RARE DISEASE
Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency
Synonyms: OCT deficiency, OTC deficiency, Ornithine carbamoyltransferase deficiency
Synonyms: OCT deficiency, OTC deficiency, Ornithine carbamoyltransferase deficiency
Synonyms: OCT deficiency, OTC deficiency, Ornithine carbamoyltransferase deficiency
Drug discovery
22
drugs
With orphan designations
Overview
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder caused by mutations in the OTC gene, leading to impaired ammonia detoxification. Accumulated ammonia causes neurotoxicity, presenting as lethargy, vomiting, seizures, or coma, with severity ranging from neonatal hyperammonemic crisis to late-onset episodic encephalopathy. Diagnosis involves elevated plasma ammonia, low citrulline, genetic testing, and urine orotic acid analysis [1][6][9]. Management combines protein restriction, nitrogen scavengers (e.g., sodium phenylbutyrate), arginine/citrulline supplementation, and emergent hemodialysis for acute crises [5][10]. Liver transplantation remains the only curative option [3][15].
Population
Prevalence: Estimated 1:14,000–1:77,000 [1][8][9]; neonatal-onset predominantly affects males, while 10–40% of heterozygous females develop symptoms due to skewed X-inactivation [6][16].
Mortality: ~43–50% in untreated neonatal-onset cases [1][16]; 11-year survival rates: 35% for early-onset vs. 87% for late-onset hyperammonemia [4].
Burden
Neurological: Intellectual disability, developmental delays, or metabolic stroke in 20–50% of survivors [1][7][16].
Systemic: Chronic liver dysfunction, coagulopathy, and risk of acute liver failure during decompensation [6][15].
Quality of life: Lifelong dietary/medication adherence, recurrent hospitalizations, and high economic burden [4][14].
Therapies
Acute: Hemodialysis (for氨 >500 µmol/L), IV sodium benzoate/phenylacetate, and arginine [5][10].
Chronic: Protein-restricted diet, oral scavengers (glycerol phenylbutyrate), citrulline/arginine supplementation [5][12].
Curative: Liver transplantation (prevents recurrent crises but requires lifelong immunosuppression) [3][15].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
370 drug discovery papers about Ornithine transcarbamylase deficiency, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
370 drug discovery papers about Ornithine transcarbamylase deficiency, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-25 | Unilateral cerebral injury mimicking hemiconvulsion-hemiplegia-epilepsy syndrome in a boy with newly diagnosed infantile-onset ornithine transcarbamylase deficiency: A case report and literature review
Background Ornithine transcarbamylase deficiency, the most common urea cycle disorder, typically presents with neurological symptoms caused by hyperammonemia. Although brain injuries are typically diffuse, unilateral lesions have been reported. Hemiconvulsion–hemiplegia–epilepsy syndrome is a neurological disorder occurring in infancy or early childhood, characterized by prolonged unilateral seizures, subsequent cerebral hemiatrophy, and epilepsy. These conditions may have overlapping clinical features. Case A 4-month-old boy presented with fever and asymmetric seizures during an adenovirus infection. Blood tests revealed hyperammonemia, elevated liver enzyme levels, coagulopathy, and lactic acidosis. Brain MRI showed diffuse cortical edema in the left hemisphere with abnormal EEG discharges. Hemiconvulsion–hemiplegia–epilepsy syndrome was provisionally suspected, and steroid pulse therapy and supportive treatment were initiated. Due to fluctuating blood ammonia levels, arginine was administered. Further metabolic evaluation demonstrated increased urinary orotic acid excretion, low plasma citrulline and arginine levels, and elevated plasma glutamine. A family history of neonatal-onset disease supported the clinical diagnosis. The patient was treated with a protein-restricted diet, citrulline, arginine, and sodium phenylbutyrate. At 1 year and 2 months of age, he showed mild right upper limb weakness without epilepsy. A review of the literature identified seven cases of urea cycle disorders with unilateral brain lesions, six involving ornithine transcarbamylase deficiency. Conclusion In ornithine transcarbamylase deficiency, acute infection may trigger unilateral cerebral injury, mimicking the hemiconvulsion–hemiplegia–epilepsy syndrome. Early metabolic intervention may help mitigate hyperammonemia and reduce the risk of neurological injury, highlighting the importance of considering metabolic disorders in infants with unilateral brain injury.
2026-04-01 | Ornithine Transcarbamoylase Deficiency
Abstract This chapter provides a picture and clinical details of Ornithine Transcarbamoylase Deficiency, an XLID condition caused by chronic or intermittent hyperammonemia resulting from deficiency of ornithine transcarbamoylase. The OTC gene is located in Xp11.4. Intrauterine growth is normal. Those who experience hyperammonemic encephalopathy early in infancy have subsequent growth failure, including microcephaly. Delay of developmental milestones may likewise be related to early hyperammonemia. Neonatal hyperammonemia causes intellectual disability. Later onset hyperammonemic encephalopathy results in some cognitive impairment. Agitation or irritability followed by disorientation and lethargy may be associated with hyperammonemia. Cerebral edema and subsequent compromise of cerebral perfusion lead to a variety of neurological findings, including changes in sensorium, ataxia, hemiparesis, slurred speech, seizures, amblyopia, and coma.
2026-03-17 | Rifaximin Ameliorates Urea Cycle Disorder in a Murine Model of humanOrnithine Transcarbamylase Deficiency
Introduction: Urea cycle disorder (UCD) is one of the major groups of inherited rare diseases that cause hyperammonaemia requiring early detection and appropriate clinical management to avoid neurological damage and death. Besides protein intake reduction, ammonia scavenger pharmacological therapy is used to prevent or treat acute hyperammonaemia episodes and related damage. Among recent treatments, the Ravicti prescription has been shown to reduce plasma ammonia, hyperammonaemia episodes, and hospital admissions. Another product, potentially able to counteract hyperammonemia in urea cycle disorder via modulation of the intestinal microbiota, is rifaximin, also approved by the FDA for prevention and treatment of hepatic encephalopathy. This study aims to investigate possible pharmacological interactions between Ravicti and rifaximin in the translational murine model of UCD induced by ornithine transcarbamylase (OTC) deficiency Methods: We characterized B6EiC3Sn a/A-Otcspf-ash/J (disease model, which is OTC-deficient, hereafter referred to as Otcspf-ash mouse/mice) as a valid UCD murine model to evaluate the tolerability and efficacy of rifaximin with and without ammonia scavenger Ravicti. 15-week old Otcspf-ash mice expressing the variant (c.386G>A, p.Arg129His) in the OTC enzyme of liver, also found in patients, were given by oral route for 2 weeks rifaximin and 4 weeks Ravicti or the combination. After sacrifice, liver, small intestine, colon, hippocampus, and brain motor cortex were collected for whole-mount immunostaining. Results: Analysis of OTC-deficient mice showed increased plasma ammonia, liver damage, and colonic inflammation, as well as brain alterations in terms of astrocyte swelling, microglia activation, and neuronal apoptosis, in addition to abnormal mouse behavior with impaired motor coordination. Administration of rifaximin and Ravicti alone was shown to improve mice behavior and significantly hinder hepatic impairment, intestinal inflammation, and neuronal dysfunction. The combination of the two drugs showed no additional improvement over their individual efficacy. Discussion: Interestingly, rifaximin enhanced bacteria with protective functions towards the host, SCFAs producers, or involved in ureagenesis or stimulation of FX receptors. showing a consistent ability to reduce bacteria able to lyse urea or positively correlated to urea cycle or bile salts pathway disorders Conclusion: Otcspf-ash was a good model to study UCD and investigate novel therapeutic strategies. Rifaximin seems promising regarding its capability to protect patients with UCD and warrants further investigation
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25–30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
2026-03-06 | Clinical heterogeneity, genotype, and neurological outcomes in six Palestinian patients with ornithine transcarbamylase deficiency.
Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. This X-linked condition, mapped to Xp21.1, results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes a critical step in ureagenesis. Disease severity ranges from a complete enzymatic block, presenting as neonatal hyperammonemic coma with high mortality, to partial deficiencies that can cause life-threatening hyperammonemia at any age. This report describes six patients diagnosed with OTCD, with ages ranging from 8 days to 17 years at the time of diagnosis. The onset of symptoms occurred at different ages, from just 2 days to 17 years. Two male patients experienced severe neonatal courses and, unfortunately, died from hyperammonemic coma shortly after birth. In contrast, four other patients (three males and one female) presented with symptoms later in life. Molecular analysis identified pathogenic variants in the OTC gene, which included four missense variants and one in-frame deletion. Notably, a recurrent variant was found in two individuals from unrelated families. The cohort comprised six patients with two distinct clinical presentations. Two hemizygous males presented neonatally and progressed to severe hyperammonemic coma within the first days of life. The other four patients (3 males, 1 female) exhibited a late-onset form, with symptom onset ranging from infancy to 17 years. Their phenotypes were highly variable, encompassing acute hyperammonemic episodes and a chronic neurological course characterized by speech and motor delay, muscle cramps, and persistent toe-walking. Genetic analysis revealed five distinct pathogenic or likely pathogenic variants (four missense substitutions and one in-frame deletion). These were identified by whole-exome sequencing in five patients and by targeted Sanger sequencing in one patient. This study highlights the molecular and phenotypic heterogeneity of OTCD and explores the correlation between genotype and phenotype. The manifestation of the disease in a heterozygous female suggests that skewed X-inactivation may serve as a potential pathogenic mechanism. The variation in age at symptom onset, alongside the genetic diversity observed, underscores the continuum between neonatal and late-onset OTCD. The online version contains supplementary material available at 10.1186/s12887-026-06673-1.
cell therapies
2023-12-06 | Induced pluripotent stem cell technology as diagnostic tool in patients with suspected ornithine transcarbamylase deficiency lacking genetic confirmation.
Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. In females - undergoing random X chromosomal inactivation (XCI) - disease severity depends on the XCI pattern. Hence, female OTCD subjects with favorable XCI display normal OTC expression and activity and are healthy carriers. Whereas females undergoing less favorable XCI may suffer from severe and fatal OTCD. In approximately 20% of patients with biochemical evidence of OTCD, no mutation can be identified hampering definitive diagnosis and adequate treatment.Here, we describe a female patient with high suspicion of OTCD in whom molecular genetic work-up did not reveal pathogenic variants in the OTC gene. In her case, this was particularly challenging, since she was awaiting liver transplantation due to metabolic instability. In order to substantiate the suspected diagnosis of OTCD, we applied our previously reported in vitro OTCD liver disease model. Patient-derived skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) followed by differentiation into hepatocytes (hiPSC-Heps). Among five randomly selected hiPSC clones - differentiated into hiPSC-Heps - one clone expressed OTC protein, while the four remaining clones lacked OTC expression, supporting the patient's suspected diagnosis of OTCD.To conclude, we demonstrate that hiPSC technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation. Furthermore, selecting clones that exclusively express the wild-type OTC protein, could be used strategically as cellular therapy in future. Ultimately, this approach might be applicable to virtually any X-linked disease. Induced pluripotent stem cell technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation.
2022-08-11 | Aquaporin 9 induction in human iPSC-derived hepatocytes facilitates modeling of ornithine transcarbamylase deficiency.
Patient-derived human-induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes (hiPSC-Heps) have facilitated the study of rare genetic liver diseases. Here, we aimed to establish an in vitro liver disease model of the urea cycle disorder ornithine transcarbamylase deficiency (OTCD) using patient-derived hiPSC-Heps. Before modeling OTCD, we addressed the question of why hiPSC-Heps generally secrete less urea than adult primary human hepatocytes (PHHs). Because hiPSC-Heps are not completely differentiated and maintain some characteristics of fetal PHHs, we compared gene-expression levels in human fetal and adult liver tissue to identify genes responsible for reduced urea secretion in hiPSC-Heps. We found lack of aquaporin 9 (AQP9) expression in fetal liver tissue as well as in hiPSC-Heps, and showed that forced expression of AQP9 in hiPSC-Heps restores urea secretion and normalizes the response to ammonia challenge by increasing ureagenesis. Furthermore, we proved functional ureagenesis by challenging AQP9-expressing hiPSC-Heps with ammonium chloride labeled with the stable isotope [15 N] (15 NH4 Cl) and by assessing enrichment of [15 N]-labeled urea. Finally, using hiPSC-Heps derived from patients with OTCD, we generated a liver disease model that recapitulates the hepatic manifestation of the human disease. Restoring OTC expression-together with AQP9-was effective in fully correcting OTC activity and normalizing ureagenesis as assessed by 15 NH4 Cl stable-isotope challenge. Our results identify a critical role for AQP9 in functional urea metabolism and establish the feasibility of in vitro modeling of OTCD with hiPSC-Heps. By facilitating studies of OTCD genotype/phenotype correlation and drug screens, our model has potential for improving the therapy of OTCD.
2021-07-19 | Acute liver dysfunction with delayed peak of serum aminotransferase levels as a presentation of ornithine transcarbamylase deficiency in females.
We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.
2019-09-12 | Human Hepatocytes and Differentiated Adult-Derived Human Liver Stem/Progenitor Cells Display In Vitro Immunosuppressive Properties Mediated, at Least in Part, through the Nonclassical HLA Class I Molecule HLA-G.
One of the main challenges in liver cell therapy (LCT) is the induction of a tolerogenic microenvironment to promote graft acceptance in the recipient. Little is known about the immunomodulatory potential of the hepatic cells used in liver cell therapy. In this work, we wanted to evaluate the immunosuppressive properties of human hepatocytes and adult-derived human liver stem/progenitor cells (ADHLSCs), as well as the potential involvement of the immunomodulatory molecule HLA-G. We demonstrated that both cell types were capable of inhibiting the proliferative response of PBMCs to an allogenic stimulus and that the immune inhibitory potential of ADHLSCs, although lower than that of hepatocytes, increased after hepatogenic differentiation. We demonstrated that liver cells express HLA-G and that the immune inhibition pattern was clearly associated to its expression. Interestingly, HLA-G expression increased after the third step of differentiation, wherein oncostatin M (OSM) was added. A 48 hr treatment with OSM was sufficient to induce HLA-G expression in ADHLSCs and result in immune inhibition. Surprisingly, blocking HLA-G partially reversed the immune inhibition mediated by hepatocytes and differentiated ADHLSCs, but not that of undifferentiated ADHLSCs, suggesting that additional immune inhibitory mechanisms may be used by these cells. In conclusion, we demonstrated that both hepatocytes and ADHLSCs present immunomodulatory properties mediated, at least in part, through HLA-G, which can be upregulated following hepatogenic differentiation or liver cell pretreatment with OSM. These observations open up new perspectives for the induction of tolerance following LCT and for potential therapeutic applications of these liver cells.
