RARE DISEASE
Argininemia
Argininemia
Argininemia
Synonyms: Arginase deficiency, Hyperargininemia
Synonyms: Arginase deficiency, Hyperargininemia
Synonyms: Arginase deficiency, Hyperargininemia
Drug discovery
9
drugs
With orphan designations
Overview
Argininemia is a rare autosomal recessive urea cycle disorder caused by ARG1 gene mutations, resulting in arginase deficiency. This impairs arginine metabolism, leading to hyperargininemia and intermittent hyperammonemia. Onset typically occurs in early childhood with progressive spastic diplegia, developmental regression, seizures, and intellectual disability. Diagnosis involves plasma amino acid analysis, enzyme activity assays, and genetic testing. Management focuses on protein-restricted diets, ammonia scavengers, and symptomatic therapies, though neurological complications often persist despite treatment [1][2][6][10][12].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
187 drug discovery papers about Argininemia, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
187 drug discovery papers about Argininemia, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-07-11 | Control of Coagulation Abnormalities with Sodium Benzoate in Patients with Argininemia
Aim: This study aimed to evaluate coagulation disorders in patients with argininemia associated with arginase 1 gene mutations and the control of these disorders with sodium benzoate treatment.Materials and Methods: Five argininemia patients followed up in the Pediatric Metabolism Clinic in University of Health Sciences Trkiye, Baakehir am and Sakura City Hospital, were included in this study.The patients initially received protein-restricted diet treatment, while their ammonia, platelet count, liver enzymes and coagulation parameters were measured regularly.Later, sodium benzoate was added to the treatment and the same parameters were measured at 1-month intervals.Results: In the coagulation parameters measured after sodium benzoate treatment, one out of the five patients showed complete improvement, three had partial improvement, and one had no change.In the patients with coagulation disorders, factor VII and IX levels were low, while arginine levels remained above 250 mol/L. Conclusion:The pathophysiology of coagulation disorders in patients with argininemia has not yet been fully elucidated, but it is thought that high arginine levels may affect the synthesis of short-lived coagulation factors.Adding sodium benzoate to dietary therapy may contribute to both the control of arginine levels and an improvement in coagulation parameters.This study demonstrates the importance of coagulation monitoring in those patients with argininemia and the potential therapeutic role of sodium benzoate.
2025-01-31 | First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours.
The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed. In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy). A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50-100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti-PD-1/PD-L1-naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response. INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted. NCT02903914.
2025-01-24 | Protective effects of berbamine against arginase-1 deficiency-induced injury in human brain microvascular endothelial cells.
Endothelial cell dysfunction plays a crucial role in the early development of cerebral small vessel disease (CSVD). Arginase-1 (ARG1) is expressed in endothelial cells, and its deficiency may exacerbate cerebrovascular damage by increasing reactive oxygen species (ROS) production, thereby inducing endothelial cell apoptosis. Berbamine (BBM) has shown potential in neuroprotection and cardiovascular disease prevention. This study aimed to investigate the impact of ARG1 deficiency on human brain microvascular endothelial cells and the protective effects of BBM against ARG1 deficiency-induced damage. Human brain microvascular endothelial cells (HCMEC/D3) were cultured in vitro, and ARG1 knockdown or overexpression was achieved using plasmid transfection techniques. We examined the effects of ARG1 expression levels on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis through cellular experiments. Additionally, we explored how ARG1 expression levels influenced arginine (Arg), nitric oxide (NO), and ROS levels in HCMEC/D3 cells. The results demonstrated that ARG1 deficiency inhibited HCMEC/D3 cell viability, migration, adhesion, and angiogenesis, while promoting apoptosis and elevating Arg, NO, and ROS levels in HCMEC/D3 cells. Next, the effect of different BBM concentrations on HCMEC/D3 cell viability was assessed using the CCK-8 assay, revealing that BBM at a concentration of 5 µM had no significant impact on cell viability. Subsequently, after successfully knocking down ARG1 in HCMEC/D3 cells, the cells were treated with BBM. The results showed that BBM effectively mitigated the negative effects of ARG1 deficiency on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis, while also reducing Arg, NO, inducible nitric oxide synthase (iNOS), and ROS levels in HCMEC/D3 cells. In conclusion, this study suggests that ARG1 deficiency may damage HCMEC/D3 cells by increasing Arg levels, leading to elevated NO and ROS levels. BBM may provide protection to ARG1-deficient HCMEC/D3 cells by reducing Arg, NO, iNOS, and ROS levels. These findings deepen our understanding of the pathogenesis of CSVD and provide a theoretical basis for the clinical application of BBM.
