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Systems Medicine of Mitochondrial Parkinson’s Disease

Periodic Reporting for period 4 - SysMedPD (Systems Medicine of Mitochondrial Parkinson’s Disease)

Reporting period: 2019-12-01 to 2020-11-30

Parkinsons’s disease (PD) is a difficult and complex condition. Between 90–95% of Parkinson’s cases are idiopathic, which means they have no known cause. The remaining 5–10% are genetic and can be traced to familial heritage. The latest figures from the Parkinson’s Disease Foundation report that approx. 8 million people are living with the disease globally. In Europe alone, the direct and indirect costs associated with the disease are in the region of €14 billion p.a. In countries with increasing life expectancy this is a growing burden with personal, social and economic consequences.
Over the last two decades our knowledge of specific genetic risk factors that contribute to the cause of PD has increased greatly, however, this has failed to result in any treatment to slow down disease progression. Experts believe this is due to the fact that the cause of PD differs between individuals and ultimately that everybody’s Parkinson’s disease is different. The overall goal of SysMedPD is to reduce this variability by identifying patients that have a known gene abnormality that disrupts normal mitochondrial activity, the latter being a vital component of human cells that is responsible for energy production. The involvement of dysfunctional mitochondria in PD is well accepted and could contribute to a large proportion of both sporadic and familial PD cases. Therefore, identifying a particular subset of PD patients with a known cause will allow researchers to focus on new treatments to slow down the progression of that particular form of PD. The consortium will achieve this through a number of objectives.
- Clinical researchers will generate stem cells from skin samples obtained from patients with experimentally proven mitochondrial abnormalities.
- Researchers will grow the specific brain cells associated with PD (dopamine neurons) from these patient stem cells in 3D cell culture and test the effect of (a) particular drug(s) that has(ve) been shown to improve mitochondrial deficits.
- Researchers will also investigate the effect of the drug on human brain cells that have been transplanted into the brain of mice.
- Researchers will identify new improved methods of validating the data generated from the patient derived cells confirming PD with disrupted mitochondrial activity.
- PD relevant computational models will be constructed to assist with identification of promising novel therapies.
Clinical recruitment has been completed and exceeded or almost met recruitment targets. Independent analysis of genetic, biochemical and metabolomic data revealed a spectrum of mitochondrially associated dysfunction in idiopathic Parkinson’s disease patients. It has been possible to stratify such patients by their degree of mitochondrial dysfunction as assessed by biochemical assays, however, in order to increase our confidence in this stratification, further work to complement the genetic and biochemical assays with metabolomic and integrative computational analyses is required. Computational modelling of neuronal metabolism has been used to predict a set of therapeutic targets for monogenic and idiopathic PD with mitochondrial dysfunction. In vitro phenotyping of stem cell derived cultures from monogenic PD patients with mitochondrial dysfunction has been challenging due to ostensibly intrinsic variability between cell lines. Nevertheless, partners have identified a number of repurposed compounds capable of ameliorating mitochondrial phenotypes observed in patient stem cell derived cell culture models. Furthermore, humanised mouse modelling has demonstrated a beneficial effect of a candidate neuroprotectant on Pink1 oxygenation profiles as assessed by live amperometry, a form of electrical readout made specific to oxygen levels. Integrative analysis of amperometry data together with metabolomic data on microdialysis samples is ongoing in an attempt to mechanistically underpin these amperometry results. Altogether, SysMedPD has begun to develop new candidate neuroprotection compounds that show promise to ameliorate the effects of monogenic PD with mitochondrial dysfunction. Whether these compounds can slow the progression of neurodegeneration in idiopathic Parkinson’s disease patients with mitochondrial dysfunction will require future research and development.
A new set of junior researchers have been trained in systems medicine, preparing them for a career spanning the multiple disciplines required for a multifaceted approach to the development of new candidate neuroprotectants for neurodegenerative diseases. Furthermore, supported in part by the SysMedPD project, the two small and medium sized companies involved in SysMedPD, Khondrion B.V. and Mimetas B.V. continue to develop commercially. For example, Mimetas B.V. has generated over 80 new jobs since the start of the SysMedPD project. Mimetas flagship product, the OrganoPlate™ is now used by the majority of the top 50 big pharma companies. Increased adoption of the OrganoPlate and advanced tissue culture models in big pharma generates revenue for Mimetas but more importantly accelerates drug research in these pharma companies.
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