Designing the right MSC therapeutic product for OA
alloreactions
HYPOXIC, DISEASE
As discussed above, the immunomodulatory basal fitness of MSCs, which can be modulated by age, sex, BMI, comorbidities, manufacturing parameters and cryopreservation and can be quantified by a range of quantitative CQAs [Functional high-content in vitro potency assays that are relevant to the mechanisms of action may also be useful for characterizing MSCs to better understand the influence of basal fitness levels on treatment efficacy [As discussed above, dosing, carrier choice and selection are also not fully understood, and in many cases medium to high (≥40 × 10Limited short-term clinical evidence supports repeat dosing of autologous and allogeneic MSCs, albeit without a full understanding of the potential implications of alloreactions to repeat allogeneic MSC dosing. Clinical trials using allogeneic MSCs should incorporate measurements of humoral and cellular responses to better discern the correlation, if any, between alloreactions and reduced clinical efficacy. Importantly, data on longer-term structural changes as well as symptom and disease modification are not sufficient to recommend repeat injections, but they merit investigation in future clinical trials.Ultimately, there are conflicting data regarding dosing from the RCTs and non-RCTs, and this seems to be driven in part by the baseline patient characteristics or clinical phenotyping; from our analyses, it appears that often the patients receiving lower doses of MSC products seem to have lower baseline pain/symptom scores, which confounds the analysis on dosing. Of the 15 RCTs, we noted differences in dose ranges tested for autologous (4.11–100 × 10Next-generation MSCs, with improved immunomodulatory basal fitness and designed to be fit-for-purpose (for OA treatment), are also being evaluated preclinically and clinically. Small-diameter MSC(CB) grown in hypoxic conditions in calcium-rich medium with improved basal fitness, including the ability to polarize MΦs to proresolving subtypes [Induced-pluripotent stem cell (iPSC)-derived MSCs (iMSCs) represent another next generation MSC product currently under clinical evaluation for the treatment of tibiofemoral knee OA in a Phase III double-blinded, randomized, controlled trial [MSC-derived EVs with cargo consisting of proteins, mitochondria, miRs, ions, and lipids are also being evaluated preclinically [In summary, there are several technologies to aid in the selection or engineering of basally fit autologous or allogeneic MSC therapeutic products or engineering MSC-derived EVs that can be specifically curated for OA therapeutics. Ultimately, MSCs with multimodal anti-inflammatory, immunomodulatory, chondroprotective and antifibrotic functionalities will likely be of greatest benefit. Dosing remains an open question, although meta-analysis results seem to suggest that cartilage structural changes are feasible with >40–50 × 10