Targeting the innate immune system in Huntington's disease

Huntington's disease (HD) is a fatal, inherited neurological condition. The earliest symptoms are often subtle problems with mood or cognition, followed by a lack of coordination and an unsteady gait. As the disease progresses, jerky body movements become more apparent, along with a decline in mental abilities and behavioural and psychiatric problems. Affected individuals also suffer progressive weight loss and muscle wasting. The disease typically progresses over several decades until death. There are a few effective treatments for some of the symptoms, but there is no cure that will halt or slow progression of the disease. The inherited nature of HD means that the children of affected individuals have a 50% chance of developing the disease themselves.

The disease is caused by a mutation in a single gene that encodes for a protein called huntingtin (HTT). The only difference between the mutated and normal versions of the gene is an increase in the number of repeats of the DNA sequence CAG close to its beginning. This causes an increase in the number of glutamines (an amino acid, the building blocks of proteins) in the HTT protein. This causes the HTT protein to behave in an aberrant fashion in the cells in which it's made.

HD is primarily thought of as disease of the brain, but the HTT protein (both the mutant and normal forms) is expressed in all the cells of the body. It is becoming increasingly recognised that there are significant changes outside of the brain in HD, including in muscle, heart, fat and, of interest here, the immune system. In fact, people carrying the HD gene show signs of increased inflammation, as shown by elevated levels of certain molecules in their blood. Beyond the urgent need for new therapies, one advantage of studying HD is that genetic testing can establish with 100% accuracy whether an individual carries the mutant gene or not, enabling us to study the disease before an individual develops any symptoms. In doing this, we have discovered that the increased inflammation in HD is observed many years before symptom onset. This suggests that inflammation might have long-term effects that are important in the development of the disease.

We have also discovered that inflammation in HD is probably due to the aberrant behaviour of a particular group of immune cells, called monocytes and macrophages. These cells are hyper-responsive to immune stimulation and produce excessive levels of the inflammatory molecules detected in the blood of HD patients. It is becoming clear that the immune system causes changes in the brain and other tissues. Hence, it is conceivable that elevated inflammation in HD patients might be contributing to some of the changes in the brain and/or other tissues that cause the symptoms of the disease to worsen. There are already safe treatments available that will reduce inflammation in humans, but this strategy has not yet been tried in HD.

Our aims are to determine whether inflammation really does contribute to HD progression and if so, whether we can use specific therapeutic agents to lower the inflammation to help treat the disease. We also want to discover the exact means by which the mutant HTT protein causes monocytes and macrophages to behave aberrantly, which may help identify alternative targets for developing treatments for HD.

To achieve these aims, we will undertake a range of experiments in cells from HD patients and in mouse models. We will determine exactly which genes are altered in HD monocytes and macrophages, and will attempt to discover how mutant HTT causes these changes to occur. We will treat HD mice with various agents that are expected to increase or decrease their levels of inflammation, including drugs that reduce inflammation and are already used for this purpose to treat other diseases. We hope that any positive results from these studies will lead to clinical trials in HD patients.

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene, leading to an expanded poly-glutamine tract in the HTT protein. Considerable evidence suggests that HD is associated with increased systemic inflammation that may contribute to progression of the disease. We have shown previously that myeloid cells from HD patients are hyper-responsive to stimulation and that this is due to the intrinsic expression of the mutant HTT protein in these cells.

Our hypothesis is that mHTT primes myeloid cell hyper-reactivity to immune stimulation and that the resultant low-level systemic inflammation contributes to HD progression. We aim to determine the mechanisms by which mHTT affects myeloid cells isolated from the blood of HD patients as compared to those from non-HD individuals, by means of full-transcriptome sequencing and methods to monitor transcription factor activation and binding.

We also aim to establish the extent to which components of the peripheral innate immune system contribute to HD and to determine whether systemic inflammation can be targeted to modify disease progression. We will specifically target cells and pathways by genetic and/or pharmacological means in ways that might ameliorate aspects of disease, allowing us to dissect the contribution of specific cell populations, signalling pathways and molecules to HD progression. We hope this will form the basis of further work seeking therapeutic intervention that targets in peripheral innate immune system and systemic inflammation in HD.

Understanding the contribution that systemic inflammation makes to pathogenesis is essential in determining whether targeting it might be a viable therapeutic strategy in HD. A complete mechanistic understanding of these events may identify targets that lead to the development of novel therapies.

The potential beneficiaries of our research include Huntington's disease patients and families, scientists and clinicians working on HD and/or neuroinflammation, as well as biotechnology and pharmaceutical companies with research and development and/or commercial interests in these areas.

For researchers, an improved understanding of neuroinflammatory events will aid all researchers with an interest in the pathogenic basis of HD. It will also have important implications for the potential development a new therapeutic strategy in HD. To that end, if results are positive, we expect to receive the active support of the CHDI Foundation (whose letter of support is enclosed), a not-for-profit research organisation that works with scientists internationally to discover therapies that slow the progression of HD. The discovery of such therapies will be of considerable commercial interest to companies working in this area.

For patients, we hope the work will form the basis of developing treatments for those who have developed or are likely to develop the disease. HD is a devastating disease that places an intolerable burden on those who suffer from the disorder and their families. The inherited nature of the disease means that family members who act as carers may be doing so with the absolute knowledge that they themselves are going to develop the disease later in life. There are currently no disease-modifying treatments for HD. Significant breakthroughs in our understanding of the pathogenesis of the disease conveys hope to patients and families, and will encourage participation in clinical trials. Understanding the mechanistic underpinnings of the disease will assist in the development of treatments for the benefit of patients.

More widely, the discovery of underlying pathogenic processes and/or therapeutic targets in one neurodegenerative disorder offers hope for researchers working on and patients affected by many others. Neurodegenerative disease is having a serious and long-term impact on an aging UK population, with effects extending from the immeasurable burden on the lives of those affected, to the wider social and economic implications of long-term care. Studies estimate that neurodegenerative disease already costs the UK economy more than cancer and heart disease combined. Due to the likely irreversible nature of the neuronal loss during neurodegeneration, therapies need to target the pre-degenerative disease state. Research in HD, for which there is predictive genetic test that can establish with absolute certainty whether a person will develop the disease later in life, may form the basis of the development of preventative treatments in other neurodegenerative disorders.

Finally, this grant will provide Ralph Andre with the resources to capitalise on his work to date on neuroinflammation as a modifier of disease in HD. He has made a large contribution to the preparation of this grant application; this funding will allow him to build a highly competitive CV from which he can launch his independent career. It will benefit the field by ensuring that a highly capable young investigator is committed to work on HD for the foreseeable future.