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Development of a cell based system to investigate which Leigh syndrome patients could benefit from treatment with decanoic acid or ketone bodies

Kanabus, MM; (2016) Development of a cell based system to investigate which Leigh syndrome patients could benefit from treatment with decanoic acid or ketone bodies. Doctoral thesis , UCL (University College London).

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Abstract

Mitochondrial diseases are the most common group of inherited metabolic disorders, with a minimum birth prevalence of ~ 1 in 5000. They are an unusually heterogeneous group of diseases, both phenotypically and genetically. To date over 200 genes which result in a mitochondrial diseases have been identified. It is this heterogeneity that renders statistically powered clinical trials for potential treatments virtually impossible, explaining why there are still no effective cures for mitochondrial disorders. A vast range of potential therapeutic approaches has been investigated to determine their suitability for treatment of mitochondrial diseases. Strategies to increase mitochondrial biogenesis appear to be the most promising. The ketogenic diet, a high fat, low carbohydrate and low protein diet which has been used to treat refractory epilepsy since the 1920s, has also been suggested to increase mitochondrial biogenesis, although its exact mechanism of action is not well understood. Furthermore, more recently, it has been shown that decanoic acid (C10), a component of the medium chain triglyceride diet, may also increase mitochondrial biogenesis through the activation of the peroxisome proliferator activated receptor-gamma (PPAR-γ). In this study, the role of ketone bodies (β-hydroxybutyrate (BHB) and acetoacetate (ACA)), and C10 in increasing mitochondrial biogenesis and function was investigated. Fibroblasts derived from 7 patients and 2 controls were treated with BHB, ACA or C10. A 6 day treatment of fibroblasts with 5mM BHB or ACA was found to have inconsistent effects on citrate synthase enzyme (CS) activity, with some fibroblasts showing a reduced activity, while others showed increased or unchanged CS enzyme activity. In contrast, treatment with 250µM C10, was found to increase CS enzyme activity in control fibroblasts as well as in the majority of patient derived fibroblasts. Additionally, BADGE - a PPAR-γ antagonist, was found to diminish the effects of C10 on CS enzyme activity, thereby confirming that CS enzyme activity is upregulated through the PPAR-γ pathway. Further studies including the assessment of Complex I and IV actives, as well as mitochondrial reactive oxygen species and mitochondrial membrane potential were performed, to determine whether these treatments were associated with any adverse side effects on mitochondrial function. Overall, the results were found to vary from patient to patient, and no consistent trends were observed. Surprisingly however, it was found that C10 was able to consistently reduce ROS levels in “stressed” fibroblasts exposed to the Complex I inhibitor rotenone. Finally, gene expression analysis (using microarray and qPCR studies) suggested that treating cells with C10 may support fatty acid metabolism, by increasing ACADVL and CPT1 expression, whilst downregulating genes involved in glucose metabolism such as PDK3 and PDK4. Additionally genes PCK2 (involved in inhibiting glucose metabolism) and CAT (encoding catalase) were also found to be upregulated. These findings suggest that C10 (but not BHB and ACA), may be able to upregulate mitochondrial biogenesis, increase mitochondrial resistance to oxidative stress and stimulate fatty acid metabolism, and thus be a potentially useful therapeutic approach for some mitochondrial patients. However, prior cellular testing in vitro needs to be employed as a means for selecting individuals suitable for clinical trials involving C10 preparations. The fact that not all patient cells appeared to respond to C10 highlights the importance of considering a personalised medicine approach, especially when searching for treatments for such heterogeneous diseases.

Type: Thesis (Doctoral)
Title: Development of a cell based system to investigate which Leigh syndrome patients could benefit from treatment with decanoic acid or ketone bodies
Event: UCL (University College London)
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1485726
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