In summary, the earlier research, conducted in rats, showed that it was possible to induce hibernating stem cells to develop into medium spiny neurons (the ones affected by HD) which would then migrate over to the damaged part of the striatum and establish themselves as functioning neurons. The next step in the research was to conduct experiments to see if this technique would work as a treatment for an HD mouse model.
The next step has been completed and the landmark results are reported in a new journal article. The introduction of genes for the neurotrophic factor BDNF and the polypeptide noggin into the brain through an adenoviral vector does indeed prolong health and increase lifespan by 17 percent in the R6/2 mouse. These exciting results were achieved after only one treatment.
The treatment works by generating new neurons. The researchers concluded this was the mechanism because when they added an inhibitor of mitosis, the good results were suppressed. BDNF alone generates new neurons but the addition of noggin, which stops the progenitor cells from becoming glial cells (as some would otherwise do) doubles the numbers of neurons.
The new neurons also have the HD gene but they are new cells which are not overwhelmed by challenges presented by the HD protein. Remember that brain cells are able to cope for years before symptoms appear.
This technique boosts a natural process. The brain already responds to HD by generating new neurons although not enough to keep countering the damage. Many of the stem cells die probably because there's a reduction in BDNF which protects them and some develop into glial cells instead. By introducing BDNF the cells are protected and with noggin, they don't develop into glial cells.
Obtaining these kinds of results is good news in and of itself. However, the authors argue that it is reasonable to expect even better results with multiple treatments. They got this result will just a small increase of new cells and it seems likely that the pool of progenitor cells is still greater in the mice (see Batista 2006). They note that research by Curtis and colleagues (2003) shows that there is an abundant, potentially functional pool of these progenitor cells in human beings as well.
There's some evidence to believe that the technique would work in people. The Lighthouse has already covered an experiment by Claude Gravel and colleagues (2005) which showed that introducing the BDNF gene through an adenoviral vector stimulates the growth of functional medium spiny neurons in primates.
Why do I consider this to be a landmark study important to HD families?
- This is a very significant extension of health and survival with potential for better results with subsequent treatments.
- This potential treatment is independent from other treatment strategies we've been covering on the Lighthouse such as increasing cellular energy (through CoQ10 and creatine and perhaps new analogs), restoring gene transcription through HDAC inhibitors, and caspase inhibition. As the authors point out, their neurogenesis strategy could be a significant addition to the combination treatment approach that the researchers are already working towards.
- Once we can stop Huntington's Disease, we need a technique for brain restoration. Based on research with the HD mice, we can expect some improvements when that happens but more will be needed for some patients. This looks like a feasible strategy.
Resources and references:
You can download a free copy of the 2007 Goldman article here: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1978427&blobtype=pdf
Read Ann Covalt's earlier update on Goldman's earlier research here: http://www.hdlighthouse.org/research/bdnf/updates/1255bdnf.php
Read about the Gravel study with primates here: http://www.hdlighthouse.org/research/brain/updates/1202bdnf.php
C Batista,T Kippin, S Willaime-Morawek M K Shimabukuro, W Akamatsu, and D van der Kooy, "A Progressive and Cell Non-Autonomous Increase in Striatal Neural Stem Cells in the Huntington's Disease R6/2 Mouse," The Journal of Neuroscience, October 11, 2006, 26(41):10452-10460.
You can download a free copy of the Batista article here: http://www.jneurosci.org/cgi/reprint/26/41/10452
M Curtis, E Penney, A Pearson, W van Roon-Mom, N Butterworth, M Dragunow, B Connor, and R Faull, "Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain," Proceedings of the National Academy of Sciences July 22, 2003 vol. 100 | no. 15, 9023-9027.
You can download a free copy of the Curtis article here: http://www.pnas.org/cgi/reprint/100/15/9023
Chief, Division of Cell and Gene Therapy
Glenn-Zutes Chair in Biology of the Aging Brain
Professor of Neurology, Neurosurgery and Pediatrics
University of Rochester Medical Center
|Dr. Benraiss, another member of the research team, shown here at a recent HDF conference.|