number. For example, patients with a condition known as systemic sclerosis associated PAH (a condition associated with decreased Treg function) have a three year survival rate of 56%. A treatment or cure is desperately needed for PAH.
Because animal models of autoimmune disease have shown that Treg cells, injected as therapy, can prevent or treat disease, there has been considerable enthusiasm for giving Tregs back to patients with autoimmune diseases. Physicians ideally would take a patient's blood sample, grow up Tregs in the lab (outside of the patient's body), and then, when enough functional Tregs were present, would administer these cells back to the patient. Unfortunately, this approach has not proven feasible for Tregs; it has proven too difficult to raise sufficient numbers of cells to be useful as a therapy. Clearly, a new strategy is needed, and fortunately, stem cell technologies are now available to provide the answer.
We have developed an animal model of PAH which looks very similar to the human PAH. These animals (rats) develop inflammation in the blood vessels of the lung and develop severe PAH. These animals also have poor Treg function and, importantly, do not develop PAH if they are given Treg therapy. It currently takes about 3 rat donors to provide enough Treg cells to treat one rat. Our group is interested in using this animal model to show that it is possible to overcome the problem encountered with patients and generate Tregs directly from stem cells. This approach has the promise of producing sufficient numbers of Tregs to treat PAH. Proving that this approach is feasible in animals is an important first step before going to clinical trials. The aims of this project are, first, to create rat stem cells which have the capacity to grow into multiple cell types (i.e. a pluripotent cell), then mature these cells further into Tregs. Next, we will inject genetically- labeled cells into the animals' bodies to learn where these cells go and how long they live. Finally, we will give these manufactured Tregs to our animals to see if PAH is prevented. With success, this approach could provide a much-needed treatment for PAH patients as well as for other patients suffering autoimmune diseases.
Statement of Benefit to California:
The proposed research will be of potential benefit for patients and families impacted by autoimmune diseases which are significant health problems for the residents of California and other states. The science outlined in this proposal involves creating cells, called regulatory T cells, which can be used to prevent or treat autoimmune conditions. We are specifically targeting a deadly heart and lung disease known as pulmonary arterial hypertension, which affects thousands of Californians every year. The proposed research is testing the principle that regulatory T cells can be grown up from stem cells and be effective for treating experimental pulmonary arterial hypertension in laboratory animals. Knowledge gained from this science could then be used to help humans with pulmonary arterial hypertension and other autoimmune disorders.