ABSTRACT
Strategic drug design is used to meet the needs of numerous diseases for which there is no other recourse. Take the T315I mutation, for example, which occurs in Philadelphia chromosome-positive leukemias and renders all currently available tissue kinase inhibitors useless. The US FDA therefore saw it fit to avail ponatinib, the therapeutic result of careful drug design, to patients based on early data. However, its sales and marketing were later suspended due to emerging safety concerns. This drug has now returned to market albeit with tighter labeling. While the lesson for early approvals may be to restrict the drug to as narrow a patient population as possible, the potential benefits of this drug for the target population must not be lost amidst the controversy.
Subject(s)
Imidazoles/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Blood Coagulation/drug effects , Clinical Trials as Topic , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , Humans , Imidazoles/adverse effects , Philadelphia Chromosome , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/adverse effects , Pyridazines/adverse effectsABSTRACT
Mesenchymal stem cells (MSCs) have a vastly unharnessed therapeutic potential with close to 400 studies currently registered on clinicaltrials.gov for evaluation of their clinical promises. While many of these investigations are for immune-mediated disorders, there is no established consensus on how to optimize the immunomodulatory properties of MSCs. Factors that could be used to predict efficacy of MSC therapies include donor heterogeneity, recipient environment and drug interactions. Incorporating pertinent quality control parameters to maximize the clinical potential of MSCs through good manufacturing practice (GMP) production of clinical grade cells could lead to the realization of greater therapeutic success.
Subject(s)
Immunotherapy, Adoptive/methods , Mesenchymal Stem Cell Transplantation/methods , HumansABSTRACT
The fetal sheep model has served as a biologically relevant and translational model to study in utero haematopoietic stem cell transplantation (IUHSCT), yet little is known about the ontogeny of the bone marrow (BM) niches in this model. Because the BMmicroenvironment plays a critical role in the outcome of haematopoietic engraftment, we have established the correlation between the fetal-sheep and fetal-human BM niche ontogeny, so that studies addressing the role of niche development at the time of IUHSCT could be accurately performed. Immunofluorescence confocal microscopic analysis of sheep fetal bone from gestational days (gd) 25-68 showed that the BM microenvironment commences development with formation of the vascular niche between 25 and 36 gd in sheep; correlating with the events at 10-11 gestational weeks (gw) in humans. Subsequently, between 45 and 51 gd in sheep (c. 14 gw in humans), the osteoblastic/endosteal niche started developing, the presence of CD34(+) CD45(+) cells were promptly detected, and their number increased with gestational age. IUHSCT, performed in sheep at 45 and 65 gd, showed significant haematopoietic engraftment only at the later time point, indicating that a fully functional BM microenvironment improved engraftment. These studies show that sheep niche ontogeny closely parallels human, validating this model for investigating niche influence/manipulation in IUHSCT engraftment.