2013-10-19 | Liver Engraftment and Repopulation by In Vitro Expanded Adult Derived Human Liver Stem Cells in a Child with Ornithine Carbamoyltransferase Deficiency
A 3-year-old girl suffering from ornithine carbamoyltransferase (OTC) deficiency was poorly equilibrated under conventional diet and scavenger treatment. Following unsuccessful cryopreserved hepatocyte transplantation, she received two infusions of Adult Derived Human Liver Stem/Progenitor Cells (ADHLSCs) expanded in vitro under GMP settings, the quantity being equivalent to 0.75% of her calculated liver mass. Using FISH immunostaining for the Y chromosome, the initial biopsy did not detect any male nuclei in the recipient liver. Two liver biopsies taken 100 days after ADHLSC transplantation showed 3% and 5% of male donor cells in the recipient liver, thus suggesting repopulation by donor cells. Although limited follow-up did not allow us to draw conclusions on long-term improvement, these results provide a promising proof of concept that this therapy is feasible in an OTC patient.
oligonucleotides
2026-07-14 | Citrulline drives age-related lipid deposition for healthspan
Too much or too less lipid deposition increases mortality, while in contrast, modest lipid deposition during aging is crucial for healthspan. How animals determine the aging state and then promote appropriate lipid deposition for lifespan benefits are largely unknown. In this study, we identified citrulline as a key metabolite driving aging-related lipid deposition for healthspan in Caenorhabditis elegans. Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan, an effect reversible by dietary supplementation. Mechanistically, during aging, the transcription factor MXL-3 is activated to upregulate the expression of pyr-1, encoding ornithine transcarbamylase (OTC), for the production of citrulline, which then activates the lipogenic enzymes DGAT-2 and MBOA-2 to consequently promote lipid synthesis and deposition for lifespan extension. Collectively, we uncover a MXL-3-citrulline-lipogensis axis to ensure healthspan, providing distinct insights into metabolic aging. Modest lipid deposition during aging benefits healthspan. Li et al reported that aging activates transcription factor MXL-3, which triggers citrulline biosynthesis to promote lipogenesis for lipid deposition, thereby driving healthspan.
2026-04-23 | Profiling and Targeting of Regulatory RNAs to Upregulate Gene Expression
Abstract Transcription of long noncoding RNAs (lncRNAs), including enhancer RNAs (eRNAs) and promoter-associated RNAs (paRNAs), collectively termed regulatory RNAs (regRNAs), is a hallmark of active gene expression, yet it remains unknown whether regRNAs can be targeted to selectively enhance transcription in cis . We developed regRNA Capture-seq, a high-throughput method to profile regRNAs, and applied it to primary human hepatocytes, annotating thousands of regRNAs at ∼2,000 enhancers and promoters. Using this approach, we interrogated a genetically validated enhancer of the ornithine transcarbamylase ( OTC ) gene, mutations of which cause OTC deficiency (OTCD), the most common urea cycle disorder. Antisense oligonucleotides (ASOs) targeting enhancer-derived regRNAs led to dose-dependent upregulation of OTC in hepatocytes. Mechanistically, ASOs altered regRNA structure, elevated regRNA levels, displaced transcriptional repressors, and increased H3K27 acetylation at the targeted enhancer. This work establishes a potential therapeutic strategy for addressing haploinsufficiency and highlights regRNAs as actionable targets for ASO-mediated upregulation of gene expression.
2022-07-19 | A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error caused by loss of function variants in the OTC gene typically associated with severe neonatal hyperammonemia. Rare examples of late-onset OTCD have also been described. Here, we describe an OTC promoter variant, c.-106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the same OTC variant segregating in a large family with late-onset OTCD with variable expressivity (Family 2). We show that this OTC promoter variant reduces expression >5-fold in a dual-luciferase assay that tests promoter function. Addition of an upstream OTC enhancer increases expression of both the wild type and the c.-106C>A variant promoter constructs >5-fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower OTC expression. Under normal demand on urea cycle function, OTC expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate OTC expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.
2022-05-11 | Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.
Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf-ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.
2021-12-01 | OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfash mice, and govern susceptibility to RNA-based therapies
Aberrant splicing is a common outcome in the presence of exonic or intronic variants that might hamper the intricate network of interactions defining an exon in a specific gene context. Therefore, the evaluation of the functional, and potentially pathological, role of nucleotide changes remains one of the major challenges in the modern genomic era. This aspect has also to be taken into account during the pre-clinical evaluation of innovative therapeutic approaches in animal models of human diseases. This is of particular relevance when developing therapeutics acting on splicing, an intriguing and expanding research area for several disorders. Here, we addressed species-specific splicing mechanisms triggered by the OTC c.386G>A mutation, relatively frequent in humans, leading to Ornithine TransCarbamylase Deficiency (OTCD) in patients and spfash mice, and its differential susceptibility to RNA therapeutics based on engineered U1snRNA.Creation and co-expression of engineered U1snRNAs with human and mouse minigenes, either wild-type or harbouring different nucleotide changes, in human (HepG2) and mouse (Hepa1-6) hepatoma cells followed by analysis of splicing pattern. RNA pulldown studies to evaluate binding of specific splicing factors.Comparative nucleotide analysis suggested a role for the intronic +10-11 nucleotides, and pull-down assays showed that they confer preferential binding to the TIA1 splicing factor in the mouse context, where TIA1 overexpression further increases correct splicing. Consistently, the splicing profile of the human minigene with mouse +10-11 nucleotides overlapped that of mouse minigene, and restored responsiveness to TIA1 overexpression and to compensatory U1snRNA. Swapping the human +10-11 nucleotides into the mouse context had opposite effects. Moreover, the interplay between the authentic and the adjacent cryptic 5'ss in the human OTC dictates pathogenic mechanisms of several OTCD-causing 5'ss mutations, and only the c.386+5G>A change, abrogating the cryptic 5'ss, was rescuable by engineered U1snRNA.Subtle intronic variations explain species-specific OTC splicing patterns driven by the c.386G>A mutation, and the responsiveness to engineered U1snRNAs, which suggests careful elucidation of molecular mechanisms before proposing translation of tailored therapeutics from animal models to humans.
gene therapies
2026-07-10 | Functional Editing of the OTC locus by Targeted Integration with Phenotype Correction and Restoration of Physiological Patterns of Expression.
