“It's an excellent piece of work,” said Flint Beal, MD, chairman of neurology and neuroscience at Weill Medical College of Cornell University. “This is an interesting approach to stimulating endogenous stem cells and it is showing efficacy. It offers potential, but there are problems. It isn't a cakewalk by any means.” Other growth factors have been tried unsuccessfully in the treatment of Parkinson disease, he said. But it is an “important proof of principle,” said Scott Small, MD, associate professor of neurology at Columbia University Medical Center. “Growth factors may ultimately work to treat human disease.”
The animals in the study lived 20 percent longer than expected, explained Rochester's Steven A. Goldman, MD, PhD, the lead author of the study. The new neurons were working several months later. “The animals lived longer because of the neurons generated between the first two months of life.”
Dr. Goldman and his colleagues used an adenovirus vector to carry genes for two proteins responsible for making new neurons in the adult canary brain during song learning. The region where this neurogenesis occurs is the same area — the neostriatum — hit hard in Huntington disease. The new neurons are medium spiny neurons, the same ones depleted in the disease process.
“The challenge now is to increase this effect,” said Dr. Goldman, who predicts that the longer-acted viruses may be used to express the growth factors for prolonged periods of time, precluding the need for multiple injections. They will try to replicate the findings in primates, and that would open the door to human trials.
“There is no treatment for Huntington disease,” added Dr. Goldman. “Now there is something that delays the disease progression and enhances survival. Since the viruses we gave expressed BDNF [brain-derived nerve growth factor] and noggin for only a month or two, the effect that we noted was probably just the tip of the iceberg in terms of what might be possible with this approach.”
FROM SONG BIRDS TO HUNTINGTON DISEASE
Dr. Goldman, University of Rochester Medical Center Glenn-Zutes Chair in Biology of the Aging Brain, and professor of neurology, neurosurgery, and pediatrics, has been drawn to canaries and their annual mating song for decades. In 1983, Dr. Goldman and Fernando Nottebohm, PhD, at Rockefeller University discovered that neurogenesis was taking place in the adult canary brain during song learning, an unexpected finding providing hope that similar mechanisms could be made to promote neurogenesis for the treatment of human brain diseases. They have characterized these brain circuits and have shown how new neurons replaced old ones as the adult canary learned a new song.
The “song” nucleus in the canary brain resides in the neostriatum, the same region damaged in Huntington disease. Dr. Goldman and colleagues recapitulated the canary's brain circuitry during vocal learning in rat models. And while the rats didn't sing, the scientists found that it was possible to trigger the growth of new brain cells in a region that wasn't meant to generate new neurons — at least in humans. During these studies, they discovered that brain-derived nerve growth factor, BDNF, was driving the formation of the new neurons and another protein, called noggin, was suppressing the production of glial cells. Normally, stem cells generate gliosis.
The investigators decided to try to over-express noggin and see whether stem cells could be coaxed to divide into neurons and not glial cells. They over-expressed in an adenovirus and injected into the ventricles, and it worked like a factor to pump out BDNF. Stem cells bathed in BDNF become neurons. This cellular manufacturing plant was located in the ventricular wall directly adjacent to the neostriatum, the rodent's equivalent of the human caudate-putamen, and the new cells became medium spiny neurons — the same cell type lost in Huntington disease. The medium spiny neuron is also the target of dopaminergic neurons damaged in Parkinson disease.
With the generation of medium spiny neurons, could they replace the neurons lost in Huntington disease? The answer is yes — at least temporarily. The r62 mice are engineered to develop Huntington disease. By adolescence, they have seizures and coordination problems. They can't feed themselves and just lie supine and die. They live 12 weeks, much of it spent in this miserable condition.
In Dr. Goldman's study, the Huntington mice were injected with a cocktail of two adenoviruses — one delivering BDNF and the other carrying noggin — into the lateral ventricles of the brain. Stem cells normally live just under the ventricular wall near the neostriatum. An identically engineered group of mice received injections of adenovirus that carried no active substances. They watched the animals grow up and conducted behavioral tests to measure locomotion and coordination.
Animals that received the growth factors were much more active, remaining more coordinated and inquisitive — and lived a month longer — than their untreated counterparts. The viruses expressed BDNF and noggin for about a month, and delayed the onset of disease for about the same period of time. When the investigators examined the brains of treated animals there were far more neurons made than had been lost. The researchers counted thousands of new medium spiny neurons in the neostriatum.
In collaboration with Beverly Davidson, PhD, of the University of Iowa Medical Center, Dr. Goldman's group has now made viral vectors that express these proteins for up to four months and are repeating the experiments. They are also gearing up to treat monkeys. “If we get the same kind of results, this would be a straight shot to the clinic,” Dr. Goldman said. He added that there were no major adverse effects observed in the animals tested.
Dr. Goldman's 20-year exploration of the neural substrates that underlie vocal learning in canaries may someday alter the way neurodegenerative brain diseases are treated. “Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to trigger their regeneration in Huntington disease,” he said. “This offers a strategy to restore brain cells lost in this disease.”
This is the first time scientists have triggered neurogenesis in an area that does not do so normally. “The mammalian brain is not like a canary brain, but the method works,” said Dr. Goldman. “We are hopeful that we can translate it into a therapeutic strategy.”The research was funded by the NINDS, the Hereditary Disease Foundation, and the High-Q Foundation, a private philanthropic organization.
©2007 American Academy of Neurology
• Cho S-R, Beraiss A, Goldman SA, et al. Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest
2007; E-pub 2007 Sept. 20.
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