Basic Biology III
The life expectancy of persons diagnosed with Idiopathic Pulmonary Fibrosis (IPF) is 2 to 3 years, worse than many cancers. It belongs to the family of idiopathic interstitial pneumonias (IIPs), and represents the most aggressive form of diffuse parenchymal lung disease (DPLD). As many as 500,000 patients are presently affected in the EU and US. We and others think that progression of lung fibrosis in IPF and related forms of DPLD is primarily based on an overwhelming, albeit insufficient progenitor cell response, which exceeds the regenerative capacity of the alveolar lining epithelium. Therefore, stem cell-based therapies appear as a promising and probably the only effective approach to change the dire fate of this disease. Goal: To devise and optimize novel pre-clinical stem cell based therapeutic solutions to DPLD. Future Aim. To show that amniotic fluid derived stem cells are a novel, safe, scalable and well immune tolerated source of ethically neutral cells that have major pro-homeostatic effects on the alveolar milieu in DPLD and thus to justify an IND filing for a phase 1 trial of these cells in human patients with terminal DPLD. Significance: If, as we expect, and our preliminary data supports, this novel stem/progenitor cell based therapeutic approach works and is not toxic in murine models of IPF, it will be a major innovation, leading to a potentially important translational advance for several human DPLDs, including IPF, which presently have no effective therapy.
Statement of Benefit to California:
The life expectancy of persons diagnosed with Idiopathic Pulmonary Fibrosis (IPF) is 2 to 3 years, worse than many cancers. It belongs to the family of idiopathic interstitial pneumonias (IIPs), and represents the most aggressive form of diffuse parenchymal lung disease (DPLD). As many as 500,000 patients are presently affected in the EU, US and California. We and others think that progression of lung fibrosis in IPF and related forms of DPLD is primarily based on an overwhelming, albeit insufficient progenitor cell response, which exceeds the regenerative capacity of the alveolar lining epithelium. Therefore, stem cell-based therapies appear as a promising and probably the only effective approach to change the dire fate of this disease. If proven effective, this innovative treatment would provide a major translational and biotechnology business opportunity for the State and citizens of California.
Project Synopsis: The goal of the proposed research is to devise, characterize, and optimize novel human amniotic fluid stem cell (hAFSC) based therapeutic solutions for diffuse parenchymal lung disease (DPLD), a life-threatening family of pulmonary disorders for which there are no cures. In Aim 1, the applicant proposes to employ a primary culture model to determine whether hAFSCs can accelerate alveolar endothelial repair and whether this activity might be augmented or inhibited by factors derived from injured lung. For Aim 2, the applicant proposes to compare the ability of AFSCs alone versus AFSCs primed with factors identified in Aim 1 to ameliorating lung fibrosis in murine models of DPLD. Significance and Innovation: - The proposed studies are phenomenological and do not appear well designed for elucidating or impacting understanding of basic cellular or molecular mechanisms. - The use of AFSCs for therapeutic solutions is not a novel concept, as these cells are being investigated for treating a variety of conditions. However, this plan is somewhat innovative in that it addresses lung disease, an important area that has received limited attention. - The rationale for use of AFSCs as opposed to other cell types is not presented compellingly. Furthermore, the advantages that AFSCs might offer over other potentially anti-inflammatory, immune modulatory, or regenerative stem cell populations is not likely to be uncovered by the proposed research. - If successful, the proposed studies could lead to translational advances in the treatment of fibrotic lung disease. Feasibility and Experimental Design: - The experimental plan seems designed to produce data more akin to filing an investigational new drug application (IND) than to addressing a scientific hypothesis. - The preliminary data document the technical capabilities of the team and support the concept that AFSCs can potentially ameliorate symptoms in an experimental model of lung fibrosis. Several statements and claims were made, however, that were not substantiated. - The proposal does not directly test the applicant╒s general hypothesis that Idiopathic Pulmonary Fibrosis (IPF), an aggressive form of DPLD, results from dysregulated turnover of lung progenitor cells, nor does it test mechanisms by which hAFSCs might exert therapeutic effects. - It is not clear how many of the proposed mouse models are already available, validated, or even necessary for the proposed studies. The relative advantages of each were not adequately discussed. - The proteomic and array approaches to be employed seem open-ended and may lead to a complex set of data that will be difficult to exploit. - The feasibility of Aim 2 is dependent on the success of Aim 1. The timelines are not clearly laid out as a logical sequence of experiments. Principal Investigator (PI) and Research Team: - The principal investigator (PI) is a highly lauded, productive scientist with a strong track record in pulmonary fibrosis, tissue regeneration, and stem cell research. A key collaborator provides valuable expertise in the isolation and growth of AFSC. - The partner PI and team bring strength to this proposal for their extensive experience with IPF models, relevant read-out parameters and translation into clinical medicine. - Reviewers noted the clear intellectual and technical synergies of the collaborative teams but were uncertain of the specific roles and logistics by which their efforts would be coordinated. - The publication record of the investigators does not demonstrate strong expertise in immunology or mechanisms of regeneration. The team seems better suited for translational studies than pursuing fundamental basic research. Responsiveness to the RFA: - The proposal does not adequately address the goals and objectives of the RFA. Rather than addressing basic mechanisms relevant to stem cell biology, the application describes research that is translational in nature.