Phase I/II clinical trial evaluating AAV-mediated gene therapy for a severe paediatric metabolic liver disease: Ornithine Transcarbamylase deficiency

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Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is a key element of the urea cycle, whereby the liver breaks down and removes surplus nitrogen from the body. OTCD patients accumulate nitrogen in the form of excess ammonia (hyperammonemia) in the blood. Ammonia is toxic and patients suffer 'hyperammonaemic decompensations' with symptoms including vomiting, impaired voluntary movement, and progressive lethargy. If left untreated these may progress to coma and life-threatening complications. Symptoms present within a few days of birth of males with severe OTCD. As well as significant risk of mortality, the neurotoxic effects of excess ammonia result in longer-term neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. As with milder forms of this disease (which may present later in both male and female children and adults), infants are managed with ammonia-scavenging drugs and dietary intervention, however hyperammonaemic decompensations still occur. Neonatal-onset OTCD patients require liver transplantation (LT) for long-term survival. Whilst LT can be life-saving, opportunity for this intervention remains limited and not without risk of mortality and morbidity. Advances have been made in surgical practices to facilitate access to donor liver tissue, including 'living-donor partial liver grafts' and 'reduced-liver transplantation' whereby infants and children receive a portion of an adult liver. However, both the patient and their family still remain with the challenge of life-long immunosuppression and medical follow-up. European guidelines recommend LT for those patients with severe phenotype, aged between 3 and 12 months as neonatal transplant in such metabolically unstable patients is considered too great a risk. Of 15 paediatric OTCD patients transplanted in the UK this past decade, there were only 4 of this age. All others were over 3 years old and all had long-term neurological impairment. We have developed an Adeno associated virus (AAV)-based gene therapy (AAV-LK03-OTC) to specifically target the liver and restore functional expression of OTC. Our approach encompasses the single administration of gene therapy to OTCD infants to provide immediate normalisation of liver metabolism, thereby reducing acute risk of mortality from hyperammonaemic decompensations. Such treatment would serve as a 'bridge-to-transplant' enabling paediatric patients to continue to grow in a metabolically stable condition until such time that transplantation is possible, also minimising longer-term neurological morbidity associated with hyperammonaemia. Our laboratory experiments have demonstrated the enhanced ability of AAV-LK03-OTC to target liver cells over other AAV, and to elicit elevated expression of functional OTC. We have demonstrated that AAV-LK03-OTC restores liver function in experimental mouse models of this genetic disease and are currently testing the safety of AAV-LK03-OTC in animal studies. Recent success with other viral gene therapies advanced to early clinical trials (e.g. AAV8 for Haemophilia B) and the increased targeting to liver cells (AAV-LK03 >10-fold more transformation of liver cells than AAV8) reinforce confidence in this approach as being safe. We will now translate our pre-clinical findings to conduct a Phase I/II dose-finding clinical trial assessing the safety and efficacy of AAV-LK03-OTC. As children are the OTCD population with greatest unmet need, we aim to recruit 12 paediatric patients in the UK to provide early clinical data for later stage development and commercialisation of this transformative advanced therapy. This project aims to deliver a step-change in the clinical management of paediatric OTCD patients and provide critical gene therapy evidence applicable to many other liver-inherited metabolic diseases.