2024-11-13 | Disease burden among patients with Arginase 1 deficiency and their caregivers: A multinational, cross-sectional survey.
Arginase 1 deficiency (ARG1-D) is an ultrarare, metabolic disease which may cause spastic paraplegia, cognitive deficiency, seizures, and ultimately severe disability. The aim of this study was to assess disease burden in ARG1-D by performing a cross-sectional survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, and the United Kingdom). Patients were enrolled at participating clinics and data were collected using a web-based questionnaire. The findings indicate that there is a significant share of patients who experience severe cognitive and mobility impairment but also that there is a considerable variance in symptom severity among patients. Disease management was mostly in line with treatment guidelines and self-reported adherence to treatment was reported to be high among a majority although following diet restrictions was perceived as difficult. However, despite this, since a large share of patients experienced severe cognitive and mobility impairment an unmet need among this patient population is suggested. The introduction of disease-modifying therapies and early identification and diagnosis may help alleviate the disease burden associated with ARG1-D in the future.
2024-09-07 | Societal costs and quality of life associated with arginase 1 deficiency in a European setting - a multinational, cross-sectional survey.
Arginase 1 deficiency (ARG1-D) is a ultrarare disease with manifestations that cause mobility and cognitive impairment that progress over time and may lead to early mortality. Diseases such as ARG1-D have a major impact also outside of the health care sector and the aim of this study was to estimate the current burden of disease associated with ARG1-D from a societal perspective. The study was performed as a web-based survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, United Kingdom). The survey was distributed at participating clinics and included questions on e.g. symptoms (including the Gross Motor Function Classification System, GMFCS, and cognitive impairment), health care use, medication, ability to work, caregiving, and impact on health-related quality-of-life (HRQoL) using the EQ-5D-5L. The estimated total mean societal cost per patient and year was £63,775 (SD: £49,944). The cost varied significantly with both mobility impairment (from £49,809 for GMFCS level 1 to £103,639 for GMFCS levels 3-5) and cognitive impairment (from £43,860 for mild level to £99,162 for severe level). The mean utility score on the EQ-5D-5L for patients was 0.498 (SD: 0.352). The utility score also varied significantly with both mobility impairment (from 0.783 for GMFCS level 1 to 0.153 for GMFCS level 3-5) and cognitive impairment (from 0.738 for mild level to 0.364 for severe level). Similar to other studies of rare diseases, the study is based on a limited number of observations. However, the sample appear to be reasonably representative when comparing to previous studies of ARG1-D. This study shows that ARG1-D is associated with a high societal cost and significant impact on HRQoL. Earlier diagnosis and better treatment options that can postpone or withhold progression may therefore have a potential for improved HRQoL and savings for the patient, caregiver, and society.
gene therapies
2025-12-05 | Comparing CRISPR-Cas9 Gene Therapy Delivery Systems: Implications and Optimization for Hyperargininemia
Hyperargininemia is a rare autosomal recessive metabolic disorder caused by a deficiency in the urea cycle enzyme arginase 1, resulting in severe systemic and neurological complications. Given the shortcomings of conventional treatment paradigms, there is an increasing demand for gene therapies, such as CRISPR-Cas9, that address hyperargininemia at its genetic root and reverse its diverse manifestations. Homology-directed repair offers high specificity and durable genetic correction. The strategic delivery of CRISPR components, including homology arm-flanked, wild-type ARG1 cDNA, Cas9 endonucleases, and appropriate sgRNAs, is necessary to enable homology-directed repair in arginase 1-deficient hepatocytes. This review summarizes the methodology, strengths, and weaknesses of three prominent CRISPR delivery methods: lipid nanoparticles, recombinant adeno-associated viruses, and electroporation. We also highlight ongoing efforts to optimize these delivery methods and analyze the relevance of existing preclinical CRISPR-Cas9 studies to hyperargininemia. Among these delivery systems, recombinant adeno-associated viruses currently show the most promise for clinical translation, although further enhancements in safety and scalability remain necessary.
