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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.
This project is focused on developing an approach for the treatment of pulmonary arterial hypertension (PAH), which is caused by blood vessel dysfunction in the lung. Although the pathophysiology of PAH is not completely understood, autoimmune diseases and other forms of immune dysregulation are thought to contribute to the development of PAH. Since regulatory T cells (Tregs) suppress activation of the immune system and thereby maintain immune tolerance to self-antigens, the Principal Investigator (PI) proposes to treat PAH by administering Tregs derived from induced pluripotent stem cells (iPSCs). To test this concept, the PI proposes to generate and characterize Tregs from rat iPSCs in Aim 1. The PI will then follow the fate of iPSC-derived Tregs injected into a rat model of PAH in Aim 2, and will determine whether the injected cells attenuate PAH in Aim 3. Reviewers appreciated the potential impact of this proposal on the treatment of a currently incurable condition. Overall, reviewers described the proposal as well organized, but expressed doubts about its rationale and feasibility. The proposal presents several significant challenges. Critical to the proposal is the development of large numbers of Tregs; this is not a new concept and reviewers did not believe that the proposal offered new solutions to the challenge of doing so from pluripotent stem cells. The rat model of PAH is in hand, and the PI provides preliminary data to demonstrate ameliorating effects of injected spleen-derived Tregs on development of PAH in this model. However, a reviewer pointed out that in PAH patients, elevated Treg levels have been found, an observation that undermines the proposed therapeutic rationale of administering Tregs. A third concern related to the feasibility of generating rat iPSCs. Given the differences between mouse and rat pluripotent stem cells and the limited experience with rat iPSC in the field, reviewers questioned whether rat iPSC would be readily generated, especially since no relevant preliminary data are presented. Similarly, reviewers questioned whether protocols developed in mouse systems to generate Tregs from iPSC would readily transfer to a rat system, and commented that this has not been straightforward for the field. The PI acknowledged these potential difficulties, but alternate plans were not well delineated. Reviewers felt the PI is highly qualified and has extensive expertise in immunology and PAH, but noted that his/her publication record reveals low productivity in recent years. The co-investigator is a notable stem cell biologist who contributes critical expertise in iPSC biology. Additional key expertise is provided by a renowned T cell researcher, but reviewers expressed concern that this investigator’s effort appears to be limited to an advisory role. In summary, this proposal focuses on the generation of Tregs from rat iPSC to treat PAH in a rat model. Reviewers’ expressed major concerns regarding rationale and feasibility of the proposed approach, and did not recommend the proposal for funding.