RARE DISEASE
Disorder of urea cycle metabolism and ammonia detoxification
Disorder of urea cycle metabolism and ammonia detoxification
Disorder of urea cycle metabolism and ammonia detoxification
Drug discovery
13
drugs
With orphan designations
Overview
Urea cycle disorders (UCDs) are rare genetic defects in enzymes or transporters required to convert ammonia into urea, leading to toxic hyperammonemia. Manifestations range from acute encephalopathy in neonates to chronic neurocognitive and hepatic dysfunction. Lifelong management focuses on ammonia reduction via dietary protein restriction, nitrogen-scavenging medications, and metabolic stabilization. Untreated, hyperammonemia causes irreversible brain damage or death [1][4][8].
Burden
Mortality: 24% in neonatal-onset vs. 11% in late-onset cases [1][8].
Chronic morbidity: Neurocognitive impairment (55%), hepatocellular injury (57%), recurrent hyperammonemic crises [1][3][16].
High healthcare utilization: Frequent monitoring, crisis management, and dietary/lifestyle restrictions [2][11].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
155 drug discovery papers about Disorder of urea cycle metabolism and ammonia detoxification, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
155 drug discovery papers about Disorder of urea cycle metabolism and ammonia detoxification, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-01-05 | Radiation therapy in a ductal carcinoma in situ patient with ornithine transcarbamylase deficiency: a case report.
Ornithine transcarbamylase (OTC) deficiency is a rare urea cycle disorder that impairs ammonia detoxification, increasing the risk of hyperammonemic crises under metabolic stress. While chemotherapy-related risks have been reported, data on the safety of ionizing radiation therapy (RT) in this population are limited. This case describes a 30-year-old woman with late-onset OTC deficiency diagnosed with right-sided ductal carcinoma in situ. She underwent segmental mastectomy followed by adjuvant 3D conformal RT (40 Gy in 15 fractions with a concomitant boost to 48 Gy). Her multidisciplinary care involved preoperative hydration, close nutritional monitoring, and serial ammonia measurements. She completed RT without treatment interruptions or signs of hyperammonemia. This case illustrates that breast RT can be delivered safely in patients with OTC deficiency with a multidisciplinary, preventative approach. To our knowledge, this is the first report describing RT planning and metabolic surveillance in this population.
2025-07-25 | Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions-including dietary modulation, cofactor replacement, and gene therapy-are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer.
2022-10-10 | Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency
Abstract Objective Ornithine transcarbamylase deficiency (OTC‐D) is an X‐linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity‐adjusted classification system based on in vitro residual enzymatic OTC activity. Methods Applying a cell‐based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC‐D (mOTC‐D) as reported in the UCDC and E‐IMD registries. Results Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC‐D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation Residual enzymatic OTC activity reliably predicts the disease severity in mOTC‐D and could thus serve as a tool for severity‐adjusted evaluation of therapeutic strategies and counselling patients and parents.
2022-10-10 | Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice
Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spfash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spfash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy.
2019-09-12 | Robust, Long-Term Culture of Endoderm-Derived Hepatic Organoids for Disease Modeling
Organoid technologies have become a powerful emerging tool to model liver diseases, for drug screening, and for personalized treatments. These applications are, however, limited in their capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we generated and characterized the hepatic organoid (eHEPO) culture system using human induced pluripotent stem cell (iPSC)-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, we modeled citrullinemia type 1, a urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild-type ASS1 gene, which also indicated that this model is amenable to genetic manipulation. Thus, eHEPOs are excellent unlimited cell sources to generate functional hepatic organoids in a fast and efficient manner.
