1:Vivet Therapeutics, S.L., Pamplona, Spain.; 2:Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, Pamplona, Spain.; 3:Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital Zurich, Switzerland.; 4:Vivet Therapeutics, S.A.S., Paris, France

Citrullinemia type I (CTLN-1) is a rare autosomal recessive genetic disorder caused by mutations in the Argininosuccinate Synthase 1 (ASS1) gene that catalyzes the third reaction of the urea cycle. CTLN-1 patients suffer from toxic accumulation of circulating ammonia and urea cycle byproducts that causes metabolic encephalopathy and death at a very young age. Standard of care (SOC) management of CTLN-1 consists of daily nitrogen-scavenger administration and lifelong low-protein, high-calorie diet. Early restoration of hepatic ASS1 expression based on recombinant adeno-associated virus (rAAV) gene therapy represents an attractive prospect for treatment.
Vivet Therapeutics is developing VTX-804, a rAAV vector expressing the human ASS1 enzyme under the control of a liver-specific promoter. The long-term therapeutic efficacy of VTX-804 (6 months post-vector administration) was evaluated in 3-week-old CTLN-1 mice (Ass1^fold/fold) treated or untreated from birth to weaning with nitrogen-scavenger agents as per SOC in patients. Combination of VTX-804 with SOC restores CTLN-1 mice survival, normalizes weight gain and ammonia levels, while mice receiving VTX-804 alone present 90% survival, did not normalize weight gain and ammonia levels are normalized just transiently.
Similar to CTLN-1 patients; CTLN-1 mice showed several behavioral abnormalities such as anxiety and reduced welfare and innate behaviors that were notably improved when they were treated with VTX-804, and even more with the SOC in combination that improved rAAV-transduction and hASS1 transgene expression at 3 and 6 months post-VTX-804 injection. Therefore, combination of the SOC prior to gene therapy administration represents a very promising therapeutic strategy for very young CTLN-1 patients.