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Systems Medicine of Mitochondrial Parkinson’s Disease

Periodic Reporting for period 3 - SysMedPD (Systems Medicine of Mitochondrial Parkinson’s Disease)

Reporting period: 2018-12-01 to 2019-11-30

Parkinsons’s disease (PD) is a difficult and complex condition. Between 90–95% of Parkinson’s cases are sporadic, which means they have no family history. 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 in a spectrum of mitochondrially associated dysfunction in idiopathic Parkinson’s disease patients. Integrative analysis of genetic, biochemical, metabolomic, computational and magnetic resonance spectroscopy data is envisaged in the next funding period to confirm the stratification achieved thus far. 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, that seems sufficient in magnitude to make development of a mitochondrial drug repurposing assay unlikely at present. Nevertheless, parallel efforts by multiple partners, especially on PINK1 mutant cell lines, indicates that there are phenotypic differences at group level, including in metabolomic data and computational models of dopaminergic neuronal metabolism. Humanised mouse modelling suggest a beneficial effect of a candidate neuroprotectant on Pink1 oxygenation profiles as assessed by live amperometry. In the next period, integrative analysis of amperometry data together with metabolomic data on microdialysis samples, as well as immunofluorescence staining and FACS data shall attempt to mechanistically underpin these amperometry results. The overall objective of SysMedPD is to develop new candidate neuroprotection compounds to slow the progression of neurodegeneration in advanced preclinical models of Parkinson’s disease with mitochondrial dysfunction. During the next funding period, integrative analysis of clinical, in vitro and in vivo, using advanced statistical techniques, complemented by mechanistic computational modelling and substantial effort at biochemical interpretation by all partners, will be required to reach this objective.
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.
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