small molecules
2026-03-01 | 4CPS-063 Late-onset ornithine transcarbamylase deficiency in a paediatric patient: successful management of a metabolic emergency –a case report
Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder that impairs ammonia detoxification, leading to hyperammonaemia, acute liver dysfunction and potentially life-threatening metabolic encephalopathy. Late-onset forms are often misdiagnosed due to non-specific symptoms, delaying treatment. Early diagnosis and pharmacological intervention are crucial to prevent neurological damage or death. To describe the clinical management of a paediatric patient with late-onset OTCD and highlight the therapeutic role of hospital pharmacists in metabolic decompensations. An 11-year-old male was admitted with vomiting, somnolence, and hyperammonaemia (480 µmol/L), alongside hyperlactacidaemia and hepatic dysfunction, with no relevant family history. On admission, he received hydroxocobalamin, biotin, and cerebral oedema management. Continuous veno-venous haemodiafiltration (CVVHDF) was initiated as an extracorporeal technique to achieve a rapid decrease in ammonia levels. Initial pharmacological therapy included sodium benzoate with sodium phenylacetate (alternated with phenylbutyrate), arginine, carnitine, carglumic acid, L-citrulline, paromomycin, and lactulose. Phenylbutyrate was discontinued due to nasogastric tube obstruction and replaced by sodium benzoate with phenylacetate. The hospital pharmacist adjusted and validated parenteral nutrition with protein restriction, compensated by higher carbohydrate intake to promote anabolism and protein synthesis, and provided basal fat to meet energy needs without overloading metabolism or causing acidosis/stress. CVVHDF rapidly reduced ammonia levels with clinical improvement, and pharmacological therapy helped maintain stable ammonia levels. Although genetic results were not yet available, diagnosis was supported by metabolic findings: marked elevation of urinary orotic acid, elevated glutamine, and decreased citrulline, leading to clinical suspicion of OTCD. Genetic testing later confirmed a hemizygote OTC gene mutation. Maternal testing revealed mutation G4A1V3, despite an uncomplicated pregnancy and delivery. Therapy was adjusted for outpatient management, maintaining phenylbutyrate, citrulline, and strict protein control. Regular monitoring of ammonia, amino acids, and liver enzymes was implemented. The patient remained stable, with no further metabolic decompensations and good adherence to treatment. OTCD can occur beyond the neonatal period with subtle or non-specific symptoms, delaying diagnosis. Early multidisciplinary intervention, including metabolic specialists and hospital pharmacists–who play a key role in the rapid initiation and adjustment of therapy and parenteral nutrition–is essential to secure favourable outcomes and avoid irreversible neurological damage. No conflict of interest
2026-01-31 | Impact of glycerol phenylbutyrate on biochemistry and outcomes in paediatric patients with urea cycle disorders: a multicentre case series from Saudi Arabia.
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited conditions that disrupt ammonia detoxification, leading to hyperammonaemia and potential neurological harm. In Saudi Arabia, high consanguinity rates increase UCD birth incidence. Traditional nitrogen scavengers - sodium benzoate (NaBz) and sodium phenylbutyrate (NaPBA) - are limited by poor palatability, high sodium burden, and large dosing volumes. Glycerol phenylbutyrate (GPB) offers improved pharmacological and practical properties, including slow intestinal hydrolysis, reduced dosing frequency, absence of sodium and propylene glycol, and better tolerability. This study assessed real-world outcomes of GPB in a paediatric UCD population. METHODS: We conducted a retrospective analysis of 37 paediatric patients from three Saudi hospitals. Pre- and post-GPB data were compared for plasma ammonia, hyperammonaemic crises (HACs), HAC-related hospitalisations and durations, growth z-scores, and adverse events. A caregiver survey (n = 15) captured treatment experiences and preferences. RESULTS: GPB significantly reduced routine plasma ammonia levels by 21% (median 72 to 57 µmol/L, p = 0.011), with the proportion of patients above the local reference range dropping from 74% to 42%. Annualised HAC rates fell by 55% (2.2 to 1.0/year), HAC-related hospitalisations by 27% (1.1 to 0.8/year), and annualised HAC-related hospital stays by 24% (3.3 to 2.5 days/year), though these did not reach statistical significance. Growth z-scores showed small, non-significant upward trends (+ 0.2 for height and weight). GPB was well tolerated, with no treatment-related adverse events. All survey respondents (15/15) preferred GPB over NaBz and NaPBA. 100% rated GPB equal or superior in controlling ammonia levels and being easier to adhere to, and 85% found it equal or better for palatability. CONCLUSIONS: GPB improved biochemical control and showed consistent trends toward reduced clinical burden in a real-world paediatric UCD cohort. Although some outcomes were not statistically significant, likely due to sample size and inter-individual variability, the magnitude and direction of change - supported by unanimous patient preference - highlight GPB’s advantages. These findings support its use as a first-line or step-up therapy in paediatric UCDs.
2025-11-09 | Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway.