2025-04-29 | Updated Gene Therapy for Renal Inborn Errors of Metabolism
Inborn errors of metabolism (IEMs) are a group of disorders resulting from defects in enzymes in metabolic pathways. These disorders impact the processing of metabolites, leading to a wide array of effects on each organ system. Advances in genetic screening have allowed for the early identification and intervention of IEMs, traditionally in the form of enzyme replacement or vitamin supplementation. However, many IEMs disrupt essential metabolic pathways where simple supplementation proves ineffective, resulting in substantial disease burden. In the case of renal IEMs, metabolic pathway disruption leads to the onset of chronic kidney disease (CKD). For these diseases, genetic therapy provides hope. Over the past few decades, the technology for genetic therapy has emerged as a promising solution to these disorders. These therapies aim to correct the source of the defect in the genetic code so that patients may live full, unencumbered lives. In this review, we searched a large database to identify IEMs that affect the kidney and investigated the current landscape and progression of gene therapy technology. Multiple promising genetic therapies were identified for IEMs affecting the kidney, including primary hyperoxaluria, argininemia, glycogen storage diseases Ia and Ib, and Fabry disease. Emerging gene therapy approaches using adeno-associated virus (AAV) vectors, lentiviral vectors, and CRISPR/Cas9 techniques hold promising potential to provide curative treatments for additional single-mutation disorders.
2019-07-26 | Genetic-Based Approaches to Inherited Metabolic Liver Diseases
In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all of these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Indeed, liver-directed gene therapy trials for hemophilia A and B have demonstrated the potential of gene therapy to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. Herein, we review the advances and limitations of gene therapy for such disorders, covering therapeutic strategies based on gene addition and gene editing and the exciting clinical results obtained with the use of ribonucleic acid as therapeutic molecules.
2018-12-13 | Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency.
Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible arginase-1 deficient mouse model harboring a deletion of Arg1 exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with piggyBac technology to target and reincorporate exons 7 and 8 at the specific Arg1 locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophages in vitro. While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of "repaired" arginase. Our studies provide proof-of-concept for gene-editing at the Arg1 locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders.
2016-11-29 | Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells
Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism. Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.
cell therapies
2025-09-25 | Nanogram of Arg 1 Delivered by extracellular vesicles restore ARG1 activity in a mouse model of ARG1-D and improve lifespan
Abstract Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor’s StealthX™ platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of its localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1- encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies and results showed that STX-Arg1-in EVs were non-toxic and able to restore the arginase activities in the liver of the Arg1 -/- mice, which leads to a lowered plasma arginine concentration similar to wildtype mice. Most importantly, Arg1-in expanded the life span of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthX™-engineered STX-Arg1-in EVs have a better safety profile due to extreme low dosage and had great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement Intracellular delivery of recombinant protein and improved life span are endpoints of a successful enzyme replacement therapy for the treatment of ARG1-D. Using StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed intracellular delivery of ARG1 protein in vitro and in vivo, with improvement of life span in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with low dose, setting the base for an improved therapeutic approach.
2022-04-01 | The effect of liver transplantation for argininemia—the largest experiences in a single center
Argininemia, a rare urea cycle disorder resulting from an arginase-1 deficiency, is characterized by a progressive spastic paraplegia. While advances in diagnosis and treatment have increased the management of this condition, not all symptoms are resolved in response to traditional therapies. Interestingly, there exist some rare reports on the use of liver transplantation (LT) for the treatment of argininemia.We conducted a retrospective study of eleven patients with argininemia receiving a LT as performed at our center over the period from January 2015 to November 2019. These patients were included due to their poor responses to protein restriction diets and alternative therapies of nitrogen scavengers. Detailed information on coagulation, liver function, histopathological and morphological examination of liver samples, and other clinical presentations were extracted from these patients. A grading scale was used for evaluating the neurological status, classification of physical growth and quality of life of these patients in response to the LT.Prior to LT, high levels of arginine were detected in all of argininemia patients and liver enzymes were elevated in nine of those patients. Nine patients presented with coagulation dysfunction without bleeding symptoms. Spastic paraplegia, irritability, intellectual developmental disability, and growth deficits were hallmarks of these nine patients, while four patients showed repeated, generalized tonic-clonic seizures before the operation. Seven novel mutations were found in these patients. The indication for LT in this series of patients was a presentation of progressive neurological impairments. After LT, the coagulation index and plasma arginine levels returned to normal and episodes of seizure were controlled in four patients. To date, all patients have survived and their LT has resulted a restoration of arginine metabolism and liver function, along with preventing further neurological deterioration, all of which provided an opportunity for future recuperation. Overall, the neurological status, growth deficits and quality of life were all significantly improved after LT with no evidence of severe complications.LT can serve as an effective treatment for argininemia in patients who respond poorly to traditional therapy. An early intervention of LT should be conducted in these patients to prevent neurological damage and improve their quality of life.
