MAYO CLINIC STEM CELL TREATMENT FOR MS TRIAL
As complex perianal fistulas refractory to conventional medical treatment strategies often require surgery with suboptimal outcomes, the success of this trial validated Alofisel as a novel therapeutic for addressing an unmet clinical need. Greater incidences of remission in the Alofisel treatment group persisted in a subsequent 52-week follow-up (~56% in treated group versus ~38% in placebo group), demonstrating the potential of MSCs to substantially improve the standard-of-care in chronic illnesses like CD. At the primary end point of 24 weeks, combined remission was significantly higher in patients treated with Alofisel (~50% in treated group versus ~34% in placebo group). In this study, adult CD patients with treatment-refractory, draining, complex perianal fistulas were enrolled in a randomized, double-blind, placebo-controlled phase 3 trial and treated with either a single intralesional injection of 120 million allogeneic AT-MSCs (Alofisel) or saline ( 14). The TiGenix/Takeda phase 3 clinical trial that studied the use of MSCs for complex perianal fistulas in CD is arguably the most successful late-stage MSC trial to date (NCT01541579). With more than 300 completed clinical trials using MSCs as of 2020, there is a wealth of information available to better understand what dictates their success and failure when investigated in humans. Because the properties of secreted biologics and MSC-derived EVs have been thoroughly reviewed elsewhere ( 11– 13), the current article focuses on MSC therapies. In line with this, many studies have shown that secreted biologics and MSC-derived EVs containing biologically active molecules (such as proteins, lipids, and nucleic acids) retain the biological activity of parental MSCs and demonstrate a similar therapeutic effect in selected animal models ( 10). Here, paracrine effectors from their secretome, including soluble cytokines, growth factors, hormones, and miRNA, are transferred to target cells such as immune cells and cells of damaged tissues through secretion, the uptake of biologics-loaded submicrometer extracellular vesicles (EVs), and immune-mediated phagocytosis ( 6– 9), which can lead to long-term effects. MSCs are generally distinct from other cell therapies as their therapeutic effect not only is dictated by cell-cell contact but also may include a so-called hit-and-run mechanism. To this end, MSCs have been investigated as a treatment for graft-versus-host disease (GvHD), multiple sclerosis (MS), Crohn’s disease (CD), amyotrophic lateral sclerosis (ALS), myocardial infarction (MI), and acute respiratory distress syndrome (ARDS), among others ( Table 1) ( 3– 5). While initial therapeutic efforts were based on their multipotency, the discovery of their immunomodulatory and trophic properties motivated harnessing MSCs as a treatment for neurodegenerative and inflammatory diseases. MSCs can also be easily isolated from multiple tissues including adipose tissue (AT), umbilical cord (UC), Wharton’s jelly, and the placenta ( 2). ( 1) in the late 1970s and continue to be the most commonly studied MSC source in preclinical and clinical studies.
Bone marrow–derived MSCs (BM-MSCs) were first described by Friedenstein et al.
Multipotent mesenchymal stromal cells (MSCs) have been extensively investigated as a cell therapy, showing promise in treating an array of diseases by restoring organ homeostasis in inflamed, injured, or diseased tissues.
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