Ammonia (NH3), a core toxic byproduct of amino acid metabolism in the body, poses a severe threat to cell survival when its homeostasis is disrupted. Maintaining low systemic ammonia concentrations is crucial. Under physiological conditions, the kidneys regulate ammonia metabolism precisely through glutaminase 1 (GLS1)-mediated ammonia production and the urea cycle, ensuring efficient detoxification. Hyperuricemic nephropathy (HN), a common complication of hyperuricemia, impairs patient health significantly. However, whether and how ammonia toxicity triggers cell death under this pathological condition remains unclear. Here, we demonstrated that HN promoted ammonia-dependent cell death by blocking autophagic flux, revealing a novel mechanism of HN injury. In vivo and in vitro models were used to evaluate the lysosome mitochondria damage and autophagic flux arrest mechanism caused by ammonia metabolism disorder through ultrastructural analysis, fluorescent probe and autophagic flux detection, and the causal association was verified by ammonia scavengers and gene intervention. Mechanistically, chronic hyperuricemic stress accelerates renal glutaminolysis to mitigate injury and generate sufficient ATP, resulting in excessive mitochondrial ammonia production. The ammonia accumulated undergoes RHCG-dependent transmembrane transport, causing lysosomal alkalinization and dysfunction, further resulting in mitochondrial ammonia retention and swelling. This ultimately inhibited autolysosomal disassembly, which impaired the clearance of damaged mitochondria and constitutes autophagic flux blockade, consequently driving cell death. These findings identified a distinct form of cell death in HN, mechanistically divergent from previously known mechanisms such as apoptosis or pyroptosis. It redefined HN pathogenesis through a metabolic lens, identifying druggable targets to mitigate renal damage in hyperuricemic patients.
2025-10-30 | Nitrogen Scavengers: History, Clinical Considerations and Future Prospects.
Nitrogen scavengers play a critical role in treating acute and chronic hyperammonemia, especially in urea cycle disorders (UCDs), where impaired ammonia detoxification leads to toxic nitrogen accumulation. These agents complement low-protein diets and urea cycle intermediates. Sodium benzoate and sodium phenylacetate are the main scavengers, conjugating with glycine and glutamine to form hippurate and phenylacetylglutamine, which are excreted in urine. This therapeutic approach, introduced in the 1980s, was based on early findings linking benzoate to reduced urea excretion. Nitrogen scavengers are also used in secondary hyperammonemia from organic acidemias and fatty acid oxidation disorders, though they may become increasingly ineffective in progressing liver failure due to their reliance on hepatocyte function. To improve tolerability, phenylbutyrate was developed as an oral alternative to phenylacetate and is available in sodium-bound and prodrug forms, but issues with taste and side effects persist. While effective, current treatments target nitrogenous waste products rather than ammonia directly, offering an avenue of future drug development for UCDs. This review discusses the chemical properties, clinical use, and limitations of nitrogen scavengers, hereby focusing on phenylacetate and related substances, and highlights the need for improved therapies, including approaches that directly target ammonia removal. For the benefit of readers already experienced in nitrogen scavengers for UCDs, we also include considerations concerning the use of these drugs in animal experiments and a viewpoint on ornithine phenylacetate as a related substance.
2025-10-01 | S5598 A Case Series on the Intersection of Cirrhosis, Bariatric Surgery, and Urea Cycle Dysfunction
Introduction: Urea cycle disorders (UCDs) are rare inborn errors of metabolism that impair ammonia detoxification, causing hyperammonemia (HA), leading to severe neurological damage and death if untreated. The urea cycle comprises 5 key enzymes, and defects in any can result in varying severity, from neonatal to adult onset. Diagnosis relies on biochemical markers, genetic testing, and ammonia levels. Treatment focuses on dietary management, nitrogen-scavenging drugs, and, in rare cases, transplantation. We present 4 patients with prior Roux-en-Y gastric bypass (RYGB) admitted for symptomatic HA. Case Description/Methods: Four female patients' status post RYGB presented with encephalopathy and were found to have elevated ammonia levels (112-256 umol/L) via venous blood samples. They were screened for underlying UCDs with plasma quantitative amino acid (AA) levels, molecular genetic testing, and urinary orotic acid levels. Infectious and other metabolic etiologies of encephalopathy were ruled out. Two patients had a high glutamine-to-citrulline ratio, suggesting a proximal urea cycle deficit, whereas the other 2 patients had essential amino acid (AA) deficiencies. Of the 2 patients with AA deficiencies, the one with cirrhosis improved with nitrogen-scavenging drugs (lactulose and rifaximin). Marked AA deficiencies impair ammonia detoxification despite preserved synthetic hepatic function. The patients improved with supportive therapy and nutritional repletion. The case of the patient with a history of recurrent HA encephalopathy and a negative genetic workup emphasizes the diagnostic challenge of adult-onset or partial UCD. However, the elevated glutamine-to-citrulline ratio pointed to a proximal UCD. The patient had clinical improvement following continuous renal replacement therapy. Discussion: These cases highlight the complex interplay of liver dysfunction, altered GI anatomy, and UCD in the pathogenesis of HA in adults. These pathophysiologic processes independently contribute to the development of HA encephalopathy. The presence of RYGB reflects the existence of post-bariatric surgery hyperammonemia as a distinct clinical entity. The alteration of GI anatomy and microbiome increases bacterial urease activity and promotes protein malabsorption, contributing to increased ammonia production and reduced clearance. Evaluation of UCDs in cirrhotic and non-cirrhotic patients with RYGB can be considered as part of the evaluation of hepatic encephalopathy in this population.