Here we report highly efficient functional repair of the ornithine transcarbamylase (OTC) locus in mutant mouse and human hepatocytes in vivo using a dual AAV system delivering CRISPR-Cas9 editing reagents and a promoterless donor for targeted integration. The approach was mutation agnostic and targeted intronic sequences to prevent inadvertent inactivation of hypomorphic alleles. Notably, in a murine model, we corrected the metabolic defect and simultaneously achieved liver-wide restoration of physiological metabolic zonation of Otc expression by capturing native cis-acting regulatory elements. The effectiveness of this approach was confirmed using a universally configured therapeutic cassette in patient-derived primary human hepatocytes in vivo. These data provide a powerful template to guide further optimization of this approach and, given the high editing efficacy required for phenotypic effect in OTC deficiency, have broader relevance to other liver disease phenotypes.
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-04-02 | Harnessing Gene Correction for Endemic Disease: A Review of CRISPR-Cas9 Potential in Treating Genetic Diseases in Africa
Clustered regularly interspaced short palindromic repeats (CRISPR) alongside Cas9 has been a promising innovative genomic editing technology with potential to treat genetic diseases. It offers scientists the chance to edit DNA structures and change gene function. This review synthesises pre-clinical and early-phase data on its application against Africa’s highest-burden inherited disorders sickle-cell disease, β-thalassaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency and ornithine transcarbamylase (OTC) deficiency, cystic fibrosis, Duchenne muscular dystrophy and HIV-1 infection many of which are endemic and carry African-specific mutations. Using a structure review approach, we analysed > 80 peer-reviewed studies published 2015-2025 that employed African donor cells or relevant animal models. Key findings include ≥ 70 % on-target correction of prevalent variants (G6PD A− variant, CFTR A559T, BCL11A enhancer), functional rescue of enzyme activity or viral resistance, and absence of high-level off-target events when high-fidelity nucleases are used. The convergence of falling reagent costs, continent-specific mutation atlases and newly commissioned GMP facilities provides a realistic pathway for First-in-Human trials within 5–7 years. Implications include the potential to leapfrog from lifelong palliative care to one-shot cures, provided that Africa builds scientific infrastructure, trains local genome engineers and enacts harmonised regulatory frameworks that are both stringent and context-sensitive.
2025-08-08 | Highly Efficient Functional Editing of the Native Ornithine Transcarbamylase Locus by Targeted Integration with Phenotype Correction and Restoration of Physiological Patterns of Gene Expression
Here we report unprecedented efficacy in the functional repair of an exemplar locus, ornithine transcarbamylase (OTC), in mutant primary mouse and human hepatocytes in vivo using a dual AAV vector system configured to deliver CRISPR-Cas9 editing reagents and a promoterless donor for targeted integration by non-homologous end joining. The approach was mutation agnostic and targeted editing events to intronic sequences to prevent inadvertent inactivation of hypomorphic alleles. Notably, in a murine model, we corrected the metabolic defect and simultaneously achieved liver-wide restoration of physiological metabolic zonation of OTC expression by capture of the native promoter. The effectiveness of this approach was confirmed using a universally configured therapeutic cassette in patient-derived primary human hepatocytes in vivo. These data provide a powerful template to guide further optimization of this approach and, given the high editing efficacy required for phenotypic effect in OTC deficiency, have broader relevance to other liver disease phenotypes.
2023-09-21 | Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.
Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.
other
2026-04-03 | Enzyme Structure and Substrate Binding: From Atomic Mechanisms to Therapeutic Drug Development
This comprehensive technical whitepaper explores the intricate relationship between enzyme structure, substrate binding mechanisms, and catalytic efficiency, highlighting their profound implications for drug discovery and industrial biotechnology. The article begins by detailing the four hierarchical levels of enzyme architecture, explaining how covalent and non-covalent forces stabilize these structures to create highly specific active sites. It critically evaluates molecular recognition models, transitioning from the classical lock-and-key hypothesis to the more dynamic induced-fit and conformational selection models, which better account for the structural flexibility required during the catalytic cycle. A significant portion of the text is dedicated to advanced methodologies used to interrogate enzyme function. Experimental techniques such as X-ray crystallography, cryo-electron microscopy, and nuclear magnetic resonance spectroscopy are discussed alongside cutting-edge computational approaches, including molecular docking, molecular dynamics simulations, and machine learning frameworks. These tools enable researchers to visualize transition states, map complex energy landscapes, and predict kinetic parameters like the Michaelis constant and turnover number. The article also emphasizes the critical role of non-protein cofactors and the surprising impact of distal mutations, residues located far from the active site that significantly enhance catalytic efficiency through allosteric networks and structural dynamics. Practical applications are heavily featured, particularly rational drug design strategies aimed at overcoming drug resistance through multi-target-directed ligands, allosteric inhibitors, and structure-based optimization. Case studies on isovaleric acidemia and ornithine transcarbamylase deficiency illustrate how disease-associated mutations disrupt enzyme stability and function, underscoring the necessity of integrating multi-omics data with structural kinetics. Ultimately, the integration of AI-driven predictive models and high-throughput experimental validation is presented as a transformative paradigm for engineering robust biocatalysts and developing targeted therapeutics. Source: https://www.enzymestudy.com/posts/enzyme-structure-and-substrate-binding-from-atomic-mechanisms-to-therapeutic-drug-development
2022-01-17 | Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan.
Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 μmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 μmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.
2021-05-20 | Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.
Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild-type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild-type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis-interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.
2016-10-01 | Valproate induced encephalopathy during treatment of bipolar disorder
We present a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period, and discuss the long-term development outcome of survivors. The families of 32 infants, among 43 identified prenatally as being at risk for a urea cycle disorder, chose to have their infants treated according to a diagnostic and therapeutic protocol, beginning at birth. The therapy was effective in avoiding neonatal hyperammonemic coma and death in seven patients with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency. When treated prospectively, five of eight patients with ornithine transcarbamylase deficiency avoided severe hyperammonemia and survived the neonatal period. Two patients with carbamoyl phosphate synthetase deficiency and two with ornithine transcarbamylase defiency have subsequently died; three additional patients with the latter disorder have received orthotopic liver transplants. Our experience suggests that these surviving patients have had a more favorable neurologic outcome than patients rescued from neonatal hyperammonemic coma. However, all of them require a burdensome medical regimen and may have handicaps that include impairment of development and recurrent episodes of hyperammonemia. Further, those with deficiency of carbamoyl phosphate synthetase or ornithine transcarbamylase have a high mortality rate.
