Huntington’s disease is a devastating, hereditary neurodegenerative disease affecting about 1 out of every 10,000 people in the USA, Europe and Australia. It typically causes involuntary movements of the face and body and dementia. Symptoms worsen over time, eventually leaving the affected person totally dependent on help from others. There are no effective therapies available today. How might stem cell research lead to new treatments?
Huntington's disease was first described in medical literature in 1872 by Dr. George Huntington, a physician from Long Island, New York.
Left: rosette neurons - an intermediate stage between stem cells and fully specialised neurons; Right: fully differentiated neurons grown from embryonic stem cells.
However, scientists discovered that the gene first appeared without any CAG repeats at all, in an amoeba called Dictyostelium Discoideum. As new species evolved, the CAGs appeared and increased in number in species with progressively more complex nervous systems.
There are indications that the number of CAG repeats in the normal gene may correlate with neuronal capacities and that in healthy humans, the more CAGs there are in the gene (up to a maximum of 35) the more grey matter is present in their brain. It might thus be that CAG repeats correlate with brain complexity and function both in evolution and in human beings, although this has not yet been proven and for now remains simply an interesting hypothesis.
What is clear is that more than 35 CAG repeats results in Huntington's disease in humans.
Huntington’s Disease (HD) mainly affects nerve cells in the brain called medium spiny neurons (MSNs). MSNs receive and coordinate information from other neurons in the brain to control movement of the body, face and eyes.
In Huntington’s Disease large numbers of MSNs are damaged and destroyed. Some other types of neurons in the brain also appear to be affected, such as cortical neurons. Patients usually first notice symptoms when they are around 35-50 years old, typically weak spasmodic movements of the muscles in the face and limbs. As the disease progresses, these spasmodic movements become more evident and frequent and other symptoms appear. Patients are affected in different ways, but symptoms may include difficulty speaking and swallowing, dementia or trouble concentrating.
HD is an hereditary disease. Children with an affected parent have a 50% chance of inheriting the genetic fault that causes the disease. This fault occurs in the gene that holds the code for a protein called Huntingtin. The defective gene causes the body to make a faulty, toxic version of the Huntingtin protein and this eventually results in the loss of MSNs and other neurons.
There is currently no effective treatment to stop or reverse the progress of HD. Instead, therapies are focused on managing the symptoms. To treat uncontrolled movements, the most commonly used drugs are tetrabenazine, benzodiazepines and antipsycotics, the last of which can also help with some of the possible psychological symptoms. Speech therapy is widely used to improve communication and difficulties with eating and swallowing. Other drugs may also be used, depending on the individual patient’s needs and symptoms.
These strong medications often have side effects and do not repair damage or stop the disease from progressing. Because of this, scientists are making a huge effort to find new methods to tackle the cause of the disease and to replace lost medium spiny neurons.
Although researchers know that HD is caused by a fault in the gene for making the protein Huntingtin, it is still not clear how the genetic error leads to the loss of medium spiny neurons and the resulting symptoms of the disease. Understanding this process could reveal new treatment options. Scientists also hope to find ways to replace patients’ lost MSNs.
Stem cells offer an opportunity to grow and study large numbers of cells in the laboratory. There are several different types of stem cells and scientists are investigating a number of ways they might be used to tackle the challenges of Huntington’s Disease:
Replacing lost cells
Most (though not all) of the symptoms of HD are due to the loss of medium spiny neurons in the brain. Consequently scientists’ efforts have been focused on obtaining new MSNs to replace the damaged ones. In 2000 medical doctors transplanted fetal neurons into the brains of a small number of HD patients. This gave patients a short-term improvement in both movement and psychological symptoms, but two years after surgery the HD symptoms worsened again. It is possible that improved procedures for using these fetal MSNs could help to treat HD and current clinical trials are investigating this idea, but there are some significant scientific and technical problems: for example, the use of tissue taken from aborted fetuses provides only a very limited source of cells which cannot be purified nor improved. Stem cells could provide a valuable alternative.
Researchers hope to use embryonic stem cells or induced pluripotent stem cells as an unlimited source of medium spiny neurons for HD treatment. Both these types of stem cells have the ability to make all the different cells of the body, so the challenge is to find a way to direct them to make only MSNs. The first lab-grown neurons resembling MSNs were obtained from human embryonic stem cells in 2008, but when they were transplanted into rodents they caused tumours to grow. More recently, in 2012, two laboratories obtained MSNs from human embryonic stem cells in a way that does not cause tumours to form. Transplantation of these lab-grown MSNs gives some improvement of movement in rodents with a form of HD. In one case, the neurons have also been shown to carry a number of the key properties expected for authentic MSNs of the human brain. Much more research is needed to improve the quality and quantity of the neurons obtained and to establish whether this approach could one day be safely and effectively transferred to human patients.
