Since the discovery of induced pluripotent stem cells in 2006, a great deal of basic research has been done to understand how to produce, manipulate, and utilize the stem cell type. In addition to this important basic research, a great deal of applied (“translational”) results has been done with the cell type. Induced pluripotent stem cells (also called iPS cells or iPSCs) are revolutionizing regenerative medicine because they represent a potential route for producing patient-specific stem cells for research or clinical use.
In the future, iPS cells will facilitate progress in personalized medicine by allowing a patient to use his or her own cells. In addition, iPSCs also show great promise in other areas, such as phamaco-toxicological screening, by allowing disease modeling and safety assessment of potential new drugs under development, in short, facilitating the study of a “disease in a dish.”
Major Areas of Commercialization for iPS Cells
There are four major areas of commercialization for iPS cells, each of which are discussed below.
1) Drug Development & Discovery
There are two sub-categories within this group, which include traditional drug development, as well as discovery and disease modeling.
First, iPSCs have the potential to transform drug discovery by providing physiologically relevant human cells for compound identification, target validation, compound screening, and tool discovery. iPSCs can be used to produce a wide variety of mature human cell types, allowing potential drug compounds to be screened in high-throughput systems using human cells.
iPSCs also allow for the creation of patient specific cell populations, thereby allowing researchers and clinician to perform in vitro drug testing that replicates the disease conditions of the patient population of interest. Furthermore, this approach assists with early identification of whether specific genetic populations do or do not respond well to a drug candidate, a novel approach to personalized medicine.
In disease modeling, the drug discovery process starts with the patient samples used for the derivation of iPSCs, followed by directed differentiation of those cells into ones that have a crucial role in the disease. The reason this approach is valuable for drug discovery is that it allows for the ability to reproduce critical aspects of the disease and create a “disease in a dish” model for drug screening. While it is unlikely that such an in vitro system can perfectly represent all characteristics of a multi-faceted disease, the ability to generate any human tissue cells, from any genotype or disease, provides unparalleled access to populations of disease-specific cells for use in research and study.
A step-by-step image of clarifying the steps in iPSC production for disease-specific modeling is shown below. The process begins with harvesting a donor patient’s cells (usually fibroblasts). Those cells are then expanded and pluripotency subsequently induced to derive disease-specific iPSCs – often termed a “disease in a dish” at this point. Next, screening of those cells against potential drug treatments and compounds can occur, leading to identification of a treatment modality specific for a patient or a disease that shows high safety and efficacy. Treatments identified as effective at positively altering cell state (or restoring “normal” function) can then be prescribed to the patient, allowing, at least conceptually, for effective application of personalized medicine.
In some instances, following derivation of disease-specific induced pluripotent stem cells from a patient, those iPSCs may be characterized, expanded, and stored in a biological tissue bank.
2) Cellular Therapy
iPSCs can be also used for cellular therapy applications, including autologous transplantation, and potentially gene therapy. The purpose of cellular therapy is to reverse injury or disease.
Autologous cell transplantation is a clinical procedure in which adult somatic stem cells are removed from an individual patient, expression of pluripotency is induced to derive iPSCs, and those patient-specific cells are later given back to the same individual. This concept is at the core of most personalized medicine approaches, and the discovery of iPSCs has made this a promising area for research and therapeutic application.
Another potential application will be the use of iPS-derived cells or genetically modified iPSCs in transplantation where there may be immunological advantages for organ engraftment. Proof of concept is now well-documented in pre-clinical models of retinal dystrophy, in reversal of liver damage, and in diabetic mouse models. However, full utilization of this range of stem cell technologies will require generation of iPSCs that are safe, stable, and able to exert a predictable effect. The use of iPSCs for autologous transplantation, potentially coupled with gene therapy, may launch an era of truly personalized medicine for the first time.
Allogeneic (“from another patient”) transplantation of iPSCs may also occur at some point, but the ease with which autologous iPSCs can be produced means that this will likely only occur if a genetic defect is present in the patient’s own cells.
3) Toxicology Screening
iPS cells can be used for toxicology screening, sometimes called pharmaco-toxicological screening, which is the use of stem cells or their derivatives (tissue-specific cells) to assess the safety of compounds or drugs within living cells.
iPSCs have the potential to transform drug discovery by providing physiologically relevant cells for toxic compound identification, target validation, compound screening, and tool discovery. The technology for generating iPSCs is advancing rapidly, as is the range of cell types that can be differentiated, which means that an even greater variety of cell and tissue types can be screened for drug compound safety and efficacy.
Furthermore, tissue-specific cells derived from iPSCs are currently being evaluated by the pharmaceutical companies for use in identifying cardiotoxic and hepatotoxic compounds, as therapeutically relevant systems for modeling cardiovascular diseases, neurodegenerative disorders, metabolic disorders, and more, and for generating patient-specific cell types against which disease-specific treatments or compounds can be screened.
In addition, current animal-based methods used to predict toxicity are poorly predictive of the human response. Using human iPSCs dramatically reduces a key obstacle of conventional drug development: that drug response differences between humans and animals can be significant. Analyzing the effects of drugs in cells differentiated from human iPSCs would provide a far more reliable process for developing safe and effective drugs than the current animal studies.
In summary, iPSCs may create breakthroughs in drug discovery, either in the generation of previously unobtainable cellular disease model systems for small molecule screening, in mechanism of action studies, or in highly predictable, animal-free systems for determining drug safety.
Potential breakthroughs in this area could include a screen of genetic diversity panels of cardiomyocytes or hepatocytes to identify rare responders, analyze drug effects on complex three-dimensional organ systems, or perform a variant of “clinical trials” using iPSC-derived diseased cells where safety, efficacy, dosage studies, and the variable role of genetics could be explored before launching clinical studies in humans.
4) Stem Cell Biobanking
The goal of stem cell biobanking is to create a repository of stem cell specimens, including source tissue from which iPSCs can be derived, differentiated cell types produced from iPSCs, and disease tissues produced from iPSCs. Large-scale stem cell repositories provide researchers with the opportunity to investigate a diverse range of conditions using iPSC derived cells produced from both healthy and diseased donors.
Importantly, these repositories can also greatly expand the capacity for global research and collaboration.
The world’s largest iPSC biobank is being created through a collaboration between Cellular Dynamics International (now owned by Fujifilm Holdings Corporation) and the Coriell Institute for Medical Research, a project which is being funded by the California Institute for Regenerative Medicine (CIRM). Specifically, CIRM awarded Cellular Dynamics International $16 million to create three induced pluripotent stem cell lines derived from 3,000 healthy and diseased donors using the episomal (“footprint-free”) reprogramming method first developed by the company.
Tissue samples are being collected from patients with Alzheimer’s disease, autism spectrum disorders, liver diseases, cardiovascular diseases, neurodevelopmental disabilities such as cerebral palsy and infantile epilepsy, diseases of the eye, and respiratory diseases, to allow for further research into these conditions. CIRM also awarded the Coriell Institute nearly $10 million to set up and biobank the iPSC lines, of which CDI will be the primary subcontractor.
To learn more, view the “Complete 2015-16 Induced Pluripotent Stem Cell Industry Report.”
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