Clinical trials for stem cell therapies – National Center …

Abstract

In recent years, clinical trials with stem cells have taken the emerging field in many new directions. While numerous teams continue to refine and expand the role of bone marrow and cord blood stem cells for their vanguard uses in blood and immune disorders, many others are looking to expand the uses of the various types of stem cells found in bone marrow and cord blood, in particular mesenchymal stem cells, to uses beyond those that could be corrected by replacing cells in their own lineage. Early results from these trials have produced mixed results often showing minor or transitory improvements that may be attributed to extracellular factors. More research teams are accelerating the use of other types of adult stem cells, in particular neural stem cells for diseases where beneficial outcome could result from either in-lineage cell replacement or extracellular factors. At the same time, the first three trials using cells derived from pluripotent cells have begun.

The rapid advance of stem cell clinical trials for a broad spectrum of conditions warrants an update of the review by Trounson (2009) [1]. There has been a rapid surge in clinical trials involving stem cell therapies over the last two to three years and those trials are establishing the clinical pathways for an emergent new medicine. These early trials are showing roles for stem cells both in replacing damaged tissue as well as in providing extracellular factors that can promote endogenous cellular salvage and replenishment.

There are many studies involving autologous therapies and some allogenic therapies, based on the recovery of mobilized bone marrow cells, including mesenchymal stem cells (MSCs) and adipose derived stem cells that also include the stromal or adherent cell type that has an MSC phenotype. Human umbilical cord blood cells have been used in a large number of trials for paraplegia, ataxia, multiple sclerosis, amyotrophic lateral sclerosis, cerebrovascular disease, multiple system atrophy, motor neuron disease, among other indications, without severe immunological response [2]. Placenta-derived stem cells are being considered for similar uses and are in Phase III clinical trial for critical limb ischemia by Israel's Pluristem Therapeutics.

A significant proportion of clinical studies that are underway involve bone marrow and cord blood stem cells for blood and immune disorders [3] and cancers. Several of those are now considered applicable for patient treatments beyond the need for regulated clinical trials. We have chosen to concentrate on the emerging therapeutics that broadly involves a wide range of cell types in clinical trials registered on the National Institutes of Health's clinical trials web site.

MSCs are a stromal cell type and the current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79(-)/HLA-DR1(-)), and multi-lineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) [4]. The public clinical trials database http://clinicaltrials.gov shows 123 clinical trials using MSCs for a very wide range of therapeutic applications (Figure ), the majority of which are in Phase I (safety studies), Phase II (proof of concept for efficacy in human patients), or a mixture of PhaseI/II studies (Figure ). This includes bone and cartilage repair, cell types into which MSCs readily differentiate, and immune conditions such as graft versus host disease and autoimmune conditions that utilize the MSC's immune suppressive properties. Expectations for patient benefits are high in these therapeutic applications. Nevertheless, there are many prospective applications where the mechanism of action is not obvious and some concerns have been expressed about the likelihood of long-term benefit of these applications. In the case of allogenic MSCs, delivery to an inflamed site can result in gain of immune potency with accelerated damage due to a heightened immune-mediated inflammatory response [5].

Diseases being addressed using mesenchymal stem cells (MSC) for clinical trials (n = number of trials).

Mesenchymal stem cell (MSC) clinical trials by clinical phase (n = number of trials).

The use of patient's own bone marrow aspirates, hematopoietic stem cells and MSCs, for heart muscle tissue repair can be puzzling because these cells do not normally contribute to the cardiac lineage types that are desired. There is some preclinical data in support of umbilical cord blood for improved cardiac function for myocardial infarction [6] but sustained patient recovery has not been clearly demonstrated. It has been shown, that these blood and stromal cells may, in vitro, form sarcomeric structures typical of cardioimyocytes with expression of some genes expected of these cell types: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and contractile proteins including myosin heavy chain, myosin light chain, and alpha actin [7]. There is little evidence, however, of myocardial regeneration in vivo, despite 3% to 4% (range 2% to 7%) improvement in the global left ventricular function and cardiac ejection fraction (contractility), but not left ventricular remodeling, in meta-analyses following intracoronary infusions for myocardial infarction [7-9]. In comparative studies of MSCs and cardiac (c-kit+) stem cells and cardiosphere derived cells, [10] the cardiomyogenic differentiation capacity was clearly more effective with the cardiac derived cells than with MSCs. There is a distinct possibility that procedure-related variables influence the positive outcomes for patients. So there is a need to optimize treatment timing, cell type and dose, and delivery methods. Also research needs to determine the potential tropic influence of stem cell secretions or cytokines released at the site of injury and the degree of cardio-repair that may be clinically relevant [11]. A recent study by Lee and colleagues at Harvard found a subset of marrow cells that was able to stimulate endogenous adult cardiac stem cells, offering a possible mechanism for the effect seen [12]. It is possible that protein-based rather than cell-based therapies may evolve from these studies. It is pretty clear that for the ventricular remodeling required, more effective cell types with significant populating capacity will be needed to replace the severely damaged infarct area of the heart.

Studies involving umbilical cord blood for neurological indications have been promoted as a result of preclinical data on the apparent formation of neurons in vitro [13] but there is little evidence of their transdifferentiation to functional neurons or glial cells in vivo. Mobilized peripheral blood cells (CD34+) delivered into the femoral artery have been used in safety studies for chronic spinal cord injury without adverse effects but with very little evidence of efficacy in follow up [14].

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Clinical trials for stem cell therapies - National Center ...