16/07/2014 → 15/07/2015
Dr Bi-xia Ke
Murdoch Childrens Research Institute
Treatment trials in the Ndufs6gt/gt mouse model of mitochondrial Complex I deficiency
Dr Ke has completed five years of post-doctoral training, and has published nine peer-reviewed journal articles. Her research focuses on the characterisation of mouse models for trialling new mito treatment strategies. This research project will look at mouse models with mitochondrial Complex I Deficiency, one of the most common forms of mitochondrial disease. Dr Ke’s work will look at two separate drugs, rapamycin and nicotinamide riboside (NR) and whether they can assist in prevention or the delay of heart disease in these mouse models. The heart is particularly vulnerable in patients with mitochondrial Complex I Deficiency, with cardiac involvement recognized in about a third of children and up to 80% of adults with the disorder. Dr Ke’s research aims to produce further development in mouse models and the eventual application of clinical trials on patients.
Summary of Findings
Dr Ke has prepared the following summary of her findings over the past year.
“Severe disorders of mitochondrial energy generation affect ~1/5000 live births. Common presentations include neurodegeneration, muscle weakness, cardiac failure, liver failure and early death, often in infancy or childhood. Currently, no effective therapies are available for mitochondrial disease. Complex I (CI) deficiency is the most common presentation of mitochondrial disease. We recently generated one of the first CI deficient mouse models that is suitable for therapeutic trials. The Ndufs6gt/gt mice present with progressive heart failure and can survive for at least 6 months. Nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor naturally found in milk has been shown to boost NAD+ levels and improve mitochondrial function in mice. We aim to set up a pilot study to determine whether treatment with NR will prevent or delay the progression of heart disease in Ndufs6gt/gt mice.
We therefore treated a small cohort of mice with either control or NR diet. All mice tolerated NR diet well with normal food and water intake, and normal weight gain. No differences in organ size or appearance were detected between the two diet groups. The NR diet partially ameliorated the cardiomyopathy of our mutant mice by delaying the development of cardiac enlargement and improving cardiac function. Currently, we are in the process of further assessing the treatment outcome to unravel the underlying mechanism. These results are very promising and will not only enable us to apply for competitive grants for expanded studies, but will add to justification for clinical trials that could improve the outlook and welfare of patients with mitochondrial diseases.”