Development of iPSCs for studying the molecular pathology of MNGIE
Research type
Research Study
Full title
Participant-derived induced pluripotent stem cells (iPSCs) for studying the molecular pathology of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
IRAS ID
168506
Contact name
Bridget E Bax
Contact email
Sponsor organisation
St George's University of London
Research summary
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a disease which particularly affects the digestive and nervous systems. The condition is relentlessly progressive and patients die from nutritional failure and muscular disability at an average age of 37.6 years. MNGIE results from a mutation in the TYMP gene which codes for thymidine phosphorylase, the enzyme responsible for breaking down thymidine and deoxyuridine. The consequent deficiency in thymidine phosphorylase leads to an accumulation of thymidine and deoxyuridine, and damage to DNA found in mitochondria (mtDNA). Mitochondria are structures within cells responsible for generating energy. As a result mutations accumulate in mtDNA and cause it to become unstable and affect mitochondrial function. Although mtDNA abnormalities underlie the digestive and neurological problems, there is little information on how defective mitochondria cause the features of MNGIE. The rarity of MNGIE and its high mortality rate impose constraints on the availability of biological samples. In addition, the molecular signatures contained within patient blood samples reflect the multi-systemic nature of the disease, thus creating complexities in teasing out the tissue-specific disease molecular mechanisms.
The aim of this project is to develop a cell model of MNGIE that would permit the study of the underlying molecular perturbations of the neuronal and gastrointestinal components of the symptomatic disease. Cells from patient blood and skin samples will be reprogrammed so they return to an unspecialised state referred to as induced pluripotent stem cells (iPSC). Once in this state they will be induced to differentiate into neuronal and gastrointestinal cells, possessing the same genetic make-up of the patient and therefore model MNGIE disease. The molecular expression profile of patient cells will be compared with the molecular signature of differentiated iPSCs derived from a group healthy individuals. Under and over expressed molecular signatures will be assessed using analysis software to gain insight into disease mechanisms.
REC name
East Midlands - Nottingham 2 Research Ethics Committee
REC reference
15/EM/0355
Date of REC Opinion
5 Aug 2015
REC opinion
Further Information Favourable Opinion