Stem cells in human neurodegenerative disorders - time for clinical translation?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798697/

Abstract

Stem cell- based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.

Introduction

Neurodegenerative disease is a term used for a wide range of acute and chronic conditions in which neurons and glial cells in the brain and spinal cord are lost. In acute cases, for example, in response to ischemic stroke or spinal cord injury, different types of neurons and glial cells die within a restricted brain area over a short time period. In chronic cases, there is either a selective loss of a specific cell population, such as dopamine (DA) neurons in Parkinson disease (PD) and motor neurons in amyotrophic lateral sclerosis (ALS), or a widespread degeneration of many types of neuron, such as occurs in Alzheimer disease (AD), over a period of several years. Stem cel - based approaches could be used therapeutically to restore function in neurodegenerative disease. For example, it might be possible to replace lost neurons or glial cells by transplantation of stem cell - derived cells that have been predifferentiated in vitro to various stages of maturation, e.g., into neuroblasts (i.e., immature neurons). Cell replacement might also be achieved by inducing endogenous stem cells in the adult CNS to form new neurons and glial cells. Besides these mechanisms, grafted stem cells and their derivatives could induce functional improvement by releasing therapeutic molecules that are neuroprotective or modulate inflammation.

Although some scientifically founded clinical trials using stem cells to treat neurodegenerative disorders have already been performed or initiated (e.g., for the rare, fatal, autosomal recessive neurodegenerative disorder Batten disease)no stem cell based therapy has yet been proven beneficial for any such condition. Despite this fact, unproven treatments for several neurodegenerative diseases are offered at "clinics" around the world without rationale and with poor scientific and clinical basis. The vast majority of these sites overpromise the results and gravely underestimate the potential risks (1).

For the successful development of stem cell based therapies for neurodegenerative diseases, clinical roadmaps need to be defined. Specifically, the major milestones in basic and clinical research that need to be reached before such therapies can be tested in patients need to be established, and all the associated ethical, regulatory, societal, and economical issues need to be addressed. Here, we discuss some general issues relating to the clinical translation of stem cells. We also describe how far stem cell based approaches for treating some acute and chronic neurodegenerative disorders have advanced and define the critical milestones that remain if these are to reach the clinic.