Mesenchymal Stromal Cells as a Novel Therapy for MS
Mesenchymal Stromal Cells as a Novel Therapy for MS
The complex cellular interactions discussed herein position MS as one of many diseases for the therapeutic application of MSCs in ameliorating disease course. Clinical applications of MSCs originally focused on engraftment, given that MSCs are a normal BM constituent. Furthermore, many investigators demonstrated that both cytokines and hematopoietic growth factors could be induced by MSCs, as well as constitutively secreted by MSCs, into media. Preclinical animal studies corroborated the hematopoietic-stimulating potential of these cells. The first in-human MSC clinical trial focused on showing the safety and feasibility of ex vivo expansion and reinfusion. A logical next step was assessing in humans if a stromal cell boost could accelerate engraftment in the setting of high-dose myeloablative therapy with autologous peripheral blood progenitor cell transplantation, as noted in breast cancer patients.
Given the success of these initial clinical results, Horwitz and colleagues pursued seminal MSC transplantation studies in children with osteogenesis imperfecta. These investigations focused on exploiting the mesenchymal origin of osteoblasts to increase bone mineralization in osteogenesis imperfecta patients. Bone fracture rates were decreased and overall growth patterns were enhanced in MSC-treated patients; however, engraftment rates of the donor-derived osteoblasts were surprisingly low (1.5–2.0%). Another first in-human study using allogeneic MSCs provided insights leading to the refocus of MSCs as an immunosuppressive therapy. Lazarus and colleagues cotransplanted ex vivo-expanded MSCs obtained from histocompatible sibling donors as an adjunct therapy for patients undergoing myeloablative matched related donor allogeneic hematopoietic stem cell transplantation. Although engraftment did not appear to be enhanced, findings suggested that adjuvant administration of MSCs contributed to an immunosuppressive benefit, as less GvHD was observed compared with historic data, opening the door for exploring the use of MSCs as immunosuppressive therapy in the context of GvHD.
Following those original studies, a shift in the desired clinical benefits associated with MSC therapy has occurred. One focus has been redirecting the cellular transport of packaged soluble mediators, given the potential of MSCs to elaborate a vast array of cytokines and chemokines. Another focus has been to generate a more universal MSC clinical product, rather than a directed, donor-derived, patient-specific product. Several commercial cellular products have emerged as target applications for immunosuppression and for regenerative medicine in such diverse clinical scenarios as acute and chronic GvHD, acute myocardial infarction, critical limb ischemia, osteoarthritis, traumatic spine injury, acute lung injury, inflammatory bowel disease, diabetes mellitus and MS. Universally, safety has been demonstrated. Additionally, in nearly all Phase I and II studies, a maximum tolerated dose has not been demonstrated. Given the high production cost of an expanded MSC product, the focus has shifted towards identifying what may be a more relevant end point, such as the maximum deliverable dose or the minimally effective biologic dose. Unfortunately, these studies have not provided a better understanding of biodistribution or clearance of the infused or injected MSC. In addition, the failure to develop reliable biomarkers and in vivo cell tracking methods for assessing therapeutic efficacy have significantly hampered the scientific community's ability to define MSC as a therapeutic agent.
If MSC therapeutic intervention for MS is to evolve further, then this latter point is worthy of additional comment. Many of the current academic and industrial efforts are focused on defining MSCs as a therapeutic agent or 'drug.' It is important to understand the pharmacodynamics of the drug and the impact of the body on the drug (pharmacokinetics), as well as develop the means to track in vivo drug delivery. Finally, one must address the issue of whether there are physiologic barriers impeding generalized drug distribution. Classical pharmacologic analysis, as well as emerging techniques in systems biology focused at analyzing static and dynamic relationships between drugs and tissues across time and space can be utilized in this regard. However, the major classical impact of the drug is a molecular rather than cellular event; receptor–ligand binding leading to agonist or antagonist signaling, interactions with carrier or structural proteins, enzymatic interactions, ion channel blockade or direct cytotoxicity; these examples are all molecular actions that can be quantified with appropriate tools. It is critical to recognize that none of these functions have been delineated and quantified for cellular products. On the contrary, standard ELISA assays and now more advanced proteomics are identifying a vast array of molecules with multiple functions that are generated by the MSCs in vitro, including growth factors, immunomodulatory soluble factors and matrix components. Emerging technologies have the potential to quantify these parameters at nanogram and picogram levels, recognizing that the MSCs are not drugs, but rather drug-delivery systems.
If the regenerative medicine community is to continue to exploit MSCs for therapeutic purposes, multiple questions remain. What is the optimal time of application? What is the minimum number of cells required to achieve a therapeutic response? Should MSC populations be pretreated ex vivo or activated post-treatment in vivo? What is the preferred route of delivery? Can single applications suffice or must applications be repeated? Is there a need for simultaneous immune suppression? These answers must be generated, recognizing that the available healthcare funding to support these efforts are diminishing. Such approaches require close scrutiny balancing the cost of production and optimization of the MSC effect.
It is naive to think that an off-the-shelf product will have been optimized for universal application for such a vast array of diverse disease entities. For example, the MS patient obviously differs greatly from a patient who has sustained a recent acute myocardial infarction. For MSCs to continue to emerge as an effective therapeutic tool, in the near future we must recognize how to optimize the development of cost-effective therapeutics in this current financial climate. Manipulations of MSCs will probably lead to more optimal therapeutic outcomes. However, therapeutic success will need to be validated, not just in clinical trials, but under the critical scrutiny of evidence-based analyses and be affordable within the constraints of a financially challenged healthcare delivery system.