small molecules
2026-05-25 | Unilateral cerebral injury mimicking hemiconvulsion-hemiplegia-epilepsy syndrome in a boy with newly diagnosed infantile-onset ornithine transcarbamylase deficiency: A case report and literature review
Background Ornithine transcarbamylase deficiency, the most common urea cycle disorder, typically presents with neurological symptoms caused by hyperammonemia. Although brain injuries are typically diffuse, unilateral lesions have been reported. Hemiconvulsion–hemiplegia–epilepsy syndrome is a neurological disorder occurring in infancy or early childhood, characterized by prolonged unilateral seizures, subsequent cerebral hemiatrophy, and epilepsy. These conditions may have overlapping clinical features. Case A 4-month-old boy presented with fever and asymmetric seizures during an adenovirus infection. Blood tests revealed hyperammonemia, elevated liver enzyme levels, coagulopathy, and lactic acidosis. Brain MRI showed diffuse cortical edema in the left hemisphere with abnormal EEG discharges. Hemiconvulsion–hemiplegia–epilepsy syndrome was provisionally suspected, and steroid pulse therapy and supportive treatment were initiated. Due to fluctuating blood ammonia levels, arginine was administered. Further metabolic evaluation demonstrated increased urinary orotic acid excretion, low plasma citrulline and arginine levels, and elevated plasma glutamine. A family history of neonatal-onset disease supported the clinical diagnosis. The patient was treated with a protein-restricted diet, citrulline, arginine, and sodium phenylbutyrate. At 1 year and 2 months of age, he showed mild right upper limb weakness without epilepsy. A review of the literature identified seven cases of urea cycle disorders with unilateral brain lesions, six involving ornithine transcarbamylase deficiency. Conclusion In ornithine transcarbamylase deficiency, acute infection may trigger unilateral cerebral injury, mimicking the hemiconvulsion–hemiplegia–epilepsy syndrome. Early metabolic intervention may help mitigate hyperammonemia and reduce the risk of neurological injury, highlighting the importance of considering metabolic disorders in infants with unilateral brain injury.
2026-04-01 | Ornithine Transcarbamoylase Deficiency
Abstract This chapter provides a picture and clinical details of Ornithine Transcarbamoylase Deficiency, an XLID condition caused by chronic or intermittent hyperammonemia resulting from deficiency of ornithine transcarbamoylase. The OTC gene is located in Xp11.4. Intrauterine growth is normal. Those who experience hyperammonemic encephalopathy early in infancy have subsequent growth failure, including microcephaly. Delay of developmental milestones may likewise be related to early hyperammonemia. Neonatal hyperammonemia causes intellectual disability. Later onset hyperammonemic encephalopathy results in some cognitive impairment. Agitation or irritability followed by disorientation and lethargy may be associated with hyperammonemia. Cerebral edema and subsequent compromise of cerebral perfusion lead to a variety of neurological findings, including changes in sensorium, ataxia, hemiparesis, slurred speech, seizures, amblyopia, and coma.
2026-03-17 | Rifaximin Ameliorates Urea Cycle Disorder in a Murine Model of humanOrnithine Transcarbamylase Deficiency
Introduction: Urea cycle disorder (UCD) is one of the major groups of inherited rare diseases that cause hyperammonaemia requiring early detection and appropriate clinical management to avoid neurological damage and death. Besides protein intake reduction, ammonia scavenger pharmacological therapy is used to prevent or treat acute hyperammonaemia episodes and related damage. Among recent treatments, the Ravicti prescription has been shown to reduce plasma ammonia, hyperammonaemia episodes, and hospital admissions. Another product, potentially able to counteract hyperammonemia in urea cycle disorder via modulation of the intestinal microbiota, is rifaximin, also approved by the FDA for prevention and treatment of hepatic encephalopathy. This study aims to investigate possible pharmacological interactions between Ravicti and rifaximin in the translational murine model of UCD induced by ornithine transcarbamylase (OTC) deficiency Methods: We characterized B6EiC3Sn a/A-Otcspf-ash/J (disease model, which is OTC-deficient, hereafter referred to as Otcspf-ash mouse/mice) as a valid UCD murine model to evaluate the tolerability and efficacy of rifaximin with and without ammonia scavenger Ravicti. 15-week old Otcspf-ash mice expressing the variant (c.386G>A, p.Arg129His) in the OTC enzyme of liver, also found in patients, were given by oral route for 2 weeks rifaximin and 4 weeks Ravicti or the combination. After sacrifice, liver, small intestine, colon, hippocampus, and brain motor cortex were collected for whole-mount immunostaining. Results: Analysis of OTC-deficient mice showed increased plasma ammonia, liver damage, and colonic inflammation, as well as brain alterations in terms of astrocyte swelling, microglia activation, and neuronal apoptosis, in addition to abnormal mouse behavior with impaired motor coordination. Administration of rifaximin and Ravicti alone was shown to improve mice behavior and significantly hinder hepatic impairment, intestinal inflammation, and neuronal dysfunction. The combination of the two drugs showed no additional improvement over their individual efficacy. Discussion: Interestingly, rifaximin enhanced bacteria with protective functions towards the host, SCFAs producers, or involved in ureagenesis or stimulation of FX receptors. showing a consistent ability to reduce bacteria able to lyse urea or positively correlated to urea cycle or bile salts pathway disorders Conclusion: Otcspf-ash was a good model to study UCD and investigate novel therapeutic strategies. Rifaximin seems promising regarding its capability to protect patients with UCD and warrants further investigation
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25–30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
2026-03-06 | Clinical heterogeneity, genotype, and neurological outcomes in six Palestinian patients with ornithine transcarbamylase deficiency.
Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. This X-linked condition, mapped to Xp21.1, results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes a critical step in ureagenesis. Disease severity ranges from a complete enzymatic block, presenting as neonatal hyperammonemic coma with high mortality, to partial deficiencies that can cause life-threatening hyperammonemia at any age. This report describes six patients diagnosed with OTCD, with ages ranging from 8 days to 17 years at the time of diagnosis. The onset of symptoms occurred at different ages, from just 2 days to 17 years. Two male patients experienced severe neonatal courses and, unfortunately, died from hyperammonemic coma shortly after birth. In contrast, four other patients (three males and one female) presented with symptoms later in life. Molecular analysis identified pathogenic variants in the OTC gene, which included four missense variants and one in-frame deletion. Notably, a recurrent variant was found in two individuals from unrelated families. The cohort comprised six patients with two distinct clinical presentations. Two hemizygous males presented neonatally and progressed to severe hyperammonemic coma within the first days of life. The other four patients (3 males, 1 female) exhibited a late-onset form, with symptom onset ranging from infancy to 17 years. Their phenotypes were highly variable, encompassing acute hyperammonemic episodes and a chronic neurological course characterized by speech and motor delay, muscle cramps, and persistent toe-walking. Genetic analysis revealed five distinct pathogenic or likely pathogenic variants (four missense substitutions and one in-frame deletion). These were identified by whole-exome sequencing in five patients and by targeted Sanger sequencing in one patient. This study highlights the molecular and phenotypic heterogeneity of OTCD and explores the correlation between genotype and phenotype. The manifestation of the disease in a heterozygous female suggests that skewed X-inactivation may serve as a potential pathogenic mechanism. The variation in age at symptom onset, alongside the genetic diversity observed, underscores the continuum between neonatal and late-onset OTCD. The online version contains supplementary material available at 10.1186/s12887-026-06673-1.
cell therapies
2023-12-06 | Induced pluripotent stem cell technology as diagnostic tool in patients with suspected ornithine transcarbamylase deficiency lacking genetic confirmation.