oligonucleotides
2024-01-10 | mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3- 18 F-fluoropropyl)- l -glutamate ([ 18 F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [ 18 F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.
2019-09-09 | Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency
Arginase deficiency is caused by biallelic mutations in arginase 1 (ARG1), the final step of the urea cycle, and results biochemically in hyperargininemia and the presence of guanidino compounds, while it is clinically notable for developmental delays, spastic diplegia, psychomotor function loss, and (uncommonly) death. There is currently no completely effective medical treatment available. While preclinical strategies have been demonstrated, disadvantages with viral-based episomal-expressing gene therapy vectors include the risk of insertional mutagenesis and limited efficacy due to hepatocellular division. Recent advances in messenger RNA (mRNA) codon optimization, synthesis, and encapsulation within biodegradable liver-targeted lipid nanoparticles (LNPs) have potentially enabled a new generation of safer, albeit temporary, treatments to restore liver metabolic function in patients with urea cycle disorders, including ARG1 deficiency. In this study, we applied such technologies to successfully treat an ARG1-deficient murine model. Mice were administered LNPs encapsulating human codon-optimized ARG1 mRNA every 3 d. Mice demonstrated 100% survival with no signs of hyperammonemia or weight loss to beyond 11 wk, compared with controls that perished by day 22. Plasma ammonia, arginine, and glutamine demonstrated good control without elevation of guanidinoacetic acid, a guanidino compound. Evidence of urea cycle activity restoration was demonstrated by the ability to fully metabolize an ammonium challenge and by achieving near-normal ureagenesis; liver arginase activity achieved 54% of wild type. Biochemical and microscopic data showed no evidence of hepatotoxicity. These results suggest that delivery of ARG1 mRNA by liver-targeted nanoparticles may be a viable gene-based therapeutic for the treatment of arginase deficiency.
2019-02-22 | Messenger RNA therapy for rare genetic metabolic diseases
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
2014-09-07 | Computational regulatory model for detoxification of ammonia from urea cycle in liver
A nondeterministic finite automaton was designed to monitor enzymatic regulation and detoxification of excess ammonia in the urea cycle and its disorders. The designed machine is used for the diagnosis of deficiency and for regulating the expression of any of the enzymes involved with acceptance and rejection states in the urea cycle. The urea cycle is the metabolism of excess nitrogen produced by the breakdown of protein and other nitrogen-containing molecules in liver. Disorder in the urea cycle may lead to the accumulation of toxic ammonia in the blood, which leads to hyperammonemia. The elevation of plasma ammonia concentration may ultimately lead to cerebral edema in infants and severe brain damage due to the toxicity of ammonia. The diagnosis of urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data. In this study, a new therapeutic approach for urea cycle disorders is developed based on a computational model. It is used to observe the normal process of the cycle through the state of acceptance. The state of rejection denotes a deficiency in the respective enzymatic activity. Subsequently, it assists in the creation of targeted treatment for brain damage and related enzymatic deficiency disorders.
gene therapies
2026-01-05 | Radiation therapy in a ductal carcinoma in situ patient with ornithine transcarbamylase deficiency: a case report.
