TY - JOUR
T1 - Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty
T2 - A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial
AU - Tompkins, Bryon A.
AU - Difede, Darcy L.
AU - Khan, Aisha
AU - Landin, Ana Marie
AU - Schulman, Ivonne Hernandez
AU - Pujol, Marietsy V.
AU - Heldman, Alan W.
AU - Miki, Roberto
AU - Goldschmidt-Clermont, Pascal J.
AU - Goldstein, Bradley J.
AU - Mushtaq, Muzammil
AU - Levis-Dusseau, Silvina
AU - Byrnes, John J.
AU - Lowery, Maureen
AU - Natsumeda, Makoto
AU - Delgado, Cindy
AU - Saltzman, Russell
AU - Vidro-Casiano, Mayra
AU - Da Fonseca, Moisaniel
AU - Golpanian, Samuel
AU - Premer, Courtney
AU - Medina, Audrey
AU - Valasaki, Krystalenia
AU - Florea, Victoria
AU - Anderson, Erica
AU - El-Khorazaty, Jill
AU - Mendizabal, Adam
AU - Green, Geoff
AU - Oliva, Anthony A.
AU - Hare, Joshua M.
N1 - Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Background Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair. Methods This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion. Results No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p =.01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p =.03). Serum TNF-α levels decreased in the 100M-group (p =.03). B cell intracellular TNF-α improved in both the 100M- (p <.0001) and 200M-groups (p =.002) as well as between groups compared to placebo (p =.003 and p =.039, respectively). Early and late activated T-cells were also reduced by MSC therapy. Conclusion Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder. Clinical Trial Registration www.clinicaltrials.gov: CRATUS (#NCT02065245).
AB - Background Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair. Methods This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion. Results No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p =.01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p =.03). Serum TNF-α levels decreased in the 100M-group (p =.03). B cell intracellular TNF-α improved in both the 100M- (p <.0001) and 200M-groups (p =.002) as well as between groups compared to placebo (p =.003 and p =.039, respectively). Early and late activated T-cells were also reduced by MSC therapy. Conclusion Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder. Clinical Trial Registration www.clinicaltrials.gov: CRATUS (#NCT02065245).
KW - Immunomodulation
KW - Regenerative medicine
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=85032646300&partnerID=8YFLogxK
U2 - 10.1093/gerona/glx137
DO - 10.1093/gerona/glx137
M3 - Article
C2 - 28977399
AN - SCOPUS:85032646300
SN - 1079-5006
VL - 72
SP - 1513
EP - 1521
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
IS - 11
ER -