Ornithine transcarbamylase (OTC) deficiency (OTCD) is an X-linked urea cycle disorder. In females - undergoing random X chromosomal inactivation (XCI) - disease severity depends on the XCI pattern. Hence, female OTCD subjects with favorable XCI display normal OTC expression and activity and are healthy carriers. Whereas females undergoing less favorable XCI may suffer from severe and fatal OTCD. In approximately 20% of patients with biochemical evidence of OTCD, no mutation can be identified hampering definitive diagnosis and adequate treatment.Here, we describe a female patient with high suspicion of OTCD in whom molecular genetic work-up did not reveal pathogenic variants in the OTC gene. In her case, this was particularly challenging, since she was awaiting liver transplantation due to metabolic instability. In order to substantiate the suspected diagnosis of OTCD, we applied our previously reported in vitro OTCD liver disease model. Patient-derived skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) followed by differentiation into hepatocytes (hiPSC-Heps). Among five randomly selected hiPSC clones - differentiated into hiPSC-Heps - one clone expressed OTC protein, while the four remaining clones lacked OTC expression, supporting the patient's suspected diagnosis of OTCD.To conclude, we demonstrate that hiPSC technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation. Furthermore, selecting clones that exclusively express the wild-type OTC protein, could be used strategically as cellular therapy in future. Ultimately, this approach might be applicable to virtually any X-linked disease. Induced pluripotent stem cell technology is a powerful diagnostic tool to substantiate the suspected diagnosis of OTCD in patients lacking genetic confirmation.
2022-08-11 | Aquaporin 9 induction in human iPSC-derived hepatocytes facilitates modeling of ornithine transcarbamylase deficiency.
Patient-derived human-induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes (hiPSC-Heps) have facilitated the study of rare genetic liver diseases. Here, we aimed to establish an in vitro liver disease model of the urea cycle disorder ornithine transcarbamylase deficiency (OTCD) using patient-derived hiPSC-Heps. Before modeling OTCD, we addressed the question of why hiPSC-Heps generally secrete less urea than adult primary human hepatocytes (PHHs). Because hiPSC-Heps are not completely differentiated and maintain some characteristics of fetal PHHs, we compared gene-expression levels in human fetal and adult liver tissue to identify genes responsible for reduced urea secretion in hiPSC-Heps. We found lack of aquaporin 9 (AQP9) expression in fetal liver tissue as well as in hiPSC-Heps, and showed that forced expression of AQP9 in hiPSC-Heps restores urea secretion and normalizes the response to ammonia challenge by increasing ureagenesis. Furthermore, we proved functional ureagenesis by challenging AQP9-expressing hiPSC-Heps with ammonium chloride labeled with the stable isotope [15 N] (15 NH4 Cl) and by assessing enrichment of [15 N]-labeled urea. Finally, using hiPSC-Heps derived from patients with OTCD, we generated a liver disease model that recapitulates the hepatic manifestation of the human disease. Restoring OTC expression-together with AQP9-was effective in fully correcting OTC activity and normalizing ureagenesis as assessed by 15 NH4 Cl stable-isotope challenge. Our results identify a critical role for AQP9 in functional urea metabolism and establish the feasibility of in vitro modeling of OTCD with hiPSC-Heps. By facilitating studies of OTCD genotype/phenotype correlation and drug screens, our model has potential for improving the therapy of OTCD.
2021-07-19 | Acute liver dysfunction with delayed peak of serum aminotransferase levels as a presentation of ornithine transcarbamylase deficiency in females.
We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.
2019-09-12 | Human Hepatocytes and Differentiated Adult-Derived Human Liver Stem/Progenitor Cells Display In Vitro Immunosuppressive Properties Mediated, at Least in Part, through the Nonclassical HLA Class I Molecule HLA-G.
One of the main challenges in liver cell therapy (LCT) is the induction of a tolerogenic microenvironment to promote graft acceptance in the recipient. Little is known about the immunomodulatory potential of the hepatic cells used in liver cell therapy. In this work, we wanted to evaluate the immunosuppressive properties of human hepatocytes and adult-derived human liver stem/progenitor cells (ADHLSCs), as well as the potential involvement of the immunomodulatory molecule HLA-G. We demonstrated that both cell types were capable of inhibiting the proliferative response of PBMCs to an allogenic stimulus and that the immune inhibitory potential of ADHLSCs, although lower than that of hepatocytes, increased after hepatogenic differentiation. We demonstrated that liver cells express HLA-G and that the immune inhibition pattern was clearly associated to its expression. Interestingly, HLA-G expression increased after the third step of differentiation, wherein oncostatin M (OSM) was added. A 48 hr treatment with OSM was sufficient to induce HLA-G expression in ADHLSCs and result in immune inhibition. Surprisingly, blocking HLA-G partially reversed the immune inhibition mediated by hepatocytes and differentiated ADHLSCs, but not that of undifferentiated ADHLSCs, suggesting that additional immune inhibitory mechanisms may be used by these cells. In conclusion, we demonstrated that both hepatocytes and ADHLSCs present immunomodulatory properties mediated, at least in part, through HLA-G, which can be upregulated following hepatogenic differentiation or liver cell pretreatment with OSM. These observations open up new perspectives for the induction of tolerance following LCT and for potential therapeutic applications of these liver cells.
2013-10-19 | Liver Engraftment and Repopulation by In Vitro Expanded Adult Derived Human Liver Stem Cells in a Child with Ornithine Carbamoyltransferase Deficiency
A 3-year-old girl suffering from ornithine carbamoyltransferase (OTC) deficiency was poorly equilibrated under conventional diet and scavenger treatment. Following unsuccessful cryopreserved hepatocyte transplantation, she received two infusions of Adult Derived Human Liver Stem/Progenitor Cells (ADHLSCs) expanded in vitro under GMP settings, the quantity being equivalent to 0.75% of her calculated liver mass. Using FISH immunostaining for the Y chromosome, the initial biopsy did not detect any male nuclei in the recipient liver. Two liver biopsies taken 100 days after ADHLSC transplantation showed 3% and 5% of male donor cells in the recipient liver, thus suggesting repopulation by donor cells. Although limited follow-up did not allow us to draw conclusions on long-term improvement, these results provide a promising proof of concept that this therapy is feasible in an OTC patient.
oligonucleotides
2026-07-14 | Citrulline drives age-related lipid deposition for healthspan
Too much or too less lipid deposition increases mortality, while in contrast, modest lipid deposition during aging is crucial for healthspan. How animals determine the aging state and then promote appropriate lipid deposition for lifespan benefits are largely unknown. In this study, we identified citrulline as a key metabolite driving aging-related lipid deposition for healthspan in Caenorhabditis elegans. Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan, an effect reversible by dietary supplementation. Mechanistically, during aging, the transcription factor MXL-3 is activated to upregulate the expression of pyr-1, encoding ornithine transcarbamylase (OTC), for the production of citrulline, which then activates the lipogenic enzymes DGAT-2 and MBOA-2 to consequently promote lipid synthesis and deposition for lifespan extension. Collectively, we uncover a MXL-3-citrulline-lipogensis axis to ensure healthspan, providing distinct insights into metabolic aging. Modest lipid deposition during aging benefits healthspan. Li et al reported that aging activates transcription factor MXL-3, which triggers citrulline biosynthesis to promote lipogenesis for lipid deposition, thereby driving healthspan.