Ornithine transcarbamylase (OTC) deficiency is a rare urea cycle disorder that impairs ammonia detoxification, increasing the risk of hyperammonemic crises under metabolic stress. While chemotherapy-related risks have been reported, data on the safety of ionizing radiation therapy (RT) in this population are limited. This case describes a 30-year-old woman with late-onset OTC deficiency diagnosed with right-sided ductal carcinoma in situ. She underwent segmental mastectomy followed by adjuvant 3D conformal RT (40 Gy in 15 fractions with a concomitant boost to 48 Gy). Her multidisciplinary care involved preoperative hydration, close nutritional monitoring, and serial ammonia measurements. She completed RT without treatment interruptions or signs of hyperammonemia. This case illustrates that breast RT can be delivered safely in patients with OTC deficiency with a multidisciplinary, preventative approach. To our knowledge, this is the first report describing RT planning and metabolic surveillance in this population.
2025-07-25 | Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions-including dietary modulation, cofactor replacement, and gene therapy-are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer.
2022-10-10 | Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency
Abstract Objective Ornithine transcarbamylase deficiency (OTC‐D) is an X‐linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity‐adjusted classification system based on in vitro residual enzymatic OTC activity. Methods Applying a cell‐based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC‐D (mOTC‐D) as reported in the UCDC and E‐IMD registries. Results Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC‐D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation Residual enzymatic OTC activity reliably predicts the disease severity in mOTC‐D and could thus serve as a tool for severity‐adjusted evaluation of therapeutic strategies and counselling patients and parents.
2022-10-10 | Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice
Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spfash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spfash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy.
2019-09-12 | Robust, Long-Term Culture of Endoderm-Derived Hepatic Organoids for Disease Modeling
Organoid technologies have become a powerful emerging tool to model liver diseases, for drug screening, and for personalized treatments. These applications are, however, limited in their capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we generated and characterized the hepatic organoid (eHEPO) culture system using human induced pluripotent stem cell (iPSC)-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, we modeled citrullinemia type 1, a urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild-type ASS1 gene, which also indicated that this model is amenable to genetic manipulation. Thus, eHEPOs are excellent unlimited cell sources to generate functional hepatic organoids in a fast and efficient manner.
small molecules
2026-03-01 | 4CPS-063 Late-onset ornithine transcarbamylase deficiency in a paediatric patient: successful management of a metabolic emergency –a case report
Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder that impairs ammonia detoxification, leading to hyperammonaemia, acute liver dysfunction and potentially life-threatening metabolic encephalopathy. Late-onset forms are often misdiagnosed due to non-specific symptoms, delaying treatment. Early diagnosis and pharmacological intervention are crucial to prevent neurological damage or death. To describe the clinical management of a paediatric patient with late-onset OTCD and highlight the therapeutic role of hospital pharmacists in metabolic decompensations. An 11-year-old male was admitted with vomiting, somnolence, and hyperammonaemia (480 µmol/L), alongside hyperlactacidaemia and hepatic dysfunction, with no relevant family history. On admission, he received hydroxocobalamin, biotin, and cerebral oedema management. Continuous veno-venous haemodiafiltration (CVVHDF) was initiated as an extracorporeal technique to achieve a rapid decrease in ammonia levels. Initial pharmacological therapy included sodium benzoate with sodium phenylacetate (alternated with phenylbutyrate), arginine, carnitine, carglumic acid, L-citrulline, paromomycin, and lactulose. Phenylbutyrate was discontinued due to nasogastric tube obstruction and replaced by sodium benzoate with phenylacetate. The hospital pharmacist adjusted and validated parenteral nutrition with protein restriction, compensated by higher carbohydrate intake to promote anabolism and protein synthesis, and provided basal fat to meet energy needs without overloading metabolism or causing acidosis/stress. CVVHDF rapidly reduced ammonia levels with clinical improvement, and pharmacological therapy helped maintain stable ammonia levels. Although genetic results were not yet available, diagnosis was supported by metabolic findings: marked elevation of urinary orotic acid, elevated glutamine, and decreased citrulline, leading to clinical suspicion of OTCD. Genetic testing later confirmed a hemizygote OTC gene mutation. Maternal testing revealed mutation G4A1V3, despite an uncomplicated pregnancy and delivery. Therapy was adjusted for outpatient management, maintaining phenylbutyrate, citrulline, and strict protein control. Regular monitoring of ammonia, amino acids, and liver enzymes was implemented. The patient remained stable, with no further metabolic decompensations and good adherence to treatment. OTCD can occur beyond the neonatal period with subtle or non-specific symptoms, delaying diagnosis. Early multidisciplinary intervention, including metabolic specialists and hospital pharmacists–who play a key role in the rapid initiation and adjustment of therapy and parenteral nutrition–is essential to secure favourable outcomes and avoid irreversible neurological damage. No conflict of interest
2026-01-31 | Impact of glycerol phenylbutyrate on biochemistry and outcomes in paediatric patients with urea cycle disorders: a multicentre case series from Saudi Arabia.
