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What Regenerative Medicine Research is the John Paul II Medical Research Institute Conducting for Lung Disease? Part 3

Reducing the Cost of Differentiating Induced Pluripotent Stem Cells into Lung Cells – A Goal to Make Me-Too Inhalers Obsolete for COPD Patients

by Dr. Alan Moy, November 17, 2018

As previously stated, the pharmaceutical industry has never made any research investments to develop stem cell therapies to replace the damaged cells in patients with emphysema, pulmonary fibrosis and Cystic Fibrosis. Also, inhalers (which the pharmaceutical industry is generating billions of dollars from COPD patients) provide little benefit to patients with emphysema.

There is current research to explore the use of induced pluripotent stem cells (iPSC) to treat age-related macular degeneration, Parkinson's disease, juvenile diabetes and cardiac disease. In contrast, there has been little industry, government and private foundation sponsored research devoted towards iPSC therapies to treat lung disease. The main reason for this fact is that iPSC differentiation into lung cells has been historically very inefficient, requires multiple steps, and each step requires multiple growth factors (peptides). The cost for all these growth factors to produce lung cells is in the thousands of dollars. Thus, the process is cost prohibitive to conduct an experiment, much less producing a cell therapy. As shown in the below figure, iPSC must first differentiate into definitive endoderm cells, which, in turn, must differentiate into anterior foregut cells, which, in turn, must differentiate into lung progenitor cells. Lung progenitor cells have two potential fates. They can differentiate into alveolar stem cells or airway stem cells. These two separate pathways also require different sets of growth factors. The cost of these growth factors ranges between 75-95 percent of the cost of materials to develop therapies because they are produced from a string of supply chain manufacturers. For the layperson, the take home message is that to advance the field of regenerative medicine for respiratory disease, the manufacturing cost of growth factors must be reduced by more than 75 percent.

To achieve this reduction goal, the Institute and Cellular Engineering Technologies have collaborated to produce these growth factors in-house, which will eliminate supply chains. The benefits of this approach are two-fold. First, the cost of growth factors will be reduced to pennies on the dollar. Second, this initiative provides greater quality control in cell therapy manufacturing. To produce growth factors, our research consortium is using a Chinese Hamster Ovary (CHO) cell to manufacture peptides (see figure). The CHO cell is the most popular mammalian cell used in the biopharmaceutical industry. To produce growth factors, the gene of interest (i.e. growth factor) is genetically engineered into a proprietary circular nucleic acid structure called a plasmid that we developed. The plasmid is then inserted into CHO cells whereupon the peptide or protein is synthesized and secreted out of the cell. The protein is then collected and purified for final use. While CHO-based protein production is standard practice in industry, there exist some shortcomings. Without going through all the details, we have introduced several innovations that will increase the protein yield from this process at a lower cost of manufacturing. As result of this research, the Institute will be poised to then accelerate iPSC-derived cell therapy for all diseases, not just lung disease.

Recently, scientists at Cellular Engineering Technologies, the John Paul II Medical Research Institute and the University of Iowa collaborated on a study that is in press in the scientific journal Regenerative Medicine (to be available soon to the public). The scientific work showed how our first-in-class, virus-free and oncogene-free iPSC technology could be applied to cord blood and to peripheral blood in patients with Cystic Fibrosis and Alpha 1 Antitrypsin Deficiency, the latter is a genetic cause of emphysema. The study further demonstrates how iPSC can differentiate into lung progenitor cells. It is now possible to accelerate this type of regenerative medicine research for developing treatments for lung diseases for emphysema, pulmonary fibrosis and Cystic Fibrosis.

The final step in regenerative medicine is to integrate all the previously discussed technologies from our series of posts and deliver these cells to the lung where they can maintain long-term viability and replace some of the function absent in chronic lung disease.

Based on historic timelines and cost, the Institute estimates that it will take 5 years and 10 million dollars (2 million dollars per year) to complete the FDA-required preclinical research to launch the first regenerative medicine clinical trial in COPD. According to the World Health Organization, there are 65 million individuals around the world that live with moderate to severe COPD. If only 100,000 of these 65 million were to commit to donating $20 a year, this goal would be met. That translates to sacrificing 2 packs of cigarettes per year.

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