In a perspective piece appearing in the journal Cell Stem Cell, URMC neurologist Steve Goldman, M.D., Ph.D., lays out the current state of affairs with respect to stem cell medicine and how close we are to new therapies for neurological disorders.
The dawn of stem cell medicine some 25 years ago was greeted with great enthusiasm, particularly by scientists who study diseases in the central nervous system (CNS). Many of the diseases found in the brain and spinal cord are degenerative in nature; meaning that over time populations of cells are lost due to genetic factors, infection, or injury. Because stem cell medicine holds the potential to repair or replace damaged or destroyed cells, scientists have considered these diseases as promising candidates for new therapies.
However, as with other emerging fields of medicine, the race to cures has turned out to be more of marathon than a sprint. While scientists have become very adept at manipulating stem and progenitor cells and understanding the complex choreography of genetic and chemical signals that instruct these cells to divide, differentiate, and proliferate, researchers are still grappling with the challenges of how to integrate new cells into the complex network of connections that comprise the human brain.
Goldman, co-director of the URMC Center for Translational Neuromedicine, takes a sweeping view of where we stand and which CNS diseases may or may not ultimately benefit from future stem cell-based therapies. His assessment touches upon several common themes:
The fewer the targets the better. Diseases that involve a discrete cell type, or a family of cells, and impact a defined area of the brain represent a more straightforward proposition for stem cell therapies. Multiple sclerosis (MS) is frequently cited as a promising candidate because the disease arises from the loss of single family of cells called glial – the white matter in the brain that is comprised of astrocytes, oligodendrocytes, and the myelin that insulates connections between nerve cells. Parkinson’s, Huntington’s, and certain retinal disorders are also characterized – at least in the initial stages of the disease – by the loss of a single cell type. On the other hand, complex multi-faceted disorders like stroke, spinal cord injury, and Alzheimer’s present a significant challenge because the damage involves several different cell types and can occur in different parts of the CNS simultaneously.
Can we get the cells to the right place and once they are there do they do their job? Diseases of the white matter – like MS and other rare conditions like pediatric leukodystrophies and white matter stroke – are considered strong candidates because the glial cells employed in potential therapies tend to migrate, differentiate, and proliferate once they are injected into the brain. Replacing the damaged neurons associated with cognitive and motor functions represents a far more challenging target for stem cell therapies because the cells not only have to be placed precisely where needed, but they must then be coaxed to form connections and integrate with the networks of cells around them.
Can we make the right cells types? The manipulation of stem cells can still be an imperfect process. Stem cells that are created by reprogramming the donor’s skin cells or native stem cells in the brain may carry with them the genetic defect that is causing the disease. If researchers are unable to ensure the purity of the cells that are being transplanted, dangerous side effects, such as tumors, can arise. Also, the process of growing and preparing cells for transplant can take months. Many neurological conditions require that replacement cells be available quickly, before the effects of the disease and injury become irreparable.
Are stem cell therapies the best option? While some neurological disorders meet the criteria for being good candidates for stem cell treatment, the existence of other effective treatment options may compel scientists to focus their efforts elsewhere. For example, while Parkinson’s disease is considered an ideal candidate for stem cell-therapies, new drugs and other therapies that have come to market in recent years are able to effectively manage the symptoms of the disease.
Goldman concludes that many diseases of the CNS are attractive targets for stem cell-based therapies, particularly those that involve a single cell type or family of cells. However, other neurodegenerative disorders may ultimately defy scientists’ efforts due to the nature of the disease and inability to reconstitute the complex network of connections in the brain.