Research in New Zealand on Huntington’s Disease and Stem Cells

 Professor Richard Faull
University of Auckland School of Medicine

 Worldwide attention is presently focused on the potential use of “stem cells” as a source of tissue for cell transplantation and brain repair in the treatment of neurodegenerative diseases such as Huntington’s disease Alzheimer’s disease, and Parkinson’s disease. The announcement that stem cells can be obtained from aborted human foetuses or from spare embryos from in vitro fertilisation procedures has been met with both enthusiasm and opposition.  Less controversial, and probably more notable, is the recent demonstration that stem cells can be obtained from adult brain tissue, raising the exciting possibility that these “neural stem cells” can be utilized to generate cells for autologous brain cell transplants. The term “neural stem cell” is used loosely to describe cells that can generate new brain cells and are derived from the brain or spinal cord, have the capacity for self-renewal, and can also give rise to other cell types. Neural stem cells exist in both the developing (embryonic) and the adult brains of mammals, including human. Embryonic stem cells are obtained from blastocysts developed from fertilised eggs – ie from very early foetuses; this is currently the stem cell type being proposed for use in a wide variety of commercial and clinical applications. However, there are still ethical issues associated with the use of these embryonic stem cells because they are obtained from very early foetuses

At the Auckland Medical School, we are interested in the use of adult neural stem cells for the treatment of brain diseases.  The use of adult stem cells in cell transplantation therapy could obviate the need to use stem cells derived from human embryos or human fetal tissue.  At present, there are no legal or ethical concerns regarding research with adult stem cells.  Furthermore, adult stem cells derived directly from the patient would reduce the likelihood that the transplanted cells would be rejected

 Neural stem cells have been identified and isolated from specific regions of the adult brain: (i) the subventricular zone (SVZ) lining the lateral ventricles and adjacent to the region of the basal ganglia affected in Huntington’s and Parkinson’s disease, and; (ii) the subgranular zone (SGZ) in the hippocampus, the region of the brain which is primarily affected in Alzheimer’s disease and temporal lobe epilepsy.  The stem cells located in these regions have been shown to multiply and form new replacement neurons for adjacent brain structures.  In this regard it is especially exciting that stem cells located in these regions are found immediately adjacent to the basal ganglia and hippocampus that are respectively the areas of primary degeneration in Huntington’s and Parkinson’s disease, and in Alzheimer’s disease and epilepsy.  Indeed, there is increasing evidence from animal studies that one function of stem cells in the adult brain may be to generate new cells in response to brain injury or disease.  When the brain is injured, it may try to “repair” itself with its own population of stem cells but, for most injuries that come to clinical attention, this repair process is restricted by the number of available stem cells and may even be counter-acted by a growth-inhibitory environment, especially in the adult brain.  In order to investigate whether neurodegenerative conditions in the human brain stimulates stem cells in the adult brain to try and repair the area of injury, we are investigating the presence of stem cells in the human brain in Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and epilepsy.  Our studies are most advanced in Huntington’s disease and our very recent results are very exciting. These results have shown an increase in the number of stem cells in the SVZ in Huntington’s disease compared to normal human brains and that a significant number of these cells are developing into new brain cells. This is therefore the first ever evidence that in Huntington’s disease the brain is trying to repair itself and replace the lost brain cells. However, this increase in stem cell proliferation is clearly insufficient to compensate for the progressive cell loss observed in the Huntington’s diseased brain.  Nevertheless, if this potential for cell replacement by the brain could be stimulated and augmented pharmacologically then compensation may increase to a point where neuronal cell loss is reversed and clinical improvement observed.

 Stem cells may need to be genetically and/or pharmacologically engineered to direct them to develop into the type of brain cells that die in a specific neurodegenerative disease. Alternatively, the delivery of factors that act to stimulate neural stem cells to repair the diseased brain may have potential in the treatment of neurodegenerative diseases such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease and epilepsy. At present however, we do not know what factors will promote neural stem cells to grow and multiply to make mature, adult brain cells to replace the cells that die in, for example, Huntington’s disease. We are currently studying stem cells in culture in order to determine what combination of factors will induce them to grow, multiply and develop into specific cell types. There is still much research to do. But the exciting possibility is that the human brain has the potential, just like other organs of the human body, to repair itself.  The era of the stem cell is upon us; we hope that our exciting new findings will ultimately provide a new approach and direction for treating patients with Huntington’s diseases and other neurological diseases and so provide a brighter outlook for their future.