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited conditions that disrupt ammonia detoxification, leading to hyperammonaemia and potential neurological harm. In Saudi Arabia, high consanguinity rates increase UCD birth incidence. Traditional nitrogen scavengers - sodium benzoate (NaBz) and sodium phenylbutyrate (NaPBA) - are limited by poor palatability, high sodium burden, and large dosing volumes. Glycerol phenylbutyrate (GPB) offers improved pharmacological and practical properties, including slow intestinal hydrolysis, reduced dosing frequency, absence of sodium and propylene glycol, and better tolerability. This study assessed real-world outcomes of GPB in a paediatric UCD population. METHODS: We conducted a retrospective analysis of 37 paediatric patients from three Saudi hospitals. Pre- and post-GPB data were compared for plasma ammonia, hyperammonaemic crises (HACs), HAC-related hospitalisations and durations, growth z-scores, and adverse events. A caregiver survey (n = 15) captured treatment experiences and preferences. RESULTS: GPB significantly reduced routine plasma ammonia levels by 21% (median 72 to 57 µmol/L, p = 0.011), with the proportion of patients above the local reference range dropping from 74% to 42%. Annualised HAC rates fell by 55% (2.2 to 1.0/year), HAC-related hospitalisations by 27% (1.1 to 0.8/year), and annualised HAC-related hospital stays by 24% (3.3 to 2.5 days/year), though these did not reach statistical significance. Growth z-scores showed small, non-significant upward trends (+ 0.2 for height and weight). GPB was well tolerated, with no treatment-related adverse events. All survey respondents (15/15) preferred GPB over NaBz and NaPBA. 100% rated GPB equal or superior in controlling ammonia levels and being easier to adhere to, and 85% found it equal or better for palatability. CONCLUSIONS: GPB improved biochemical control and showed consistent trends toward reduced clinical burden in a real-world paediatric UCD cohort. Although some outcomes were not statistically significant, likely due to sample size and inter-individual variability, the magnitude and direction of change - supported by unanimous patient preference - highlight GPB’s advantages. These findings support its use as a first-line or step-up therapy in paediatric UCDs.
2025-11-09 | Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway.
Ammonia (NH3), a core toxic byproduct of amino acid metabolism in the body, poses a severe threat to cell survival when its homeostasis is disrupted. Maintaining low systemic ammonia concentrations is crucial. Under physiological conditions, the kidneys regulate ammonia metabolism precisely through glutaminase 1 (GLS1)-mediated ammonia production and the urea cycle, ensuring efficient detoxification. Hyperuricemic nephropathy (HN), a common complication of hyperuricemia, impairs patient health significantly. However, whether and how ammonia toxicity triggers cell death under this pathological condition remains unclear. Here, we demonstrated that HN promoted ammonia-dependent cell death by blocking autophagic flux, revealing a novel mechanism of HN injury. In vivo and in vitro models were used to evaluate the lysosome mitochondria damage and autophagic flux arrest mechanism caused by ammonia metabolism disorder through ultrastructural analysis, fluorescent probe and autophagic flux detection, and the causal association was verified by ammonia scavengers and gene intervention. Mechanistically, chronic hyperuricemic stress accelerates renal glutaminolysis to mitigate injury and generate sufficient ATP, resulting in excessive mitochondrial ammonia production. The ammonia accumulated undergoes RHCG-dependent transmembrane transport, causing lysosomal alkalinization and dysfunction, further resulting in mitochondrial ammonia retention and swelling. This ultimately inhibited autolysosomal disassembly, which impaired the clearance of damaged mitochondria and constitutes autophagic flux blockade, consequently driving cell death. These findings identified a distinct form of cell death in HN, mechanistically divergent from previously known mechanisms such as apoptosis or pyroptosis. It redefined HN pathogenesis through a metabolic lens, identifying druggable targets to mitigate renal damage in hyperuricemic patients.
2025-10-30 | Nitrogen Scavengers: History, Clinical Considerations and Future Prospects.