2021-07-01 | Neurophysiological characteristics in argininemia: a case report
: Argininemia is a rare inherited disorder characterized by progressive spastic paraplegia, leading by mutation of the ARG1 gene. Liver transplantation (LT) had been reported to prevent symptoms progression, while its pathophysiology is still unclear. A 13-year-old male patient with argininemia for progressive neurological impairment was admitted to our center. Plasma amino acid screening showed a high concentration of arginine, and gene sequencing showed heterozygous mutation of the ARG1 gene. Spastic Paraplegia Rating Scale (SPRS), motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs), F-wave, electromyography, nerve conduction velocity (NCV), and brain MRI were used to evaluate the patient. Herein, we describe the clinical characteristics of this patient, attempting a correlation between clinical, neurophysiological, and neuroimaging data in argininemia. Pyramidal tract dysfunction of lower limbs affected him, while only MEPs showed abnormalities among all neurophysiological evaluations, and mild cerebellum atrophy was observed. He responded poorly to traditional treatment such as a protein restriction diet and sodium benzoate. The symptoms of speech disorder, irritability, and dyskinesia were gradually deteriorating, so living-donor LT (LDLT) was done to prevent the progression. The symptoms improved significantly six months after LT, and the spasticity severity score decreased 50%. The findings suggest that LDLT is effective to argininemia, and the phenotypical similarities to other disorders that affect the urea cycle (HHH syndrome and pyrroline-5-carboxylate synthetase deficiency) suggest a common mechanism may contribute to maintaining the integrity of the corticospinal tract.
2021-05-27 | Characteristics of Argininemia and Effect of Liver Transplantation-the Largest Experience in China
Abstract Background: Argininemia is a rare urea cycle disorder due to arginase-1 deficiency, characterized by progressive spastic paraplegia. Coagulation dysfunction has been reported in few researches, and the pathophysiology is still unclear. Advances in diagnosis and treatment have increased the number of patients receiving effective management; however, not all symptoms are prevented under traditional treatments, and there is no consensus on liver transplantation (LT) for the treatment of patients with argininemia. Methods: We conducted a retrospective study of patients who had been done LT in our center between January 2015 and November 2019. Eleven patients with argininemia were included for their poor response to protein restriction dietary and alternative therapy of nitrogen scavengers. The details on coagulation, liver function, histopathological and morphological examination of liver samples, and other clinical presentations were extracted. The Grading Scale for evaluating neurological status and classification of physical growth and quality of life was used to assess the effect of LT. Results: All patients demonstrated hyperarginine, progressive neurological impairments, among whom nine patients presented coagulation dysfunction pre-oparation. After LT, the coagulation index and plasma arginine returned to normal in all patients, and neurological symptoms, growth deficit, and quality of life improved significantly without any severe complications. All patients survive to date. Conclusions: Our findings indicated that coagulation abnormality was a typical presentation of argininemia. LT can prevent progressive neurological impairment and restore metabolic disorders entirely.
2020-08-25 | Liver-transplantation-corrected coagulation dysfunction and neurological impairment in patients with argininemia
Abstract Background Argininemia is a rare disease caused by inborn errors of metabolism. Advances in diagnosis and treatment have increased the number of patients receiving effective management. Argininemia is characterized by progressive spastic paraplegia, mental retardation, failure to thrive and irritability, and patients with coagulopathy are paid more attention. We studied the changes in coagulation dysfunctions and neurodevelopment in patients with argininemia before and after liver transplantation(LT). Methods The data in this study were obtained from the Liver Transplantation Center of Beijing Friendship Hospital, Capital Medical University between January 2015 and November 2019. We identified data related to argininemia in all patients diagnosed with urea cycle disorder, and extracted the details on coagulation, liver function, neurodevelopmental outcomes, histopathological and morphological examination, and other clinical presentations. The patients were followed up by telephone and/or in the clinic. Results Nine patients with argininemia diagnosed by tandem mass spectrometry and symptoms, and confirmed by gene sequencing. The symptoms deteriorated after dietary restriction in all patients with argininemia. Coagulopathy manifested before surgery, and no significant correlation was detected with plasma ammonia concentration. The coagulation dysfunction was completely resolved and progressive neurological impairment was prevented in seven patients with LT. Conclusions Coagulation dysfunctions are common manifestations of patients with
proteins
2026-07-06 | Efficacy and safety of pegzilarginase in patients below 2 years of age with arginase 1 deficiency: a phase 3, open-label, multi-centre study.
