Clinical Study of Mesenchymal Stem/Stromal Cell Therapy for the Treatment of Frailty: A Proposed Experimental Design for Therapeutic and Mechanistic Investigation

Abstract

Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in older people, is an emerging problem worldwide with major implications for clinical practice and public health. Recent preclinical and clinical studies have supported the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. Comprehensive study is needed to assess the interrelationship between the condition of frailty and the effects of MSC-based therapy. This randomized controlled phase I/II trial aims to investigate the safety and potential therapeutic efficacy of the allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with the standard treatment for frailty in Vietnam. Moreover, this study describes the rationales, study designs, methodologies, and analytical strategies currently employed in stem cell research and clinical studies. The primary outcome measures will include the incidences of prespecified administration-associated adverse events and serious adverse events. The potential efficacy will be evaluated based on improvements in frailty conditions (including those determined through a physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient plasma). This clinical trial and stem cell analysis associated with patient sampling at different time points aim to identify and characterize the potential effects of UC-MSCs on improving frailty based on the stem cell quality, cytokine/growth factor secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient CD3+ cells providing fundamental knowledge for designing and implementing research strategies in future studies. Clinical Trials Registration Number: NCT04919135.

Keywords: Allogeneic cell therapy; Clinical trial; Stem cell phenotype; Umbilical cord.

© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.

Figures

Figure 1.

Interrelationship among hallmarks of aging, clinical symptoms of frailty, and potential regenerative therapy. Aging people are constantly affected by oxidative stress and inflammatory responses throughout their later years. In an extreme condition of this interaction, frailty is developed and defined by 5 major criteria, including unintentional weight loss, exhaustion, slow gait speed, weak grip strength, and low physical activity. Frailty is strongly associated with the aging process, which includes 6 important hallmarks: genomic instability, deregulated proteostasis, nutrient sensing, metabolic malfunctions, cellular senescence, stem cell exhaustion, and compromised cellular communication. Emerging stem cell therapy provides a potential approach to tackle these problems by providing ex vivo cultured stem cells that are able to improve the frailty condition by multiple mechanisms.

Figure 2.

Proposed functional analysis to reveal the mechanism of action of UC-MSCs in the treatment of frailty. (A) The UC-MSC line was derived from Vinmec Biobank and was intensively characterized and cultured under xeno-free and serum-free conditions. These cells will be expanded to reach the transplantation dose for 22 patients (2 administrations with 1.5 × 106 cells/kg patient body weight) and cryopreserved for long-term storage. Cell viability, MSC marker, karyotype, product sterility (bacterial, fungal, and mycoplasma detection) and endotoxin will be assessed according to the Vietnamese Ministry of Health guideline and the International Society for Cell and Gene Therapy criteria of MSCs. (B) Peripheral blood at baseline and at 1, 3, 6, and 9 months will be collected, and (C) detection of cytokines/chemokines/growth factors using procartaplex technology derived from patient plasma will be performed, whereas CD3+ cells will be isolated for: (D) immunological analysis, (E) cellular senescence, and (F) metabolic analysis using Seahorse XFe96 analyzer. MSCs = mesenchymal stem/stromal cells; UC-MSCs = umbilical cord-derived mesenchymal stem/stromal cells.