2026-04-23 | Profiling and Targeting of Regulatory RNAs to Upregulate Gene Expression
Abstract Transcription of long noncoding RNAs (lncRNAs), including enhancer RNAs (eRNAs) and promoter-associated RNAs (paRNAs), collectively termed regulatory RNAs (regRNAs), is a hallmark of active gene expression, yet it remains unknown whether regRNAs can be targeted to selectively enhance transcription in cis . We developed regRNA Capture-seq, a high-throughput method to profile regRNAs, and applied it to primary human hepatocytes, annotating thousands of regRNAs at ∼2,000 enhancers and promoters. Using this approach, we interrogated a genetically validated enhancer of the ornithine transcarbamylase ( OTC ) gene, mutations of which cause OTC deficiency (OTCD), the most common urea cycle disorder. Antisense oligonucleotides (ASOs) targeting enhancer-derived regRNAs led to dose-dependent upregulation of OTC in hepatocytes. Mechanistically, ASOs altered regRNA structure, elevated regRNA levels, displaced transcriptional repressors, and increased H3K27 acetylation at the targeted enhancer. This work establishes a potential therapeutic strategy for addressing haploinsufficiency and highlights regRNAs as actionable targets for ASO-mediated upregulation of gene expression.
2022-07-19 | A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error caused by loss of function variants in the OTC gene typically associated with severe neonatal hyperammonemia. Rare examples of late-onset OTCD have also been described. Here, we describe an OTC promoter variant, c.-106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the same OTC variant segregating in a large family with late-onset OTCD with variable expressivity (Family 2). We show that this OTC promoter variant reduces expression >5-fold in a dual-luciferase assay that tests promoter function. Addition of an upstream OTC enhancer increases expression of both the wild type and the c.-106C>A variant promoter constructs >5-fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower OTC expression. Under normal demand on urea cycle function, OTC expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate OTC expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.
2022-05-11 | Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.
Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf-ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.
2021-12-01 | OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfash mice, and govern susceptibility to RNA-based therapies
Aberrant splicing is a common outcome in the presence of exonic or intronic variants that might hamper the intricate network of interactions defining an exon in a specific gene context. Therefore, the evaluation of the functional, and potentially pathological, role of nucleotide changes remains one of the major challenges in the modern genomic era. This aspect has also to be taken into account during the pre-clinical evaluation of innovative therapeutic approaches in animal models of human diseases. This is of particular relevance when developing therapeutics acting on splicing, an intriguing and expanding research area for several disorders. Here, we addressed species-specific splicing mechanisms triggered by the OTC c.386G>A mutation, relatively frequent in humans, leading to Ornithine TransCarbamylase Deficiency (OTCD) in patients and spfash mice, and its differential susceptibility to RNA therapeutics based on engineered U1snRNA.Creation and co-expression of engineered U1snRNAs with human and mouse minigenes, either wild-type or harbouring different nucleotide changes, in human (HepG2) and mouse (Hepa1-6) hepatoma cells followed by analysis of splicing pattern. RNA pulldown studies to evaluate binding of specific splicing factors.Comparative nucleotide analysis suggested a role for the intronic +10-11 nucleotides, and pull-down assays showed that they confer preferential binding to the TIA1 splicing factor in the mouse context, where TIA1 overexpression further increases correct splicing. Consistently, the splicing profile of the human minigene with mouse +10-11 nucleotides overlapped that of mouse minigene, and restored responsiveness to TIA1 overexpression and to compensatory U1snRNA. Swapping the human +10-11 nucleotides into the mouse context had opposite effects. Moreover, the interplay between the authentic and the adjacent cryptic 5'ss in the human OTC dictates pathogenic mechanisms of several OTCD-causing 5'ss mutations, and only the c.386+5G>A change, abrogating the cryptic 5'ss, was rescuable by engineered U1snRNA.Subtle intronic variations explain species-specific OTC splicing patterns driven by the c.386G>A mutation, and the responsiveness to engineered U1snRNAs, which suggests careful elucidation of molecular mechanisms before proposing translation of tailored therapeutics from animal models to humans.
gene therapies
2026-07-10 | Functional Editing of the OTC locus by Targeted Integration with Phenotype Correction and Restoration of Physiological Patterns of Expression.
Here we report highly efficient functional repair of the ornithine transcarbamylase (OTC) locus in mutant mouse and human hepatocytes in vivo using a dual AAV system delivering CRISPR-Cas9 editing reagents and a promoterless donor for targeted integration. The approach was mutation agnostic and targeted intronic sequences to prevent inadvertent inactivation of hypomorphic alleles. Notably, in a murine model, we corrected the metabolic defect and simultaneously achieved liver-wide restoration of physiological metabolic zonation of Otc expression by capturing native cis-acting regulatory elements. The effectiveness of this approach was confirmed using a universally configured therapeutic cassette in patient-derived primary human hepatocytes in vivo. These data provide a powerful template to guide further optimization of this approach and, given the high editing efficacy required for phenotypic effect in OTC deficiency, have broader relevance to other liver disease phenotypes.
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-04-02 | Harnessing Gene Correction for Endemic Disease: A Review of CRISPR-Cas9 Potential in Treating Genetic Diseases in Africa
Clustered regularly interspaced short palindromic repeats (CRISPR) alongside Cas9 has been a promising innovative genomic editing technology with potential to treat genetic diseases. It offers scientists the chance to edit DNA structures and change gene function. This review synthesises pre-clinical and early-phase data on its application against Africa’s highest-burden inherited disorders sickle-cell disease, β-thalassaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency and ornithine transcarbamylase (OTC) deficiency, cystic fibrosis, Duchenne muscular dystrophy and HIV-1 infection many of which are endemic and carry African-specific mutations. Using a structure review approach, we analysed > 80 peer-reviewed studies published 2015-2025 that employed African donor cells or relevant animal models. Key findings include ≥ 70 % on-target correction of prevalent variants (G6PD A− variant, CFTR A559T, BCL11A enhancer), functional rescue of enzyme activity or viral resistance, and absence of high-level off-target events when high-fidelity nucleases are used. The convergence of falling reagent costs, continent-specific mutation atlases and newly commissioned GMP facilities provides a realistic pathway for First-in-Human trials within 5–7 years. Implications include the potential to leapfrog from lifelong palliative care to one-shot cures, provided that Africa builds scientific infrastructure, trains local genome engineers and enacts harmonised regulatory frameworks that are both stringent and context-sensitive.
2025-08-08 | Highly Efficient Functional Editing of the Native Ornithine Transcarbamylase Locus by Targeted Integration with Phenotype Correction and Restoration of Physiological Patterns of Gene Expression
Here we report unprecedented efficacy in the functional repair of an exemplar locus, ornithine transcarbamylase (OTC), in mutant primary mouse and human hepatocytes in vivo using a dual AAV vector system configured to deliver CRISPR-Cas9 editing reagents and a promoterless donor for targeted integration by non-homologous end joining. The approach was mutation agnostic and targeted editing events to intronic sequences to prevent inadvertent inactivation of hypomorphic alleles. Notably, in a murine model, we corrected the metabolic defect and simultaneously achieved liver-wide restoration of physiological metabolic zonation of OTC expression by capture of the native promoter. The effectiveness of this approach was confirmed using a universally configured therapeutic cassette in patient-derived primary human hepatocytes in vivo. These data provide a powerful template to guide further optimization of this approach and, given the high editing efficacy required for phenotypic effect in OTC deficiency, have broader relevance to other liver disease phenotypes.
