Gene therapy for urea cycle defects: An update from historical perspectives to future prospects

Abstract

Urea cycle defects (UCDs) are severe inherited metabolic diseases with high unmet needs which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life‐long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of UCDs, improve quality of life and long‐term outcomes: adenoviral vectors, adeno‐associated viral vectors, gene editing, genome integration and non‐viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.

Genetic and functional correction of argininosuccinate lyase deficiency using CRISPR adenine base editors

“…Gene therapy options are rapidly evolving and under active investigation for urea cycle disorders. 60 Our gene editing strategy offers advantages over gene transfer by viral vectors. LNPs present lower immunogenicity compared to viral vectors, circumventing the risk of existing or triggered anti-viral antibodies, and possibly allowing for subsequent applications of the treatment.…”

Liver‐directed gene therapy for inherited metabolic diseases

“…For CPS1 deficiency, the size of CPS1 gene and the limited AAV packaging capacity required a split-approach with two AAV vectors. 25 Nevertheless, in preclinical studies for CPS1 deficiency as well as other urea cycle disorders, AAV have shown phenotype correction with increased survival, improved growth, normalization of ammonia and plasma amino acid concentrations (reviewed by Duff et al 26 ). The preclinical studies in OTC deficiency have led to a first-in-human Phase I/II AAV8 gene therapy clinical trial for adults with late-onset OTC deficiency sponsored by Ultragenyx (NCT02991144), with seven patients considered as responders out of 11 treated.…”

Mission possible: Gene therapy for inherited metabolic diseases

“…9 Duff et al review the specificities, development and perspectives of gene therapy for urea cycle defects. 10 Chandler and Venditti summarise the preclinical studies and clinical trials of genetic therapies developed for methylmalonic and propionic acidaemias and lessons learned over the years. Martinez et al provide an update on proof of concept in animal models and clinical trials of gene therapy for phenylketonuria, including recent innovative preclinical approaches of introducing an acquired competitive advantage of genetically modified hepatocytes.…”