Mitochondrial Transplantation: A Novel Therapy for Lung Fibrosis
Abstract
The strategy proposed herein addresses the Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Area of Pulmonary Fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, characterized by scarring of the lungs that eventually results in loss of lung function as oxygen flow to blood is impaired over time. It is a major cause of morbidity and mortality, especially in U.S. military active duty personnel and Veterans of the Iraq and Afghanistan wars. IPF patients die within 2-5 years of diagnosis, and there is no cure for the disease. The only effective treatment is lung transplantation. The central critical problem this proposal addresses is the lack of efficacious therapies capable of altering or preventing IPF progression. Current therapies include oxygen therapy, pulmonary rehabilitation, and drug therapies. However, these mainly alleviate symptoms or slow the progression of the disease, and are incapable of halting or reversing IPF. The objective of this proposal is to target metabolic dysregulation in IPF. Recently, insights have highlighted the important role that bioenergetics of pulmonary cells plays in IPF. Alveolar macrophages, alveolar epithelial cells, and fibroblasts undergo metabolic reprogramming in IPF from a highly efficient method of ATP production, oxidative phosphorylation (OXPHOS), to a less efficient process of glycolysis. Lower oxygen consumption rates (OCR) and decreased ATP production ensues, which drives IPF progression. As an example, metabolic reprogramming can promote fibroblast to myofibroblast transition, with myofibroblasts contributing to scar formation. Thus, targeting metabolically compromised pulmonary cells in IPF proves attractive to impede disease progression through attenuation or reversal of pro-fibrotic pathways. The objective of the proposed work is to treat IPF by restoring favorable metabolic profiles in pulmonary cells in IPF lungs through delivery of mitochondria to these cells. Cell-to-cell transfer of mitochondria in the body has been shown to be an efficient means of overcoming conditions of stress, providing a rationale for mitochondrial transplantation as a therapeutic approach. In this proposal, isolated mitochondria will be functionalized with a polymer coating meant to biocompatibilize the organelle for in vivo systemic delivery applications. Preliminary data shows that coating mitochondria with a polymer conjugate protected mitochondria ex vivo, increased their uptake in cells, and led to higher OCR and improvements in OXPHOS compared to uncoated mitochondria. Moreover, intravenously administered mitochondria were capable of accumulating in fibrotic lungs for prolonged times. The hypothesis is that mitochondrial delivery to alveolar macrophages, alveolar epithelial cells, and fibroblasts will properly regulate mitochondrial bioenergetics, and prevent disease progression in a mouse model of IPF. Work will focus on evaluating the ability of bioengineered mitochondria to restore cellular energetics in IPF fibroblasts, alveolar epithelial cells, and macrophages. Mitochondria isolated from healthy mice will be functionalized with a polymer coating and administered to cells. Cellular bioenergetics, including OCR measurements, will be examined, as well as effects of treatment on cell proliferation, migration, and fibrotic phenotype. Work will then focus on determining whether bioengineered mitochondrial transplantation can treat experimental IPF. Mitochondria isolated from healthy mice will be functionalized with a polymer coating and injected intravenously into mice undergoing pulmonary fibrosis. Efficacy will be determined by examining the lungs of mice histologically for signs of fibrosis, and by measuring expression levels of pro-fibrotic markers. This work is highly innovative, as it represents one of the few strategies seeking to target aberrant metabolism as a therapeutic option in IPF. Moreover, the conc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910129
Entities
People
- Elvin Blanco
Organizations
- Houston Methodist Research Institute
- United States Army