Incurable lung diseases pose a major challenge to medical science. Cystic fibrosis, asthma, pulmonary fibrosis, cancer, hyaline membrane disease and emphysema are examples of diseases that may be eventually conquered by stem cell therapies. However, due to its geometrical complexity it is difficult to deliver therapeutic agents to the diseased regions of the lung where they may effect cures. Fortunately, the use of other inhaled medicines has progressed to the point where stem cell delivery can now be considered. Aerosol treatments are typically painless and very effective. The challenges to therapy with inhaled stem cells are many, including; cell survival during the process of aerosolization, delivery of cells to the proper disease- specific region(s) of the lungs, and providing support for the stem cells, post deposition, that will allow them to survive and become properly established. Our project systematically attacks these challenges by establishing a team with competence in aerosol science, inhaled aerosol deposition, and clinical pulmonary medicine. Completion of this pilot project will lay the foundation for developing specific new therapies for lung diseases.
Statement of Benefit to California:
Many Californians suffer from incurable and even untreatable lung diseases. This project has the goal of developing aerosol delivery systems for human embryonic stem cells so that the advances in stem cell biology can be used to treat lung disease. California could become a world leader in treating patients with lung diseases such as cystic fibrosis, asthma, pulmonary fibrosis, cancer, hayline membrane disease, and emphysema. Another benefit is that aerosol treatments for lung diseases are typically, painless, do not require anesthesia, and tend to have fewer side effects than do alternative forms of administration. Projecting into the future, microgravity medicine will permit the administering of stem cells deeper into the lung because the deposition in bronchial airways by the sedimentation mechanism will be absent. California's significant role in space may thus be enhanced.
SYNOPSIS: The objective of this proposal is to develop an aerosol method for depositing hESCs on large respiratory tract surfaces in order to replace or establish epithelial or other cells. The proposal focuses on improving the design of different aerosol generators and adapting them to use with hSEC, while maintaining the latter's viability and function. The long term objective is to develop treatments for diseases like Cystic Fibrosis (CF). SIGNIFICANCE AND INNOVATION: The proposed work aims to contribute to the medical care of patients with respiratory tract disease by using hESCs deposited in situ from aerosols. The significance of this work relates to importance of pulmonary diseases to human health. Presumably, development of improved aerosol generators will allow better handling of cells intended to populate areas damaged by exposure or inherently unsuitable owing to genetic disease (e.g., CF). The innovation of this proposal relates to the delivery systems to be used for administration of hES cells to the respiratory tree. Success at the technology, however, as described here is essentially unrelated to the use of hESCs and their biological requirements. Thus this proposal is not innovative with respect to what will be learned regarding hES cells. An effort will be made to improve and/or develop "adjuvants", substances that can enhance the viability of the cells handled in this fashion. STRENGHTS: The principal strength of this proposal relates to the methods that will be established to aerosolize viable hES cells that have particle size distributions capable of being inhaled by patients. The PI and his collaborators are experienced in the area of aerosol formation and measurements, and they appear to have the requisite expertise in this area of pulmonary medicine with support and possibly other help from Dr. Michael Roth, Professor of Medicine in the Division of Pulmonary and Critical Care, at UCLA. They have adequate facilities for the engineering and testing aspects of the work. Federal support is unlikely because there are no preliminary data relevant to the use of hES cells in this context. WEAKNESSES: The main weakness is that the proposal shows no regard for the biological aspects of hES cells. For example, there is a lack of appropriate consideration of the hES cells to be used. There is little reason why this work could not be performed with existing NIH-approved hES cell lines. It is not discussed whether there will be an effort to differentiate these cells or just use them straight off the culture vessel. The PI imagines, it would appear, administration of undifferentiated hES cells to patients as no cell lines will be generated and only one of the Harvard lines is mentioned for use in this work. In fact, there is nothing concerning the biology and requirements of stem cells under the conditions to which these will be exposed. Given the potential for teratoma formation and the lack of directed differentiation toward pulmonary cell fates, this strategy is without any merit. Presumably, Dr. Roth's intervention will help focus on the medical aspects but there does not seem to be anyone in the team with specific understanding of stem cells. A far better approach would be to isolate pulmonary epithelial and other cells from differentiated hES cells, but since their properties would be very different than hES cells, the studies proposed in this application would have little bearing on how these cells would be administered in a therapeutic setting. The recruitment of a colleague with a specific research interest in hESCs for treatment of disease to collaborate in the proposal and carry out the necessary work would be an important and necessary improvement. DISCUSSION: There was no further discussion following the reviewers' comments