Nitrogen scavengers play a critical role in treating acute and chronic hyperammonemia, especially in urea cycle disorders (UCDs), where impaired ammonia detoxification leads to toxic nitrogen accumulation. These agents complement low-protein diets and urea cycle intermediates. Sodium benzoate and sodium phenylacetate are the main scavengers, conjugating with glycine and glutamine to form hippurate and phenylacetylglutamine, which are excreted in urine. This therapeutic approach, introduced in the 1980s, was based on early findings linking benzoate to reduced urea excretion. Nitrogen scavengers are also used in secondary hyperammonemia from organic acidemias and fatty acid oxidation disorders, though they may become increasingly ineffective in progressing liver failure due to their reliance on hepatocyte function. To improve tolerability, phenylbutyrate was developed as an oral alternative to phenylacetate and is available in sodium-bound and prodrug forms, but issues with taste and side effects persist. While effective, current treatments target nitrogenous waste products rather than ammonia directly, offering an avenue of future drug development for UCDs. This review discusses the chemical properties, clinical use, and limitations of nitrogen scavengers, hereby focusing on phenylacetate and related substances, and highlights the need for improved therapies, including approaches that directly target ammonia removal. For the benefit of readers already experienced in nitrogen scavengers for UCDs, we also include considerations concerning the use of these drugs in animal experiments and a viewpoint on ornithine phenylacetate as a related substance.
2025-10-01 | S5598 A Case Series on the Intersection of Cirrhosis, Bariatric Surgery, and Urea Cycle Dysfunction
Introduction: Urea cycle disorders (UCDs) are rare inborn errors of metabolism that impair ammonia detoxification, causing hyperammonemia (HA), leading to severe neurological damage and death if untreated. The urea cycle comprises 5 key enzymes, and defects in any can result in varying severity, from neonatal to adult onset. Diagnosis relies on biochemical markers, genetic testing, and ammonia levels. Treatment focuses on dietary management, nitrogen-scavenging drugs, and, in rare cases, transplantation. We present 4 patients with prior Roux-en-Y gastric bypass (RYGB) admitted for symptomatic HA. Case Description/Methods: Four female patients' status post RYGB presented with encephalopathy and were found to have elevated ammonia levels (112-256 umol/L) via venous blood samples. They were screened for underlying UCDs with plasma quantitative amino acid (AA) levels, molecular genetic testing, and urinary orotic acid levels. Infectious and other metabolic etiologies of encephalopathy were ruled out. Two patients had a high glutamine-to-citrulline ratio, suggesting a proximal urea cycle deficit, whereas the other 2 patients had essential amino acid (AA) deficiencies. Of the 2 patients with AA deficiencies, the one with cirrhosis improved with nitrogen-scavenging drugs (lactulose and rifaximin). Marked AA deficiencies impair ammonia detoxification despite preserved synthetic hepatic function. The patients improved with supportive therapy and nutritional repletion. The case of the patient with a history of recurrent HA encephalopathy and a negative genetic workup emphasizes the diagnostic challenge of adult-onset or partial UCD. However, the elevated glutamine-to-citrulline ratio pointed to a proximal UCD. The patient had clinical improvement following continuous renal replacement therapy. Discussion: These cases highlight the complex interplay of liver dysfunction, altered GI anatomy, and UCD in the pathogenesis of HA in adults. These pathophysiologic processes independently contribute to the development of HA encephalopathy. The presence of RYGB reflects the existence of post-bariatric surgery hyperammonemia as a distinct clinical entity. The alteration of GI anatomy and microbiome increases bacterial urease activity and promotes protein malabsorption, contributing to increased ammonia production and reduced clearance. Evaluation of UCDs in cirrhotic and non-cirrhotic patients with RYGB can be considered as part of the evaluation of hepatic encephalopathy in this population.
oligonucleotides
2024-01-10 | mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3- 18 F-fluoropropyl)- l -glutamate ([ 18 F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [ 18 F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.
