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big gap in between where there is not much ava ilable. They … have to tr udge through this trough of m a n a g i n g a nd l iv i n g w it h pa i n a nd disabilit y." Severa l sma ll-sca le clinica l stud- ies deemed MSCs sa fe a nd effective at rel iev i n g pa i n a ssociated w it h knee OA . In a 2016 study, resea rch- ers in India found t hat indiv idua ls who received a 25 -mi llion-cell dose of a llogeneic MSCs displayed a trend t owa rd i mprovement i n k nee pa i n . A 2015 Spa nish study demonstrated that a llogeneic MSCs improved pa in a nd ca r tilage qua lit y. Those f indings cor roborated a n ea rlier st udy f rom Spa in involving autologous MSCs. HINTS OF A DOSE-RESPONSE EFFECT To assess the safety of MSCs, as well as learn more about dosing, mechanisms of action and donor selection, Viswanathan and collaborators conducted the first Canadian clinical trial using patient- derived MSCs to treat knee OA. Twelve individua ls with end-stage OA i n fou r, t h r e e -p er s on c ohor t s received a single injection of their own bone marrow MSCs in a 1-million-cell, 10-million-cell or 50-million-cell dose. The participants followed up with the researchers in clinic eight times over a 24-month period. The team used a vari- ety of methods to assess the cells' effects, including patient-repor ted outcome measures, inflammation biomarkers and MRI to look for changes to cartilage. The findings appear in STEM CELLS Translational Medicine. One year after treatment, participants reported significant improvement in pain, symptoms, quality of life and knee stiffness. Those who received the highest dose of MSCs — 50 million cells — experi- enced the most improvement, suggesting a dose-response effect. " W hat wa s not sur pr ising — a nd something we hypothesized — was the cells would be safe," says Jaskarndip Cha ha l, M D, MSc, M BA , A ssista nt Professor in the Department of Surgery at University of Toronto Orthopaedic Sports Medicine and University Health Network Arthritis Program, who was part of the research team. "We had no [serious] adverse events." MRI did not reveal cartilage regen- eration, as had been observed in other st udies, possibly due to dosing a nd donor va riations or the inclusion of patients with end-stage arthritis. To Viswanathan, a striking finding was the heterogeneity of gene expression in different participants' MSCs and its effect on outcomes. "We were able to look at some genes that were expressed in these cells, and we found that when some of these genes were expressed at high levels, then the patient went on to do really well," Viswanathan says. "When the starting gene level was not ver y high in these patients, they didn't do as well, so it seemed like one of the factors that determined how well patients did was … the quality of their cells and how they varied." That, Viswanathan says, points to the importance of careful patient and donor selection. EVIDENCE OF ANTI- INFLAMMATORY EFFECTS MSCs appeared to improve synovia l inflammation, with the most signifi- ca nt effect in patients who received the highest dose of cells. Levels of pro- inflammatory cells in the synovial fluid decreased three months after treatment. The anti-inflammatory and immuno- modulator y mecha nism of action of MSCs in OA may be a first-of-its-kind clinical finding, according to the team. The interaction between MSCs and immune cells was not unexpected — the researchers had observed the two interacting in the laborator y — but Viswanathan says it was gratifying to see the team's hypothesis that MSCs reduced the number of immune cells and the factors they secreted, confirmed in a clinical setting. Reducing immune cells, she says, is important not just because it can improve symptoms, but also because it may slow disease progression. Anthony Atala, MD, Director of the Wake Forest Institute for Regenerative Medicine, says it is too soon to draw any clinica l implications from the study, given its sma ll size, but it provides a basis for future inquiry. "[T]his study shows [MSCs] are safe," says Dr. Atala, who was not involved in the research. "[A]lthough they do not lead to actual cartilage regeneration, they do have the potential to decrease inflammation." n Large-Scale Trial Needed CA N A DIA N RE SE A RCHER S HOPE to build on their phase 1 clinical trial of autologous bone marrow mesenchymal stromal cells in knee osteoarthritis by determining how to activate the cells to be more effective, which could minimize the effect of donor heterogeneity. Ultimately, they would like to conduct a large, randomized, clinical trial, the design of which presents several questions. "[W]hat the active … or experimental treatment will be next time is important," says Jaskarndip Chahal, MD, MSc, MBA, Assistant Professor in the Department of Surgery at University of Toronto Orthopaedic Sports Medicine and University Health Network Arthritis Program, who was part of the team that conducted the phase 1 trial. "Are we going to use allogeneic or autogeneic cells, and are these cells going to be activated or nonactivated? And what's the control group? There are a lot of things we have to think about." M D N E W S . C O M /// M D N E W S C E N T R A L N E W Y O R K ■ 2 019 1 3