Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD.

Automated summary

Ornithine transcarbamylase deficiency (OTCD) is a common urea cycle disorder that requires improved treatment options. Liver transplantation is currently the only curative choice, but it is limited by donor shortage, immunosuppression risks, and technical challenges. Gene therapy, including AAV gene addition, mRNA therapy, and genome editing, has shown promise as an alternative treatment approach. This review summarizes the current progress and challenges in clinical translation, discusses ongoing clinical trials, and outlines future directions for gene therapy development in OTCD.