An integrated biochemical, genetic and transcriptomic approach to defining target therapeutic pathways in Parkinson's disease

Parkinson's disease (PD) is a common brain disorder affecting 127,000 people in the UK. It causes slowness of movement and other symptoms such as constipation and memory loss. Unlike cancer medicine, there have been few advances in curative treatment for PD. In cancer medicine patients' treatment is directed not only by where the cancer has developed (e.g. breast, bowel or prostate) but also by the particular proteins that the cancer cells have, so that two people with breast cancer may be treated with two very different treatments. This idea of 'personalised medicine' has proven very successful. Currently all people with PD are given the same type of treatment to help with the symptoms of the condition but no treatments exists to stop or cure PD. Many treatments have shown promising results when tested in mice but when trialled in humans they failed to show any benefit.

A key reason for these disappointing results may be that, unlike in cancer medicine, all people with PD are treated the same. PD varies quite considerably within those with condition, for example some have symptoms that worsen over a short period and some have very little change in their symptoms over many years. The reason for this variation is still largely unknown, but one possibility is that although the same part of the brain is affected in all people with PD, how that particular area becomes affected may differ from person to person. Damage to mitochondria (the "power stations" of nerve cells) has long been implicated as an important feature of PD. However, there is now growing consensus that mitochondrial impairment may be greater in some people with PD than others. Therefore if a medicine targets improving the function of mitochondria then it should be trialled on those people where mitochondrial impairment is more important. Unfortunately there is no current way of detecting by symptoms, brain scans or blood tests if a person with PD has significant mitochondrial impairment. As such previous trials of medications targeted at mitochondria have been carried out in an unselected group of people with PD, many of which would not have significant mitochondrial impairment, therefore reducing the chance that the medication would show any benefit.

For future trials of medicines in Parkinson's I believe it is important we identify those who would most likely benefit from the medication and target those people to the appropriate trial. Using a novel approach I wish to try and identify a reliable test that detects which people with PD have mitochondrial impairment from a blood sample. Such a blood test would revolutionise drug trials for mitochondrial therapy as not only would it allow the 'right' medication to be directed to the 'right' person (as it is in cancer medicine) but may also act as test to judge if the medication is effective.

Parkinson's disease (PD) is a common neurodegenerative disorder that currently does not have any neuro-protective treatments. Experimental compounds have shown promise in animal models of PD but have failed to show efficacy in human clinical trials. There is a growing consensus that PD is a heterogeneous condition and this may explain some of the failures of drug trials to date.

Based on previous assessment of mitochondrial function in peripheral tissues from PD patients, we hypothesise that there are subgroup of PD patients in which mitochondrial dysfunction is more prominent than others. This has important implications for the future of neuro-protective drug discovery, as trials on drugs targeting mitochondria are likely to fail in a proportion, if not the majority of PD patients.

Currently there are no reliable biomarkers of mitochondrial dysfunction in PD. As such I propose an innovative approach: that firstly revisits the earlier work delineating mitochondrial dysfunction in peripheral blood cells in PD using state-of-art technology to assess mitochondrial function in live cells, and secondly integrates DNA and RNA data from the same patients to develop robust and accessible biomarkers for mitochondrial dysfunction.

I will use a comprehensive battery of mitochondrial function tests (including oximetry, mitochondrial membrane potential and total ATP levels) to assess mitochondrial function in lymphocytes from PD patients, both with and without mutations in genes from mitochondrial pathways known to cause PD - PARK2/PINK1. These data will be compared to age and sex matched controls. From this data I will define a subset of PD patients with mitochondrial dysfunction who will go on to have in depth clinical, genetic and transcriptomic analysis to look for reliable, accessible and importantly high throughput biomarkers of mitochondrial dysfunction. This approach could then be used to define a subset of PD patients suitable for personalised intervention.

Parkinson disease (PD) is a progressive neurodegenerative disorder that is increasingly prevalent with age, affecting 2% of those over the age of 75. Besides motor symptoms, such as tremor, rigidity, bradykinesia, and postural instability, PD patients often experience a variety of non-motor symptoms, such as fatigue, depression, sleep disturbance, and dementia. Although symptomatic treatments exist to alleviate the motor symptoms, no neuro-protective treatment has yet been established to slow PD progression, which inevitably renders patients incapable of living independently. The NHS spent more than £212 million caring for people with Parkinson's in England in 2012/13, and with a demographic shift in many parts of the world toward an increasingly older population, this demonstrates both the an urgent global need to prioritise research in this area as well the potential impact of my research findings.

I believe the proposed project will have direct academic, commercial and clinical impact, as well as indirect impact on policy markers regarding health care budgets. In an academic context there will be many academic beneficiaries (as highlighted in the above section 'academic beneficiaries'). The project will impact these beneficiaries by providing increasing understanding of the role of mitochondria in PD, optimised methods for measuring mitochondrial function from lymphocytes and the discovery of accessible and reliable peripheral biomarkers of mitochondrial dysfunction. Furthermore a stratified cohort of patients based on mitochondrial function will likely be useful to collaborators who may wish to study or follow up these 'mitochondrial PD patients' using modalities we have not employed such as imaging studies.

From a commercial perspective the ability to define a specific cohort of patients with proven mitochondrial dysfunction is likely to have a major impact. As eluded to in the summary sections of this project there is a growing feeling that future drug trials of neuroprotective medication need to embrace the idea of heterogeneity, and so by providing a biomarker for mitochondrial function we will be able to define a subgroup of patients who can be taken directly forward to clinical trials. Prof Morris has established links with Bioelectron, a pharmaceutical company who focus a lot of their work on mitochondrial therapies. Bioelectron are currently running the EPI-589 trial of a potential mitochondrial therapy for PD at the Leonard Wolfson Experimental Neurology Centre, with Prof Morris being the local principle investigator. Therefore there is clear opportunity for collaboration with Bioelectron and other such pharmaceutical companies, both in terms of study cohort selection but also providing evidence of target engagement.

From a clinical perspective such collaboration with the pharmaceutical industry could have a major impact. The finding of a reliable mitochondrial biomarker would allow for novel (as we as previously trialled) medications to be developed with the aim of improving mitochondrial function which may lead to successful neuro-protective therapies that halt or even reverse the disease process.. This would clearly have a huge impact on the quality of life for a significant number of people suffering from PD. This may then lead to an indirect impact on health care budgets by significantly reducing the costs associated with PD care allowing for funds to be diverted to other areas within healthcare.