Evaluating AAV-mediated Gene Therapy for a Severe Paediatric Metabolic Liver Disease OTCD

Ornithine Transcarbamylase Deficiency (OTCD) is a rare genetic disorder characterized by complete or partial lack of a key element of the urea cycle, whereby the liver breaks down dietary protein and removes surplus nitrogen from the body. OTCD patients accumulate nitrogen in the form of excess ammonia in the blood, which is toxic and if left untreated may progress to coma and life-threatening complications. Neonatal OTCD patients require liver transplantation (LT) for long-term survival and whilst LT can be a lifesaving opportunity, this intervention remains limited and not without risk of mortality and morbidity.

Professor Paul Gissen has a longstanding collaboration with Professor Ian Alexander (Children’s Medical Research Institute (CMRI) in Sydney) who have developed an Adeno Associated Virus (AAV)-based gene therapy to specifically target the liver and restore urea cycle activity. In laboratory studies, this novel therapy normalized metabolism in mice engrafted with OTCD human liver cells. This is significant as patients with OTCD are expected to require single administration of viral gene therapy to provide a ‘bridge-to-transplant’ solution, enabling paediatric patients to continue to grow in a metabolically stable condition until such time that LT is safer, whilst also minimising longer-term neurological illness associated with excess ammonia.

The Translational Research Office (TRO) worked closely with the PI and project team to help secure two awards (£6M) from the MRC DPFS scheme which have funded the pre-clinical manufacture, safety and toxicology and the planned clinical study. Managed by the TRO, the preclinical work was successfully outsourced with results demonstrating the safe and effective action of this orphandesignated therapy for the treatment of OTCD.

Through continuous engagement with the regulatory authorities (i.e. MHRA, EMA), the project has manufactured the GMPgrade vector to conduct a dose finding, safety and efficacy clinical trial in 12 paediatric OTCD patients (recruiting in the UK to commence mid-2021). Generation of the clinical data will be pivotal to licensing the academic results to enable the translation of this life-saving gene therapy to a wider population of paediatric OCTD patients and those with other inherited liver metabolic disorders.