Human pluripotent stem cells (PSCs) can give rise to any cell type in the body. PSC derivatives are being developed for therapeutic use in diseases affecting organs and organ systems such as the eye, nervous system, heart, pancreas, liver, intestines, lung, circulatory system and skin, as well as multi-organ and systemic diseases.
Human embryonic stem cells (hESCs) and induced PSCs (iPSCs) are the two main sources of PSCs that are being used for therapeutic endeavours. The destruction of human embryos, which occurs during the hESC derivation process, led to the advent of iPSCs, which are derived from the reprogramming of somatic cells back to an embryonic-like pluripotent state.
More than ten clinical trials testing PSC-based therapies are currently being conducted around the world, with eye disease (macular degeneration) being the most common indication. Other indications currently being tested in clinical trials with PSC-based therapies are spinal cord injury, severe heart disease and type 1 diabetes.
The next generation of PSC-based clinical trials will probably include a PSC-derived dopaminergic neuron therapy for Parkinson disease, and improvements in differentiation protocols are advancing the development of other PSC-based therapies for conditions such as diabetes, liver disease and skin disorders.
Unlike hESCs, iPSCs can be generated in a patient-specific manner, thus enabling autologous and presumably non-immunogenic PSC-based therapies to be developed. iPSCs are also enabling the establishment of 'disease in a dish' cell-based models to study mechanisms of disease pathogenesis and for use in drug screening platforms.
iPSCs are being used with gene editing approaches to correct disease-causing genetic mutations in cells derived from patients afflicted with various haematological diseases, among others. The combination of these two technologies is providing the foundation for the development of gene-corrected cell-replacement strategies.
Safety is paramount in developing any new PSC-based therapy and regulations are in place to mitigate health and safety risks. However, preliminary data from ongoing first-in-man clinical trials are providing evidence that PSC-therapies can be used safely in humans.
Pluripotent stem cells (PSCs) hold great promise for drug discovery and regenerative medicine owing to their ability to differentiate into any cell type in the body. After more than three decades of research, including delays due to the potential tumorigenicity of PSCs and inefficiencies in differentiation methods, the field is at a turning point, with a number of clinical trials across the globe now testing PSC-derived products in humans. Ocular diseases dominate these first-in-man trials, and Phase l/ll results are showing promising safety data as well as possible efficacy. In addition, the advent of induced PSC (iPSC) technology is enabling the development of a wide range of cell-based disease models from genetically predisposed patients, thereby facilitating drug discovery. In this Review, we discuss the recent progress and remaining challenges for the use of PSCs in regenerative medicine and drug development.
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US FDA Code of Federal Regulations Part 1271: human cells, tissues, and cellular and tissue-based products
- Pluripotent stem cells
(PSCs). Cells that have the ability to self-renew indefinitely and to differentiate into endoderm, ectoderm and mesoderm, the three germ cell layers that give rise to all cell types in the body.
- Human embryonic stem cells
(hESCs). Pluripotent cells that are derived from early stage human embryos.
- Induced pluripotent stem cell
(iPSC). A somatic cell that has been induced to become pluripotent by adding factors to the cell to change the state of its nuclear material.
The process by which a somatic cell is induced to become pluripotent. It involves the addition of specific factors to the cell which alter the state of nuclear material so that it resembles that of a pluripotent embryonic cell rather than that of a differentiated somatic cell.
- Age-related macular degeneration
(AMD). A progressive form of vision loss that is associated with aging and is due to the deterioration of photoreceptors and retinal pigment epithelium within the macula, the area of the retina responsible for central vision. There are two forms of AMD: dry and wet. The dry form involves the accumulation of debris between the retina and choroid cell layers and accounts for ~90% of AMD cases. The wet form can arise after the dry form and involves the abnormal growth of blood vessels beneath the retina that can leak fluid. Wet AMD accounts for ~10% of AMD cases.
- Stargardt disease
An inherited disorder that results in juvenile onset of macular degeneration and often leads to blindness.
- Retinal pigment epithelium
(RPE). A single layer of hexagonal cells at the outermost edge of the retina, anchored to the choroid through the extracellular-matrix-containing Bruch's membrane. The RPE keeps the photoreceptor layer healthy by providing nutrients, secreting growth factors, exchanging ions and phagocytosing old photoreceptor parts.
- Investigational new drug
(IND). A designation used to describe a drug that has permission from the US Food and Drug Administration (FDA) to be shipped across state lines, thus allowing it to be tested in human clinical trials. IND applications are reviewed by the FDA to ensure that testing of the drug in humans does not pose excessive risk to the patient.
- Pancreatic endoderm
Multipotent progenitor cells that can give rise to various cell types within the pancreas, including glucose-sensing, insulin-producing β-cells, the mature cell type that is destroyed by a person's own immune system in type 1 diabetes.
- α1 antitrypsin
A protease inhibitor that is produced in the liver and secreted into the circulation. It protects tissue from being digested by enzymes such as neutrophil elastase and is crucial in maintaining lung function. Deficiency of α1 antitrypsin, a genetic disorder characterized by critically low levels of circulating wild type α1 antitrypsin and deposition of abnormal α1 antitrypsin in the liver, can lead to liver cirrhosis as well as emphysema and chronic obstructive pulmonary disease.
- Mesenchymal stem cells
(MSCs). A type of multipotent adult stem cell found in the stroma, or connective tissue, of a variety of different organs. In addition to multipotent differentiation capabilities, they have immunomodulatory properties that may be beneficial in treating autoimmune, degenerative and inflammatory disorders.
- Dopaminergic neuron
A neuron that is responsible for the synthesis and release of the neurotransmitter dopamine. Through dopamine release, dopaminergic neurons in the middle part of the brain are responsible for regulating neuromuscular motor control and reward-driven behaviour and are the cell population that deteriorates in Parkinson disease.
- Gene editing
The alteration of a specific genetic sequence, often done to correct disease-causing mutations. Approaches include the use of site-specific nucleases (for example, zinc finger, TALEN and CRISPR–Cas9 nucleases) to cut DNA at a precise location and the use of viruses that stimulate endogenous homologous recombination, thereby allowing the sequence of a gene to be altered or repaired.
The ability to differentiate into several different cell types (but not all cell types of the body, as is the case for pluripotent cells). Multipotency is more limited in scope than pluripotency and often used to describe adult or tissue-specific stem cells or progenitors.
- Adult stem cell
A rare somatic cell that resides in different tissues of the body and can self-renew. Adult stem cells can also repopulate or replenish mature cells in the local tissue or organ environment through the process of differentiation. Examples include hematopoietic stem cells, intestinal stem cells, neural stem cells and testicular stem cells.
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Kimbrel, E., Lanza, R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 14, 681–692 (2015). https://doi.org/10.1038/nrd4738
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