2023-09-21 | Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.
Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.
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2026-04-03 | Enzyme Structure and Substrate Binding: From Atomic Mechanisms to Therapeutic Drug Development
This comprehensive technical whitepaper explores the intricate relationship between enzyme structure, substrate binding mechanisms, and catalytic efficiency, highlighting their profound implications for drug discovery and industrial biotechnology. The article begins by detailing the four hierarchical levels of enzyme architecture, explaining how covalent and non-covalent forces stabilize these structures to create highly specific active sites. It critically evaluates molecular recognition models, transitioning from the classical lock-and-key hypothesis to the more dynamic induced-fit and conformational selection models, which better account for the structural flexibility required during the catalytic cycle. A significant portion of the text is dedicated to advanced methodologies used to interrogate enzyme function. Experimental techniques such as X-ray crystallography, cryo-electron microscopy, and nuclear magnetic resonance spectroscopy are discussed alongside cutting-edge computational approaches, including molecular docking, molecular dynamics simulations, and machine learning frameworks. These tools enable researchers to visualize transition states, map complex energy landscapes, and predict kinetic parameters like the Michaelis constant and turnover number. The article also emphasizes the critical role of non-protein cofactors and the surprising impact of distal mutations, residues located far from the active site that significantly enhance catalytic efficiency through allosteric networks and structural dynamics. Practical applications are heavily featured, particularly rational drug design strategies aimed at overcoming drug resistance through multi-target-directed ligands, allosteric inhibitors, and structure-based optimization. Case studies on isovaleric acidemia and ornithine transcarbamylase deficiency illustrate how disease-associated mutations disrupt enzyme stability and function, underscoring the necessity of integrating multi-omics data with structural kinetics. Ultimately, the integration of AI-driven predictive models and high-throughput experimental validation is presented as a transformative paradigm for engineering robust biocatalysts and developing targeted therapeutics. Source: https://www.enzymestudy.com/posts/enzyme-structure-and-substrate-binding-from-atomic-mechanisms-to-therapeutic-drug-development
2022-01-17 | Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan.
Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 μmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 μmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.
2021-05-20 | Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.
Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild-type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild-type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis-interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.
2016-10-01 | Valproate induced encephalopathy during treatment of bipolar disorder
We present a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period, and discuss the long-term development outcome of survivors. The families of 32 infants, among 43 identified prenatally as being at risk for a urea cycle disorder, chose to have their infants treated according to a diagnostic and therapeutic protocol, beginning at birth. The therapy was effective in avoiding neonatal hyperammonemic coma and death in seven patients with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency. When treated prospectively, five of eight patients with ornithine transcarbamylase deficiency avoided severe hyperammonemia and survived the neonatal period. Two patients with carbamoyl phosphate synthetase deficiency and two with ornithine transcarbamylase defiency have subsequently died; three additional patients with the latter disorder have received orthotopic liver transplants. Our experience suggests that these surviving patients have had a more favorable neurologic outcome than patients rescued from neonatal hyperammonemic coma. However, all of them require a burdensome medical regimen and may have handicaps that include impairment of development and recurrent episodes of hyperammonemia. Further, those with deficiency of carbamoyl phosphate synthetase or ornithine transcarbamylase have a high mortality rate.
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Drug Discovery Landscape
22 orphan drug designations for Ornithine transcarbamylase deficiency, including 2 approved therapies.
22 orphan drug designations for Ornithine transcarbamylase deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector serotype LK03 containing the human ornithine transcarbamylase gene | gene therapies | FDA | 2023-08-08 | — | Bloomsbury Genetic Therapies Ltd. |
A replication-deficient adeno-associated virus serotype 9 vector containing the ornithine transcarbamylase gene within the transposon and a lipid nanoparticle containing messenger RNA for the transposase | gene therapies | FDA | 2023-07-24 | — | Poseida Therapeutics, Inc. |
Adeno-associated virus serotype rh79 containing the human OTC gene, adeno-associated virus serotype rh79 encoding a meganuclease for targeted editing of the human PCSK9 gene | gene therapies | EMA | 2022-12-09 | — | Pharma Gateway AB |
non-replicating recombinant adeno-associated virus serotype rh79 (AAVrh.79) vectors: AAVrh79.TBG.M2PCSK9.WPRE.bGH and AAVrh79.hHDR.TBG.hOTCco.bGH | gene therapies | FDA | 2022-09-01 | — | iECURE, Inc. |
mRNA encoding modified human ornithine transcarbamylase | RNAs | EMA | 2022-07-18 | — | Arcturus Therapeutics Europe B.V. |
L-Citrulline | small molecules | FDA | 2020-11-03 | — | Orpha Labs, AG |
Ornithine transcarbamylase messenger RNA | gene therapies | FDA | 2019-06-26 | — | Arcturus Therapeutics, Inc. |
Sodium benzoate, sodium phenylacetate | small molecules | EMA | 2019-04-24 | — | Dipharma B.V. |
Codon-optimised human ornithine transcarbamylase mRNA complexed with lipid-based nanoparticles | RNAs | EMA | 2018-06-27 | — | Transcrip Ireland Limited |
Nanoparticle suspension containing biosynthetic codon-optimized human ornithine transcarbamylase messenger RNA | RNAs | FDA | 2018-03-28 | — | Translate Bio, Inc. |
Modified messenger ribonucleic acid encoding human ornithine transcarbamylase enzyme encapsulated into lipid nanoparticles | RNAs | EMA | 2017-04-20 | — | PhaseRx Ireland, Ltd |
Adeno-associated viral vector serotype LK03 encoding human ornithine transcarbamylase | gene therapies | EMA | 2017-03-20 | — | UCL Research Limited |
mRNA encoding human ornithine transcarbamylase | RNAs | FDA | 2016-11-23 | — | PhaseRx, Inc. |
Sodium benzoate | small molecules | EMA | 2016-07-14 | — | Lucane Pharma SA |
Adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase | gene therapies | EMA | 2016-03-21 | — | Ultragenyx Germany GmbH |
recombinant adeno-associated virus serotype AAV8 vector encoding human ornithine transcarbamylase | gene therapies | FDA | 2015-12-29 | — | Dimension Therapeutics |
Sodium phenylbutyrate [Pheburane] | small molecules | EMA | 2012-02-09 | — | Lucane Pharma |
Heterologous human adult liver-derived stem cells | cell therapies | EMA | 2011-09-27 | — | Unicyte S.R.L. |
Glyceryl tri-(4-phenylbutyrate) [Ravicti] | small molecules | EMA | 2010-06-10 | 2015-12-01 | Immedica Pharma AB |
Heterologous human adult liver derived stem cells | cell therapies | EMA | 2008-02-04 | — | Cellaion |
Human heterologous liver cells (for infusion) | gene therapies | EMA | 2007-09-14 | — | Promethera Biosciences |
Benzoate and phenylacetate [Ucephan] | small molecules | FDA | 1986-01-21 | 1987-12-23 | ImmunexImmunex |
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