Arginase 1 Deficiency (ARG1-D) is a rare metabolic disorder characterized by marked hyperargininaemia and progressive neurological impairment. Dietary protein restriction alone is often insufficient to normalize plasma arginine (pArg) or prevent disease progression. Pegzilarginase, a recombinant human ARG1 enzyme therapy, has demonstrated pArg normalization and improved clinical outcomes in patients ≥2 years. This study evaluated safety, pharmacokinetics (PK), and activity of pegzilarginase in patients <2 years. In this phase 3, open-label, single-arm study (NCT06582524, EU CT 2024-510797-25), conducted in United Kingdom, Austria and Portugal, patients received once-weekly subcutaneous pegzilarginase. As primary endpoint, change in pArg at 12 weeks was assessed. Secondary endpoints included safety, PK, plasma ornithine and Gross Motor Function Measure (GMFM-66). Descriptive analyses were performed on the Full Analysis Set. Three patients (mean age 20.3 months) were included between 30 August 2024 and 17 June 2025. After 12 weeks, mean (SD) pArg decreased by 221.5 (81.3) μmol/L, a 70.6% (4.3) reduction, reaching normal range by Visit 4 (114.1 [68.4] μmol/L). Plasma ornithine increased and plasma ammonia remained largely normal. GMFM-66 total scores improved by 21.0 (13.9) points (18.1% [5.8%]). Pegzilarginase exposure was consistent with previous studies; AUC and half-life were similar, whereas clearance and volume of distribution were lower, as expected in infants. No new safety findings were observed. In patients with ARG1-D <2 years of age, pegzilarginase demonstrated pharmacokinetic and pharmacodynamic responses comparable to older children and a favourable safety profile. Immedica Pharma AB.
2026-05-27 | Pegzilarginase in Arginase 1 Deficiency: Clinical and Biochemical Effects of Treatment Initiation, Discontinuation and Re-Initiation.
Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by hyperargininemia and progressive neurological impairment, including spasticity, loss of motor function, and reduced quality of life. Conventional management based on dietary protein restriction and ammonia scavengers rarely achieves adequate metabolic control or prevents neurological deterioration. Pegzilarginase, a recombinant human arginase 1 enzyme, is the first disease-modifying therapy for ARG1-D. We report the first Italian real-world experience with pegzilarginase in three pediatric patients with genetically confirmed ARG1-D enrolled in the phase 3 PEACE trial. Clinical, biochemical, functional, nutritional and quality-of-life data were retrospectively collected over a long-term follow-up (2003-2025). Outcomes were evaluated across three phases: treatment initiation (Start), a 13-month treatment interruption due to trial closure (Stop), and therapy re-initiation through an early access program (Restart). Pegzilarginase rapidly normalized plasma arginine levels and was associated with improvements in motor function, spasticity, walking endurance, dietary protein tolerance, bone mineral density, and quality of life. During treatment interruption, all patients experienced biochemical worsening and clinical deterioration, including increased spasticity, reduced mobility, and emotional distress. Re-initiation of pegzilarginase restored metabolic control and led to progressive neurological and functional recovery, including partial reversal of long-standing motor deficits. This real-world experience supports pegzilarginase as a disease-modifying therapy for ARG1-D. Sustained normalization of plasma arginine, rather than subthreshold biochemical control, correlates with functional and neurological improvement and may partially reverse non-lesional metabolic brain injury. Early initiation of pegzilarginase, including in newborn-screened patients, may further modify the natural history of ARG1-D.
2026-05-13 | Extracellular Vesicles Delivered a Functional ARG1 Enzyme and Restored Its Activity in a Mouse Model of ARG1-D Resulting in Improved Lifespan.
Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor's StealthXTM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1-/- mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthXTM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach.
2026-04-17 | Semi-Rational Engineering of rhArg1 via Non-Conserved Residue Mutagenesis for Enhanced Efficiency and Stability.
Arginase 1 deficiency is a rare inherited metabolic disorder characterized by progressive neurological dysfunction. Although recombinant human arginase 1 (rhArg1) has been investigated as a therapeutic enzyme, its clinical potential is limited by insufficient catalytic activity and stability. In this study, we applied an evolutionary conservation-guided design strategy to enhance rhArg1 activity by targeting low-conservation residues within the catalytic pocket. Seven candidate sites were identified, and 29 variants were generated by site-directed and combinatorial mutagenesis. Under 2 mM Mn2+ conditions, several mutants (N139K, Q143K, and Q143S) exhibited 1.4-1.6 fold increases in kcat relative to the wild type. Notably, under Mn2+-free conditions, the double mutant T136D/Q143V showed a 1.5-fold increase in kcat and a 73% improvement in kcat/KM. Molecular dynamics simulations revealed that these mutations enhance catalytic performance by promoting near-attack conformations. This work demonstrates an effective rational strategy for improving rhArg1 catalytic efficiency and stability, supporting its therapeutic development.
2025-07-28 | Long-Term Efficacy and Tolerability of Pegzilarginase in Arginase 1 Deficiency: Results of Two International Multicentre Open-Label Extension Studies.