2019-09-09 | Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency
Arginase deficiency is caused by biallelic mutations in arginase 1 (ARG1), the final step of the urea cycle, and results biochemically in hyperargininemia and the presence of guanidino compounds, while it is clinically notable for developmental delays, spastic diplegia, psychomotor function loss, and (uncommonly) death. There is currently no completely effective medical treatment available. While preclinical strategies have been demonstrated, disadvantages with viral-based episomal-expressing gene therapy vectors include the risk of insertional mutagenesis and limited efficacy due to hepatocellular division. Recent advances in messenger RNA (mRNA) codon optimization, synthesis, and encapsulation within biodegradable liver-targeted lipid nanoparticles (LNPs) have potentially enabled a new generation of safer, albeit temporary, treatments to restore liver metabolic function in patients with urea cycle disorders, including ARG1 deficiency. In this study, we applied such technologies to successfully treat an ARG1-deficient murine model. Mice were administered LNPs encapsulating human codon-optimized ARG1 mRNA every 3 d. Mice demonstrated 100% survival with no signs of hyperammonemia or weight loss to beyond 11 wk, compared with controls that perished by day 22. Plasma ammonia, arginine, and glutamine demonstrated good control without elevation of guanidinoacetic acid, a guanidino compound. Evidence of urea cycle activity restoration was demonstrated by the ability to fully metabolize an ammonium challenge and by achieving near-normal ureagenesis; liver arginase activity achieved 54% of wild type. Biochemical and microscopic data showed no evidence of hepatotoxicity. These results suggest that delivery of ARG1 mRNA by liver-targeted nanoparticles may be a viable gene-based therapeutic for the treatment of arginase deficiency.
2019-02-22 | Messenger RNA therapy for rare genetic metabolic diseases
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
2014-09-07 | Computational regulatory model for detoxification of ammonia from urea cycle in liver
A nondeterministic finite automaton was designed to monitor enzymatic regulation and detoxification of excess ammonia in the urea cycle and its disorders. The designed machine is used for the diagnosis of deficiency and for regulating the expression of any of the enzymes involved with acceptance and rejection states in the urea cycle. The urea cycle is the metabolism of excess nitrogen produced by the breakdown of protein and other nitrogen-containing molecules in liver. Disorder in the urea cycle may lead to the accumulation of toxic ammonia in the blood, which leads to hyperammonemia. The elevation of plasma ammonia concentration may ultimately lead to cerebral edema in infants and severe brain damage due to the toxicity of ammonia. The diagnosis of urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data. In this study, a new therapeutic approach for urea cycle disorders is developed based on a computational model. It is used to observe the normal process of the cycle through the state of acceptance. The state of rejection denotes a deficiency in the respective enzymatic activity. Subsequently, it assists in the creation of targeted treatment for brain damage and related enzymatic deficiency disorders.
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Drug Discovery Landscape
13 orphan drug designations for Disorder of urea cycle metabolism and ammonia detoxification, including 4 approved therapies.
13 orphan drug designations for Disorder of urea cycle metabolism and ammonia detoxification, including 4 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Single stranded RNA editing oligonucleotide against GLUL mRNA | oligonucleotides | EMA | 2026-07-24 | — | Parexel International (IRL) Limited |
recombinant human glutamine synthetase | proteins | FDA | 2026-03-12 | — | Thoeris GmbH |
single strand 20-mer antisense oligonucleotide (ASO) targeting a CPS1 regulatory RNA with a triantennary N-acetylgalactosamine (GalNAc) ligand attached at the 3' end | oligonucleotides | FDA | 2024-09-11 | — | CAMP4 Therapeutics Corporation |
Allogeneic adult liver-derived stem cells | cell therapies | EMA | 2022-08-10 | — | Unicyte S.R.L. |
spherical carbon absorbent | small molecules | FDA | 2020-05-05 | — | CT Development One, LLC |
live E. coli Nissle bacterium modified to assimilate ammonia | cell therapies | FDA | 2016-08-22 | — | Synlogic, Inc. |
sodium phenylbutyrate [Pheburane] | small molecules | FDA | 2013-06-06 | 2022-06-17 | Medunik Canada Inc |
heterologous human adult liver derived progenitor cells (HHALPC) | cell therapies | FDA | 2012-01-13 | — | Promethera Biosciences |
human heterologous liver cells | cell therapies | FDA | 2011-02-14 | — | Promethera Biosciences |
sodium phenylbutyrate | small molecules | FDA | 2010-01-19 | — | Navinta LLC |
glycerol phenylbutyrate [RAVICTI] | small molecules | FDA | 2009-04-27 | 2013-02-01 | Horizon Pharma USA, INc. |
benzoate/phenylacetate [Ammonul] | small molecules | FDA | 1993-11-22 | 2005-02-17 | Medicis Pharmaceutical Corp. |
sodium phenylbutyrate [Buphenyl] | small molecules | FDA | 1993-11-22 | 1996-04-30 | Medicis Pharmaceutical Corp. |
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