kentoh/shutterstock.com
WASHINGTON, D.C.—For patients with osteoarthritis and other age-related musculoskeletal diseases, treatment with mesenchymal stem cells may soon offer a potent way to slow and repair degenerative signs of disease. This is the goal, a goal that is moving from the laboratory to the clinic as results from ongoing randomized clinical trials show the safety and efficacy of this therapy and advances in technology are making this costly and complex therapeutic approach more feasible.
During a session titled, What Is the Science Behind Mesenchymal Stem Cell Therapy in Arthritis, at the 2016 ACR/ARHP Annual Meeting, a panel of experts who have been studying the basic science and clinical application of these cells discussed some of the key findings and issues to date in their potential application to treat patients with arthritic diseases.
Using Stem Cells to Repair Articular Cartilage
Johnny Huard, PhD, distinguished professor & vice chair for research, Department of Orthopaedic Surgery, University of Texas Health System, Houston, Texas, opened the session talking about research he and his colleagues have conducted on muscle-derived stem cells (MDSCs) and their potential use to repair joint tissue.
He walked the audience through an elegant discussion of research done primarily with his colleagues at the University of Pittsburgh (where he led a lab prior to moving to Houston) that has shown, among other findings, that MDSCs improve tissue repair through a paracrine effect that involves angiogenesis.
What role does angiogenesis play in tissue repair, such as articular cartilage repair and healing related to osteoarthritis? Dr. Huang discussed pre-clinical data from mice studies that show that blocking angiogenesis is critical to repairing articular cartilage in the context of osteoarthritis (OA). In particular, he cited data from murine studies that show that injecting a particular type of stem cell (MDSC-sFlt-1/BMP4) confers the best repair of articular cartilage after OA. He also cited a study by Kubo et al that showed the blocking angiogenesis in humans also improved the regenerative capacity of adult-derived stem cells for repair of the articular cartilage after injury.1
Dr. Huang also described research looking at whether MDSCs are affected by aging, with the goal of helping people to age better. To date, research has shown that injecting young stem cells into mice extends their lifespan and they live longer and healthier than mice who are not injected. Although he said that the mechanisms of stem cell rescue are still unknown, he said that it likely depends on the secretion of growth factors that promote angiogenesis. “Angiogenesis means more stem cells,” he said.
He ended his talk by citing the reasons why he thinks rapamycin can be used to delay aging-related disorders such as OA, and why rapamycin is so beneficial to promoting articular cartilage repair, including its effect on angiogenesis (decreasing vascular endothelial growth factor [VEGF]), hypertrophic chondrocytes (decreasing collagen type 10A1 and MMP-13 expression), decreasing mTOR expression, and increased autophagy.
Clinical Application
Christian Jorgensen, MD, PhD, director of IRMB, Institute for Regenerative Medicine & Biotherapy, Montpellier, France, discussed some of the data now emerging from clinical trials on the therapeutic application of MDSCs in arthritis and osteoarthritis, and issues that still need to be addressed in making this potential therapy more feasible.
After reviewing some of the preclinical data showing the benefit of MDSCs in mouse studies, he emphasized that transferring these results to humans “is a different feat. It is easy to treat mice,” he said, but continued that treating humans with cells requires a team approach to address the myriad issues of using a therapy (cell) that may change behavior once injected in a body. He emphasized the need for a team approach when conducting human clinical trials in stem cell therapy, one that includes working closely with regulatory agencies, pharmacists dedicated to quality controls, as well as ethics committees.
He walked participants through a phase I study in which he and his colleagues assessed the safety of injecting autologous adipose-derived stromal cells (ASCs) to treat severe knee osteoarthritis in 18 patients. Designed as a dose escalation safety study, the trial included three cohorts of patients (50 patients in each) treated with low dose (2×106 cells), medium dose (10×106 cells) and high dose (50×106 cells).2 Results of the study showed that most of the patients in the low-dose group are doing well, said Dr. Jorgensen, and that those in the high-dose group have up to one year of clinical efficacy. He also said that some patients had no response to treatment, whereas the patients with the highest disease activity had the best results.
Based on the finding that the step cell therapy was safe, Dr. Jorgensen and colleagues are currently conducting an ongoing phase II study that will include 150 patients with severe knee osteoarthritis treated with autologous stem cells over the next year.
Although Dr. Jorgensen and colleagues are using autologous stem cells in their study, Dr. Jorgensen pointed out that more studies are now using allogenic stem cells given their reduced production costs and studies showing very similar responses in terms of safety and efficacy to autologous stem cells.
Along with potential use to treat osteoarthritis, other studies are looking at the potential use of stem cells to treat other degenerative disease conditions. Dr. Jorgensen described the results of a pilot study that looked of the feasibility and safety of treating 10 patients with chronic back pain diagnosed with lumbar disc degeneration with mesenchymal stem cells.3 The study found that 70% of patients responded to treatment and maintained a response at one year. “The results of this phase I trial already show that you can improve pain and function in these patients,” said Dr. Jorgensen.
Dr. Jorgensen emphasized that the current clinical data are encouraging and confirm positive results, but that more work remains to be done. This work includes improving a potency assay that will follow the potency of the cells after injection, and improving how cells are produced to help reduce the cost. And of course, more long-term randomized controlled trials are needed.
References
- Kubo S, Cooper GM, Matsumoto T, et al. Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 2009;60(1):155–165.
- Pers YM, Rackwitz L, Ferreira R, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: A phase I dose-escalation trial. Stem Cells Trans Med. 2016;5(12):2015–2045..
- Orozco L, Soler R, Morera C, et al. Intervertebral disc repair by autologous mesenchymal bone marrow cells: A pilot study. Transplantation. 2011;92(7):822–828.