Arginase 1 deficiency (ARG1-D) is an autosomal recessive urea cycle disorder characterised by chronic hyperargininaemia, progressive spasticity, loss of mobility, and cognitive dysfunction. Standard of care (SOC), based on dietary protein restriction, rarely prevents progression. Pegzilarginase, a recombinant human enzyme, is the first approved disease-modifying therapy. We report outcomes from Study 102A (n = 14; up to 5 years) and the PEACE long-term extension (LTE) (n = 31; up to 3 years). Weekly pegzilarginase was administered with SOC. Outcomes included functional mobility (2-/6-minute walk tests [2MWT/6MWT], Gross Motor Function Measure [GMFM] D/E), spasticity (Modified Ashworth Scale [MAS]), plasma arginine, guanidino compounds, and safety. In PEACE, LTE arms were named according to initial 24-week double-blind treatment: placebo-pegzilarginase or pegzilarginase-pegzilarginase. Of 39 evaluable participants, 37 (95%) met composite response or achieved maximum score in ≥ 1 motor function domain. In 102A, mean 6MWT improved to 68.2 m (+19%; n = 12); GMFM-D/E increased by 2.7/3.7. In PEACE (pegzilarginase-pegzilarginase; placebo-pegzilarginase), 2MWT improved to 16.5 m (+25%; n = 6) and 13.5 m (+16%; n = 2); GMFM-D/E improved by 4.3/6.0 (n = 6) and 5.3/11.3 (n = 3). Spasticity improved in 21/25 (84%), with 12 reaching MAS 0 (no spasticity). Pegzilarginase sustained plasma arginine control: in 102A, means were 118 μmol/L at Week 192 (n = 9); in PEACE, < 115 μmol/L through Week 96 (n = 11). Guanidinoacetic acid normalised; N-acetylarginine approached normal; argininic acid and α-keto-δ-guanidinovaleric acid declined by > 50%. Most adverse events were mild/moderate; no treatment-related discontinuations or persistent antibodies occurred. Pegzilarginase produced sustained improvements in mobility, spasticity and biochemical control, supporting early intervention, long-term use and disease modification in ARG1-D.
other
2024-10-25 | Exploring RNA therapeutics for urea cycle disorders.
RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.
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.
2018-07-03 | Arginase I mRNA therapy – a novel approach to rescue arginase 1 enzyme deficiency
Arginase I (ARG1) deficiency is an autosomal recessive urea cycle disorder, caused by deficiency of the enzyme Arginase I, resulting in accumulation of arginine in blood. Current Standard of Care (SOC) for ARG1 deficiency in patients or those having detrimental mutations of ARG1 gene is diet control. Despite diet and drug therapy with nitrogen scavengers, ~25% of patients suffer from severe mental deficits and loss of ambulation. 75% of patients whose symptoms can be managed through diet therapy continue to suffer neuro-cognitive deficits. In our research, we demonstrate in vitro and in vivo that administration of ARG1 mRNA increased ARG1 protein expression and specific activity in relevant cell types, including ARG1-deficient patient cell lines, as well as in wild type mice for up to 4 days. These studies demonstrate that ARG1 mRNA treatment led to increased functional protein expression of ARG1 and subsequently an increase in urea. Hence, ARG1 mRNA therapy could be a potential treatment option to develop for patients.
small molecules
2025-07-11 | Control of Coagulation Abnormalities with Sodium Benzoate in Patients with Argininemia
Aim: This study aimed to evaluate coagulation disorders in patients with argininemia associated with arginase 1 gene mutations and the control of these disorders with sodium benzoate treatment.Materials and Methods: Five argininemia patients followed up in the Pediatric Metabolism Clinic in University of Health Sciences Trkiye, Baakehir am and Sakura City Hospital, were included in this study.The patients initially received protein-restricted diet treatment, while their ammonia, platelet count, liver enzymes and coagulation parameters were measured regularly.Later, sodium benzoate was added to the treatment and the same parameters were measured at 1-month intervals.Results: In the coagulation parameters measured after sodium benzoate treatment, one out of the five patients showed complete improvement, three had partial improvement, and one had no change.In the patients with coagulation disorders, factor VII and IX levels were low, while arginine levels remained above 250 mol/L. Conclusion:The pathophysiology of coagulation disorders in patients with argininemia has not yet been fully elucidated, but it is thought that high arginine levels may affect the synthesis of short-lived coagulation factors.Adding sodium benzoate to dietary therapy may contribute to both the control of arginine levels and an improvement in coagulation parameters.This study demonstrates the importance of coagulation monitoring in those patients with argininemia and the potential therapeutic role of sodium benzoate.
2025-01-31 | First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours.
