Today, we want to highlight results from human trials in which stem cell transplants have been shown to reduce age-related frailty.
Age-related frailty and stem cell transplants
Currently, there are no specific approved therapies to address age-related frailty, which can cause elderly people to suffer potentially fatal falls and injuries. There has been considerable interest in stem cell therapies to combat frailty in recent years, and the results we will discuss today are from one of the more advanced human clinical trials exploring mesenchymal stem cell (MSC) transplants [1].
Named after the Greek god of strength and power, the CRATUS series of stem cell studies involves transplanting mesenchymal stem cells into patients to try to address age-related frailty. There have been numerous studies showing that MSCs have potential in improving tissue repair, so this application is the logical conclusion of years of testing and study.
These health improvements are almost certainly linked to the reduction of chronic inflammation, which is known to impair tissue repair and regeneration, by inhibiting the activity of tissue resident stem cells. The presence of MSCs appears to reduce the background of chronic age-related inflammation and thus facilitates healing and tissue repair due to the beneficial secretions that these cells produce.
Perhaps most interestingly, MSCs rarely join with the tissues to which they are transplanted; however, they do remain active for a considerable time, often for months, and help reduce inflammation, giving damaged tissue time to recover before the inflammation returns to continue its relentless assault.
Chronic diseases and degenerative conditions are strongly linked with the geriatric syndrome of frailty and account for a disproportionate percentage of the health care budget. Frailty increases the risk of falls, hospitalization, institutionalization, disability, and death. By definition, frailty syndrome is characterized by declines in lean body mass, strength, endurance, balance, gait speed, activity and energy levels, and organ physiologic reserve. Collectively, these changes lead to the loss of homeostasis and capability to withstand stressors and resulting vulnerabilities. There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Although exercise and nutritional supplementation provide benefit to frail patients, there are currently no specific therapies for frailty. Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) provide therapeutic benefits in heart failure patients irrespective of age. MSCs contribute to cellular repair and tissue regeneration through their multilineage differentiation capacity, immunomodulatory, and anti-inflammatory effects, homing and migratory capacity to injury sites, and a stimulatory effect on endogenous tissue progenitors. The advantages of using MSCs as a therapeutic strategy include standardization of isolation and culture expansion techniques and safety in allogeneic transplantation. Based on this evidence, we performed a randomized, double-blinded, dose-finding study in elderly, frail individuals and showed that intravenously delivered allogeneic MSCs are safe and produce significant improvements in physical performance measures and inflammatory biomarkers. We thus propose that frailty can be treated and the link between frailty and chronic inflammation offers a potential therapeutic target, addressable by cell therapy.
Results of phase 1 and 2 human clinical trials
The researchers conducted phase 1 and 2 clinical trials under the CRATUS program using mesenchymal stem cell transplants to reduce frailty in aged patients [2-4]. The ultimate goal of the CRATUS program is to restore or maintain cognitive and physical function in elderly patients and lengthen their healthy lifespan. These clinical trials were designed to assess the safety and efficacy of transplanting allogeneic bone marrow-derived MSCs to patients with mild to moderate frailty, and their success was based on an improvement of physical performance, quality of life, and reduction of chronic systemic inflammation.
The phase 1 results showed that MSC therapy is well tolerated, and those results led to a phase 2 efficacy trial using both 100-million and 200-million dosages. At the 100-million dose, patients were observed to have improved physical abilities, including performance in a 6-minute walking test, a physical performance exam, and an improvement of forced expiratory volume, suggesting improved lung function. The higher 200-million dose was less effective.
Blood levels of inflammatory TNF-α and activated T-cells were reduced significantly in both dosage groups. This suggests that the MSCs reduced systemic inflammation and excessive activation of the immune system, which are typical in old age.
Conclusion
These are promising and positive results indeed, and the next step will be a 2b study with a larger test group to see if the results remain consistent. Should this prove successful, the therapy will most likely pass through the approval process, and, at last, patients will have an available solution for combating frailty.
Literature
[1] Schulman, I. H., Balkan, W., & Hare, J. M. (2018). Mesenchymal Stem Cell Therapy for Aging Frailty. Frontiers in Nutrition, 5.
[2] Tompkins, B. A., DiFede, D. L., Khan, A., Landin, A. M., Schulman, I. H., Pujol, M. V., … & Mushtaq, M. (2017). Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(11), 1513-1522.
[3] Golpanian S, DiFede DL, Khan A, Schulman IH, Landin AM, Tompkins BA, et al. Allogeneic human mesenchymal stem cell infusions for aging frailty. J Gerontol Ser A Biolog Sci Med Sci. (2017) 72:1505–12. doi: 10.1093/gerona/glx056
[4] Golpanian, S., DiFede, D. L., Pujol, M. V., Lowery, M. H., Levis-Dusseau, S., Goldstein, B. J., … & Heldman, A. W. (2016). Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: a phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget, 7(11), 11899.
