Open Label Pilot Study Using Hydroxytyrosol (HT) as a Dietary Supplement in Patients With Mitochondrial Diseases (MDs)

High phenolics-containing extra-virgin olive oil (EVOO) can be one of the potential dietary supplements for the treatment of MD. There is growing evidence to suggest that daily consumption of EVOO in Mediterranean diets have beneficial effects on preventing neurodegeneration. Previous reports demonstrated that phenolics including oleuropein, oleocanthal, hydroxytyrosol and tyrosol found in EVOO have strong antioxidant properties against the oxidative stress in brain tissue and protective effect on both acute and chronic neurodegenerative diseases by in vitro study and animal models. In addition to improvement of arsenic-induced oxidative stress by oleuropein or hydroxytyrosol treatment, hydroxytyrosol also showed a protective effect on mitochondria by restoring mitochondrial enzymatic activities in rat brain. In vitro study also demonstrated the stimulatory effect of hydroxytyrosol on mitochondrial function including in mouse 3T3-L1 adipocytes and human endothelial cells. A recent reported clinical study showed that consumption of olive oil could increase mitochondrial membrane fluidity and ATPase activity in patients with relapsing-remitting multiple sclerosis, a neurodegenerative disease associated with mitochondrial dysfunction.

Mitochondrial diseases (MDs) are the commonest group of inborn errors with a minimal prevalence of 12.5 per 100,000 and 4.7 per 100,000 adults and children respectively. These diseases are resulted from primary dysfunction of mitochondrial respiratory chain (MRC) which is mostly caused by both nuclear and mitochondrial DNA defects. They are progressive, multisystem disorders that can affect many parts of the body including brain, nerve, muscle, kidney, heart, liver, eyes, ears or pancreas and some are devastating or even life threatening. Development of effective treatments for the patients is an unmet need until now. Effective treatment strategies and clinical trials are limited, and therapies are mostly palliative. Drug developments and clinical trials for these diseases are scarce in Hong Kong when compared with other countries.

MDs are extremely heterogeneous phenotypically and genetically with the biochemical dysfunction and pathogenic mechanisms being unique in each individual molecular defect. With the advance in next generation sequencing, over 300 mitochondrial genes are implicated to cause human diseases. This wide heterogeneity has been hindering the development of new therapeutic strategies such as gene therapy which requires long term evaluation and substantial manipulation to improve efficacy and reduce toxicity risk. It is therefore not efficient nor realistic to develop unique therapy targeting at a specific molecular defect.

The future pharmaceutical development for treating mitochondrial dysfunctions will focus on boosting the residual mitochondrial function by non-specific bypassing the defective components of MRC or improving the aberrant cellular consequences. Dietary supplements were demonstrated to treat MD owing to their roles as metabolic cofactors to ameliorate mitochondrial ATP production, bypass mitochondrial complex defects and remove toxic metabolites. However, there are few randomized controlled trials to assess the cause-effect relationship of these dietary supplements.

The present study is a feasibility clinical trial to explore the longitudinal effect of receiving hydroxytyrosol (HT) as dietary supplements on primary and secondary outcomes (clinical, biochemical and radiological parameters and quality of life) and tolerability in MD patients in Hong Kong. The investigators aim to obtain relevant data to determine the sample size and treatment duration for the next phase of the clinical trial on hydroxytyrosol (HT) efficacy. Another aim of this study is to evaluate the applicability of the outcome measures in the current study for future clinical trials on different treatment strategies.