The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed. In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy). A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50-100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti-PD-1/PD-L1-naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response. INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted. NCT02903914.
2025-01-24 | Protective effects of berbamine against arginase-1 deficiency-induced injury in human brain microvascular endothelial cells.
Endothelial cell dysfunction plays a crucial role in the early development of cerebral small vessel disease (CSVD). Arginase-1 (ARG1) is expressed in endothelial cells, and its deficiency may exacerbate cerebrovascular damage by increasing reactive oxygen species (ROS) production, thereby inducing endothelial cell apoptosis. Berbamine (BBM) has shown potential in neuroprotection and cardiovascular disease prevention. This study aimed to investigate the impact of ARG1 deficiency on human brain microvascular endothelial cells and the protective effects of BBM against ARG1 deficiency-induced damage. Human brain microvascular endothelial cells (HCMEC/D3) were cultured in vitro, and ARG1 knockdown or overexpression was achieved using plasmid transfection techniques. We examined the effects of ARG1 expression levels on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis through cellular experiments. Additionally, we explored how ARG1 expression levels influenced arginine (Arg), nitric oxide (NO), and ROS levels in HCMEC/D3 cells. The results demonstrated that ARG1 deficiency inhibited HCMEC/D3 cell viability, migration, adhesion, and angiogenesis, while promoting apoptosis and elevating Arg, NO, and ROS levels in HCMEC/D3 cells. Next, the effect of different BBM concentrations on HCMEC/D3 cell viability was assessed using the CCK-8 assay, revealing that BBM at a concentration of 5 µM had no significant impact on cell viability. Subsequently, after successfully knocking down ARG1 in HCMEC/D3 cells, the cells were treated with BBM. The results showed that BBM effectively mitigated the negative effects of ARG1 deficiency on HCMEC/D3 cell viability, migration, apoptosis, adhesion, and angiogenesis, while also reducing Arg, NO, inducible nitric oxide synthase (iNOS), and ROS levels in HCMEC/D3 cells. In conclusion, this study suggests that ARG1 deficiency may damage HCMEC/D3 cells by increasing Arg levels, leading to elevated NO and ROS levels. BBM may provide protection to ARG1-deficient HCMEC/D3 cells by reducing Arg, NO, iNOS, and ROS levels. These findings deepen our understanding of the pathogenesis of CSVD and provide a theoretical basis for the clinical application of BBM.
2024-11-13 | Disease burden among patients with Arginase 1 deficiency and their caregivers: A multinational, cross-sectional survey.
Arginase 1 deficiency (ARG1-D) is an ultrarare, metabolic disease which may cause spastic paraplegia, cognitive deficiency, seizures, and ultimately severe disability. The aim of this study was to assess disease burden in ARG1-D by performing a cross-sectional survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, and the United Kingdom). Patients were enrolled at participating clinics and data were collected using a web-based questionnaire. The findings indicate that there is a significant share of patients who experience severe cognitive and mobility impairment but also that there is a considerable variance in symptom severity among patients. Disease management was mostly in line with treatment guidelines and self-reported adherence to treatment was reported to be high among a majority although following diet restrictions was perceived as difficult. However, despite this, since a large share of patients experienced severe cognitive and mobility impairment an unmet need among this patient population is suggested. The introduction of disease-modifying therapies and early identification and diagnosis may help alleviate the disease burden associated with ARG1-D in the future.
2024-09-07 | Societal costs and quality of life associated with arginase 1 deficiency in a European setting - a multinational, cross-sectional survey.
Arginase 1 deficiency (ARG1-D) is a ultrarare disease with manifestations that cause mobility and cognitive impairment that progress over time and may lead to early mortality. Diseases such as ARG1-D have a major impact also outside of the health care sector and the aim of this study was to estimate the current burden of disease associated with ARG1-D from a societal perspective. The study was performed as a web-based survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, United Kingdom). The survey was distributed at participating clinics and included questions on e.g. symptoms (including the Gross Motor Function Classification System, GMFCS, and cognitive impairment), health care use, medication, ability to work, caregiving, and impact on health-related quality-of-life (HRQoL) using the EQ-5D-5L. The estimated total mean societal cost per patient and year was £63,775 (SD: £49,944). The cost varied significantly with both mobility impairment (from £49,809 for GMFCS level 1 to £103,639 for GMFCS levels 3-5) and cognitive impairment (from £43,860 for mild level to £99,162 for severe level). The mean utility score on the EQ-5D-5L for patients was 0.498 (SD: 0.352). The utility score also varied significantly with both mobility impairment (from 0.783 for GMFCS level 1 to 0.153 for GMFCS level 3-5) and cognitive impairment (from 0.738 for mild level to 0.364 for severe level). Similar to other studies of rare diseases, the study is based on a limited number of observations. However, the sample appear to be reasonably representative when comparing to previous studies of ARG1-D. This study shows that ARG1-D is associated with a high societal cost and significant impact on HRQoL. Earlier diagnosis and better treatment options that can postpone or withhold progression may therefore have a potential for improved HRQoL and savings for the patient, caregiver, and society.
