What Have We Learned from Past Stem Cell Trial Failures in COPD?
by Dr. Alan Moy, November 12, 2018
Theoretically the lung should be a quite attractive organ for delivering stem cell therapies. Stem cells could be administered by inhalation, bronchoscopy or by an intravascular route. When stem cells are administered intravascularly, they are sequestered for several hours in the lung. Thus, the lung would be an ideal organ for treating chronic lung diseases like COPD. Bone marrow-derived mesenchymal stem cells (BM-MSC) from healthy donors (the most common adult stem cell used in hundreds of clinical trials for a variety of different diseases) have shown therapeutic benefit and safety in mouse models of COPD. However, when this stem cell is tested in human trials, they show safety but lack therapeutic benefit. This raises several important questions: (1) Why have adult stem cell therapies failed in clinical trials?; (2) What have we learned from this research so that we can advance the field?; and (3) What can we predict from stem cell therapies offered by for-profit stem cell clinics?
For regenerative medicine to be successful for treating COPD, or any lung disease, there are several prerequisites features that stem cells must accomplish. First, they must be potent. Second, there must be standard techniques to measure cell potency. Third, stem cells must home (travel) to the exact site of disease (i.e. airway vs alveoli); remain viable long enough in the lung; and then deliver its intended therapeutic effect. Lastly, since alveolar failure is major determinant towards the poor prognosis of lung disease, we also need stem cells that can differentiate into alveolar cells to replace the cells that have died or are dysfunctional.
Stem cell trials failed because BM-MSC are not potent enough to treat COPD even when provided from healthy donors. BM-MSC are missing some specific therapeutic attribute. They do not home to the precise site of disease, maintain cell viability or deliver its intended therapeutic effect. Stem cells from COPD patients are likely defective. Stem cells from COPD patients are just as impacted from the same insult that caused the lung disease in the first place. Thus, if BM-MSC from normal donors do not work, then why think that the same stem cells from COPD patients would work any better.
Also, we now know that the therapeutic effect of adult stem cells is derived from their paracrine activity (Sorry for introducing a technical term, but if you’re want to understand the fundamentals about stem cells, it’s critical to understand the paracrine term). Paracrine effects from stem cells are attributed to the release of microvesicles (e.g. organelles called exosomes), which are nanometer-sized vesicles that contain therapeutic lipids, nucleic acid and peptides/proteins. The stem cell field now recognize that it’s these microvesicles that mediate the regenerative medicine effect. Many stem cells work by homing to a site of disease and deliver their cargo of microvesicles that contain these therapeutic molecules. Additionally, there is evidence that the microvesicles from patients with chronic disease are impaired and even promote disease. Thus, using a patient’s own stem cells may not just be ineffective but could be potentially harmful. Lastly, BM-MSC and many other stem cells do not have the capacity to differentiate (convert) into alveolar cells, which are necessary to replace the cells damaged in alveolar failure. Only pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) differentiate into alveolar cells. However, embryonic stem cells carry ethical controversy and both types of pluripotent stem cells carry neoplastic risk.
I am frequently asked by COPD patients whether they should travel and pay thousands of dollars for stem cell therapies from these for-profit stem cell clinics. I tell patients that there is no scientific evidence or good scientific rationale to use their own stem cells for the above reasons. Further, the dose of stem cells harvested by these clinics is insufficient. Lastly, the source of stem cells used by these clinics (from bone marrow or fat tissue) likely exhibits poor paracrine activity. For COPD patients seeking stem cell therapies from these clinics, I recommend that their money could be better spent by buying a really nice home treadmill or stationary bike and stay in shape and get on a diet if overweight or use the money to join a gym or participate in a hospital-based pulmonary rehabilitation program.
Thus, to develop regenerative medicine therapies for COPD, the following technical milestones need to be achieved.
1. We need stem cells that have potent paracrine activity than BM-MSC.
2. We need techniques that can purify and scale up the manufacturing of microvesicles.
3. We need techniques that measure stem cell and microvesicle potency.
4. We need an ethically, non-controversial pluripotent stem cells with less neoplastic risk that can differentiate into alveolar cells, and serve as a universal stem cell with little chance of immune rejection.
5. We need to reduce the manufacturing cost of differentiating pluripotent stem cells into alveolar cells (more on this in later posts).
6. We need to figure out how to maintain stem cell and alveolar cell viability and function for extended period of time (i.e., not hours but lasting for weeks).
7. We need to control the delivery of stem cells and alveolar cells to the exact site of disease.
8. We need to develop technologies that control and supplement a stem cell’s paracrine activity to augment their potency if they are missing some natural attribute.
While these milestones appear daunting, they are theoretically solvable with the current technologies that exist today. The Institute has already accomplished many of these milestones, but more work is needed.
The good news is if these same milestones are accomplished for lung disease, they solve the barriers for developing regenerative medicines for all diseases like neurodegenerative disorders, cardiac disease, cancer and juvenile diabetes.
A good analogy is construction. Without lumber, steel, plumbing, concrete, electricity and heating, we would be living in huts and caves.