Citrullinemia: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Citrullinemia is an autosomal recessive urea cycle disorder characterized by toxic ammonia accumulation due to impaired argininosuccinate synthetase (type I) or citrin transporter (type II). Neonatal type I presents with hyperammonemia, lethargy, seizures, and coma, while type II often manifests in adulthood with neuropsychiatric symptoms. Diagnosis involves elevated plasma citrulline and genetic testing. Management includes dietary modifications, ammonia scavengers, and liver transplantation. Long-term complications include intellectual disability and hepatic dysfunction [1][3][11][14].

Population

Type I: Global incidence ~1:57,000, with localized hotspots (e.g., San Luis, Argentina: 1:2,427) [1][2][17].
Type II: Predominantly affects East Asians, notably Japanese (1:100,000–230,000) [1][7][19].

Burden

Neonatal type I mortality reaches 20% in developed nations despite treatment [4][12].
Chronic neurocognitive deficits, growth impairment, and recurrent hyperammonemic crises necessitate lifelong monitoring [9][11][19].
Liver transplantation remains the only cure but carries surgical risks and requires immunosuppression [3][4].

Therapies

Type I: Protein-restricted diet, ammonia scavengers (sodium benzoate/phenylbutyrate), L-arginine, and liver transplantation for refractory cases [3][12][14].
Type II: High-protein/low-carbohydrate diet, medium-chain triglycerides (MCT), and avoidance of traditional urea cycle drugs [3][7][18].

Categories: rare genetic diseases, rare inborn errors of metabolism

Research Papers

223 drug discovery papers about Citrullinemia, with 2 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?

Acute liver failure has been described at initial presentation of citrullinemia type 1, but recurrent hepatic decompensations during medical treatment have not been reported. We describe 5 children developing episodes of acute liver failure, including one who required emergency liver transplantation. Our findings expand the citrullinemia type 1 phenotype and support early liver transplant referral in selected cases.

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2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.

Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the ASS1 (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the Ass1fold mouse model of CTLN1. Adeno-associated virus (AAV)-mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic Ass1 mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg-1 dose in neonates and 13% after three 4 mg kg-1 doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type-like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic ASS1 mutations studied, including the most common ASS1G390R variant, were corrected with similar or higher efficiencies than Ass1fold. These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.

Open article ↗

2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?

Open article ↗

2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.

Open article ↗

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Drug Discovery Landscape

2 orphan drug designations for Citrullinemia.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
Sodium benzoate	small molecules	EMA	2016-07-14	—	Lucane Pharma SA
Heterologous human adult liver-derived progenitor cells	cell therapies	EMA	2013-07-17	—	Cellaion

Citrullinemia

Citrullinemia

Citrullinemia

Overview

Population

Burden

Therapies

Categories: rare genetic diseases, rare inborn errors of metabolism

Research Papers

2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?

2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.

2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?

2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.

Drug Discovery Landscape

Updated: Aug 25, 2026