MSC Therapy: General Considerations for Its Clinical Application
The complex cellular interactions discussed herein position MS as one of many diseases for the therapeutic application of MSCs in ameliorating disease course. Clinical applications of MSCs originally focused on engraftment, given that MSCs are a normal BM constituent. Furthermore, many investigators demonstrated that both cytokines and hematopoietic growth factors could be induced by MSCs, as well as constitutively secreted by MSCs, into media. Preclinical animal studies corroborated the hematopoietic-stimulating potential of these cells. The first in-human MSC clinical trial focused on showing the safety and feasibility of ex vivo expansion and reinfusion. A logical next step was assessing in humans if a stromal cell boost could accelerate engraftment in the setting of high-dose myeloablative therapy with autologous peripheral blood progenitor cell transplantation, as noted in breast cancer patients.
Given the success of these initial clinical results, Horwitz and colleagues pursued seminal MSC transplantation studies in children with osteogenesis imperfecta. These investigations focused on exploiting the mesenchymal origin of osteoblasts to increase bone mineralization in osteogenesis imperfecta patients. Bone fracture rates were decreased and overall growth patterns were enhanced in MSC-treated patients; however, engraftment rates of the donor-derived osteoblasts were surprisingly low (1.5–2.0%). Another first in-human study using allogeneic MSCs provided insights leading to the refocus of MSCs as an immunosuppressive therapy. Lazarus and colleagues cotransplanted ex vivo-expanded MSCs obtained from histocompatible sibling donors as an adjunct therapy for patients undergoing myeloablative matched related donor allogeneic hematopoietic stem cell transplantation. Although engraftment did not appear to be enhanced, findings suggested that adjuvant administration of MSCs contributed to an immunosuppressive benefit, as less GvHD was observed compared with historic data, opening the door for exploring the use of MSCs as immunosuppressive therapy in the context of GvHD.
Following those original studies, a shift in the desired clinical benefits associated with MSC therapy has occurred. One focus has been redirecting the cellular transport of packaged soluble mediators, given the potential of MSCs to elaborate a vast array of cytokines and chemokines. Another focus has been to generate a more universal MSC clinical product, rather than a directed, donor-derived, patient-specific product. Several commercial cellular products have emerged as target applications for immunosuppression and for regenerative medicine in such diverse clinical scenarios as acute and chronic GvHD, acute myocardial infarction, critical limb ischemia, osteoarthritis, traumatic spine injury, acute lung injury, inflammatory bowel disease, diabetes mellitus and MS. Universally, safety has been demonstrated. Additionally, in nearly all Phase I and II studies, a maximum tolerated dose has not been demonstrated. Given the high production cost of an expanded MSC product, the focus has shifted towards identifying what may be a more relevant end point, such as the maximum deliverable dose or the minimally effective biologic dose. Unfortunately, these studies have not provided a better understanding of biodistribution or clearance of the infused or injected MSC. In addition, the failure to develop reliable biomarkers and in vivo cell tracking methods for assessing therapeutic efficacy have significantly hampered the scientific community's ability to define MSC as a therapeutic agent.
If MSC therapeutic intervention for MS is to evolve further, then this latter point is worthy of additional comment. Many of the current academic and industrial efforts are focused on defining MSCs as a therapeutic agent or 'drug.' It is important to understand the pharmacodynamics of the drug and the impact of the body on the drug (pharmacokinetics), as well as develop the means to track in vivo drug delivery. Finally, one must address the issue of whether there are physiologic barriers impeding generalized drug distribution. Classical pharmacologic analysis, as well as emerging techniques in systems biology focused at analyzing static and dynamic relationships between drugs and tissues across time and space can be utilized in this regard. However, the major classical impact of the drug is a molecular rather than cellular event; receptor–ligand binding leading to agonist or antagonist signaling, interactions with carrier or structural proteins, enzymatic interactions, ion channel blockade or direct cytotoxicity; these examples are all molecular actions that can be quantified with appropriate tools. It is critical to recognize that none of these functions have been delineated and quantified for cellular products. On the contrary, standard ELISA assays and now more advanced proteomics are identifying a vast array of molecules with multiple functions that are generated by the MSCs in vitro, including growth factors, immunomodulatory soluble factors and matrix components. Emerging technologies have the potential to quantify these parameters at nanogram and picogram levels, recognizing that the MSCs are not drugs, but rather drug-delivery systems.
If the regenerative medicine community is to continue to exploit MSCs for therapeutic purposes, multiple questions remain. What is the optimal time of application? What is the minimum number of cells required to achieve a therapeutic response? Should MSC populations be pretreated ex vivo or activated post-treatment in vivo? What is the preferred route of delivery? Can single applications suffice or must applications be repeated? Is there a need for simultaneous immune suppression? These answers must be generated, recognizing that the available healthcare funding to support these efforts are diminishing. Such approaches require close scrutiny balancing the cost of production and optimization of the MSC effect.
It is naive to think that an off-the-shelf product will have been optimized for universal application for such a vast array of diverse disease entities. For example, the MS patient obviously differs greatly from a patient who has sustained a recent acute myocardial infarction. For MSCs to continue to emerge as an effective therapeutic tool, in the near future we must recognize how to optimize the development of cost-effective therapeutics in this current financial climate. Manipulations of MSCs will probably lead to more optimal therapeutic outcomes. However, therapeutic success will need to be validated, not just in clinical trials, but under the critical scrutiny of evidence-based analyses and be affordable within the constraints of a financially challenged healthcare delivery system.
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