Ornithine transcarbamylase (OTC) is a urea cycle enzyme that is mutated in individuals with a metabolic disorder - OTC deficiency. The consequence of accumulating ammonia affects many tissues, and the liver in particular is damaged. The condition affects young children with neurologic consequences, hence liver organ transplant is necessary to treat those severely affected. Cell therapy using normal hepatocytes may also be possible, but hepatocytes are difficult to maintain and store; and once transplanted may not survive for very long. In contrast LPCs are robust and have the added advantage of long-term survival and the ability to proliferate and continue to generate hepatocytes in situ means they have the potential to confer sustained benefits following transplant.
We have access to the Spf-ash mouse model of human OTC deficiency through our collaboration with Professor Ian Alexander of the Children’s’ Medical Research Institute in Sydney. This group also has expertise in ESC and iPSC technology and this allows us to test our LPC lines and LPCs generated from ESCs and iPSCs in these mice.
Projects on offer follow from recent progress we have made:
We have generated LPC lines from the Spf-ash mouse. These have to be extensively characterised to confirm their LPC status and their ability to differentiate into hepatocytes and cholangiocytes.
We have preliminary evidence to suggest that mESC maintained in culture medium that supports LPCs can assume an LPC phenotype.