Researchers have created "Huntington's Disease in a dish" by generating stem cells from skin cells obtained from a person with a severe, early-onset form of Huntington's disease  and turned them into neurons that degenerate just like those affected by the fatal inherited disorder.

Although the autosomal dominant gene mutation responsible for HD was identified in 1993, there is no cure. No treatments are available to slow its progression. The general midlife onset and progressive brain damage of HD are especially cruel, slowly causing jerky, twitch-like movements, lack of muscle control, psychiatric disorders and dementia, and — eventually — death. In some cases (as in the patient who donated the material for the cells in this study), the disease can strike earlier, even in childhood.

The new research  published in Cell Stem Cell, studied several other HD cell lines and control cell lines in order to make sure results were consistent and reproducible in different labs.  To conduct their experiment, they took a skin biopsy from a patient with very early onset HD. The patient was just seven years old and she had a very severe form of the disease, which rarely appears in childhood, and of the mutation that causes it. Using cells from a patient with a more rapidly progressing form of the disease gave them the best tools with which to replicate HD in a way that is applicable to patients with all forms of HD.

Her skin cells were grown in culture and then reprogrammed by the lab of Hongjun Song, Ph.D., a professor at Johns Hopkins' Institute for Cell Engineering, into induced pluripotent stem (iPS) cells. A second cell line was generated in an identical fashion in the lab of Christopher A. Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences, neurology, pharmacology and neuroscience at the Johns Hopkins University School of Medicine and one of the study's lead researchers,  from someone without HD. Simultaneously, other HD and control iPS cell lines were generated as part of the NINDS funded HD iPS cell consortium. 

They converted those cells into generic neurons and then into medium spiny neurons, a process that took three months. What they found was that the medium spiny neurons deriving from HD cells behaved just as they expected medium spiny neurons from an HD patient would. They showed rapid degeneration when cultured in the lab using basic culture medium without extensive supporting nutrients. By contrast, control cell lines did not show neuronal degeneration. 

The group are already testing small molecules for the ability to block HD iPSC degeneration. These small molecules have the potential to be developed into novel drugs for HD.

The ability to generate from stem cells the same neurons found in Huntington's disease may also have implications for similar research in other neurodegenerative diseases such as Alzheimer's and Parkinson's.

"These HD cells acted just as we were hoping," says Ross, director of the Baltimore Huntington's Disease Center. "A lot of people said, 'You'll never be able to get a model in a dish of a human neurodegenerative disease like this.' Now, we have them where we can really study and manipulate them, and try to cure them of this horrible disease. The fact that we are able to do this at all still amazes us."

Specifically, the damage caused by HD is due to a mutation in the huntingtin gene (HTT), which leads to the production of an abnormal and toxic version of the huntingtin protein. Although all of the cells in a person with HD contain the mutation, HD mainly targets the medium spiny neurons in the striatum, part of the brain's basal ganglia that coordinates movement, thought and emotion. The ability to work directly with human medium spiny neurons is the best way, researchers believe, to determine why these specific cells are susceptible to cell stress and degeneration and, in turn, to help find a way to halt progression of HD.

Much HD research is conducted in mice. And while mouse models have been helpful in understanding some aspects of the disease, researchers say nothing compares with being able to study actual human neurons affected by HD.

For years, scientists have been excited about the prospect of making breakthroughs in curing disease through the use of stem cells, which have the remarkable potential to develop into many different cell types. In the form of embryonic stem cells, they do so naturally during gestation and early life. In recent years, researchers have been able to produce induced pluripotent stem cells (iPSCs), which are adult cells (like the skin cells used in Ross's experiments) that have been genetically reprogrammed back to the most primitive state. In this state, under the right circumstances, they can then develop into most or all of the 200 cell types in the human body.