A number of recent studies have shown that is also possible to obtain induced pluripotent stem cells (iPS cells) from Huntington's Disease patients. A consortium of HD researchers from six American and 2 European laboratories took skin cells from HD patients and reprogrammed them to produce iPS cells. This was also achieved independently by a laboratory in California. The iPS cells obtained in this way have the same genetic code as the patients, and so the cells also have the HD-causing genetic fault and show some of the typical hallmarks of the disease. The researchers corrected the genetic problem in the lab so that the cells produce fully functional Huntingtin protein. MSNs grown from these genetically corrected iPS cells show signs of being healthy: in the lab, they are just as resistant to cell death as MSNs from people without HD. Much more research is needed, but this approach could one day become an important tool for use in cell replacement therapies for HD.
Drug screening and discovery
Today’s technology provides mechanical systems that allow researchers to test millions of chemical compounds in a relatively small amount of time to see if they might have a useful effect on cells. These systems are valuable tools for drug discovery, but there is a problem: they require huge numbers of cells of the right type (e.g. neurons) and the cells must have the disease being studied. Huntington’s Disease MSNs are impossible to obtain directly from patients because they must be surgically removed from the brain. iPS cells made from the muscle or skin of HD patients could solve this problem by providing an unlimited source of Huntington’s disease MSNs. Much research is focussed on developing robust systems for making Huntington’s disease iPS cells for such drug discovery work.
Studying disease behaviour
Mutations (or changes) in the gene that codes for the Huntingtin protein were first associated with Huntington’s disease in 1993. The Huntingtin gene contains a DNA fragment called a ‘CAG repeat’ – a piece of DNA made up of three units (C, A and G) that appear multiple times in the same order. The healthy gene contains less than 35 CAG repeats, but HD patients have a mutated version that contains more than 35 CAG repeats, in some very rare cases up to 250 CAG repeats. These extra copies of the CAG sequence make a faulty, toxic version of Huntingtin. The higher the number of CAG repeats, the more toxic Huntingtin is, and the earlier the symptoms of the disease tend to appear.
Scientists working on the mutant Huntingtin protein are focusing on identifying the mechanisms by which it contributes to the disease - how does the change in this one protein cause damage to MSNs? But the Huntingtin protein interacts with many other proteins and affects multiple processes in our cells, and exactly how it contributes to disease progression remains unknown. To study this question, scientists use models of the disease: systems designed to represent HD in the lab so it can be studied outside the patient’s body. Current models are based on rodents or genetically modified cells, but there’s not a perfect model that mimics disease exactly, and none of the models reproduce the link seen in patients between the number of CAG repeats and the toxicity of the protein.
Stem cells could be used to develop a more accurate model to study HD mechanisms and progression. iPS cells have been made from patients with different numbers of CAG repeats. When these different iPS cells are used to make MSNs, the neurons with more CAG repeats are more vulnerable to different stresses and show many of the characteristics of the diseaseas it occurs in patients. Researchers hope these iPS cell systems will now help them uncover exactly how HD works.
The use of stem cells for HD research is a very recent development. Although stem cells are already beginning to provide valuable tools for studying HD progression and for searching for new drugs, there’s still a long way to go before treatments involving transplantation of cells into patients could be considered as a reliable approach. The main questions that must first be answered are:
So, stem cells cannot be used to treat HD today, but stem cell research is providing useful tools for scientists aiming to develop new approaches for the future.
Huntington’s Disease Association
European Huntington's Disease Network
HOPES: A guide to the science of Huntington's disease
Studying Huntington’s disease using stem cells: scientists describe their latest results in December 2012
Stem cell therapies and neurological disorders of the brain: what is the truth? By Roger Barker
EuroStemCell fact sheet on reprogramming and iPS cells
EuroStemCell fact sheet on embryonic stem cells
Lead image of neurons grown from embryonic stem cells by Serafi Cambray. Medium spiny neurons labelled with green fluorescent proteins by Valentina Castiglioni. Human medium spiny neurons grown from embryonic stem cells by Charles Arber. All other images and figures by Serafi Cambray. Figure created using Servier Medical Art.