Ornithine Transcarbamylase (OTC) Deficiency
Ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia, which is formed when proteins are broken down in the body. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in neurological deficits and other toxicities.
It is estimated that approximately 10,000 patients are affected by OTC deficiency worldwide; however, many cases go misdiagnosed or undiagnosed.1 The largest percentage of living patients experience late-onset disease, representing a clinical spectrum of disease severity. Currently, the only curative approach is liver transplantation, but this is often associated with significant morbidity and mortality risks both during the procedure and over the long-term.
For less severe disease, there are special daily amino acid formulas to provide a portion of dietary protein allowance. However, compliance can be poor in some patients, and non-compliance can be life threatening. Current drug treatments include sodium phenylbutyrate and pharmaceutical grade L-citrulline; unfortunately, patients can continue to experience hyperammonemic crises, which may result in cognitive decompensation.
Despite current dietary and pharmacological treatment measures, there is a compelling need for new therapies. Based on preclinical and clinical evidence, as little as 3% of normal enzyme activity may be sufficient to ameliorate severe neonatal disease. Preclinical data in in vivo models have shown positive results for an AAV gene therapy approach in terms of stable gene expression, enhanced survival in mice, and prevention and/or reduction of hyperammonemia.