gene therapies
2025-12-05 | Comparing CRISPR-Cas9 Gene Therapy Delivery Systems: Implications and Optimization for Hyperargininemia
Hyperargininemia is a rare autosomal recessive metabolic disorder caused by a deficiency in the urea cycle enzyme arginase 1, resulting in severe systemic and neurological complications. Given the shortcomings of conventional treatment paradigms, there is an increasing demand for gene therapies, such as CRISPR-Cas9, that address hyperargininemia at its genetic root and reverse its diverse manifestations. Homology-directed repair offers high specificity and durable genetic correction. The strategic delivery of CRISPR components, including homology arm-flanked, wild-type ARG1 cDNA, Cas9 endonucleases, and appropriate sgRNAs, is necessary to enable homology-directed repair in arginase 1-deficient hepatocytes. This review summarizes the methodology, strengths, and weaknesses of three prominent CRISPR delivery methods: lipid nanoparticles, recombinant adeno-associated viruses, and electroporation. We also highlight ongoing efforts to optimize these delivery methods and analyze the relevance of existing preclinical CRISPR-Cas9 studies to hyperargininemia. Among these delivery systems, recombinant adeno-associated viruses currently show the most promise for clinical translation, although further enhancements in safety and scalability remain necessary.
2025-04-29 | Updated Gene Therapy for Renal Inborn Errors of Metabolism
Inborn errors of metabolism (IEMs) are a group of disorders resulting from defects in enzymes in metabolic pathways. These disorders impact the processing of metabolites, leading to a wide array of effects on each organ system. Advances in genetic screening have allowed for the early identification and intervention of IEMs, traditionally in the form of enzyme replacement or vitamin supplementation. However, many IEMs disrupt essential metabolic pathways where simple supplementation proves ineffective, resulting in substantial disease burden. In the case of renal IEMs, metabolic pathway disruption leads to the onset of chronic kidney disease (CKD). For these diseases, genetic therapy provides hope. Over the past few decades, the technology for genetic therapy has emerged as a promising solution to these disorders. These therapies aim to correct the source of the defect in the genetic code so that patients may live full, unencumbered lives. In this review, we searched a large database to identify IEMs that affect the kidney and investigated the current landscape and progression of gene therapy technology. Multiple promising genetic therapies were identified for IEMs affecting the kidney, including primary hyperoxaluria, argininemia, glycogen storage diseases Ia and Ib, and Fabry disease. Emerging gene therapy approaches using adeno-associated virus (AAV) vectors, lentiviral vectors, and CRISPR/Cas9 techniques hold promising potential to provide curative treatments for additional single-mutation disorders.
2019-07-26 | Genetic-Based Approaches to Inherited Metabolic Liver Diseases
In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all of these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Indeed, liver-directed gene therapy trials for hemophilia A and B have demonstrated the potential of gene therapy to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. Herein, we review the advances and limitations of gene therapy for such disorders, covering therapeutic strategies based on gene addition and gene editing and the exciting clinical results obtained with the use of ribonucleic acid as therapeutic molecules.
2018-12-13 | Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency.
Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible arginase-1 deficient mouse model harboring a deletion of Arg1 exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with piggyBac technology to target and reincorporate exons 7 and 8 at the specific Arg1 locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophages in vitro. While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of "repaired" arginase. Our studies provide proof-of-concept for gene-editing at the Arg1 locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders.
2016-11-29 | Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells
Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism. Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism.
cell therapies
2025-09-25 | Nanogram of Arg 1 Delivered by extracellular vesicles restore ARG1 activity in a mouse model of ARG1-D and improve lifespan
Abstract Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor’s StealthX™ platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of its localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1- encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies and results showed that STX-Arg1-in EVs were non-toxic and able to restore the arginase activities in the liver of the Arg1 -/- mice, which leads to a lowered plasma arginine concentration similar to wildtype mice. Most importantly, Arg1-in expanded the life span of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthX™-engineered STX-Arg1-in EVs have a better safety profile due to extreme low dosage and had great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement Intracellular delivery of recombinant protein and improved life span are endpoints of a successful enzyme replacement therapy for the treatment of ARG1-D. Using StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed intracellular delivery of ARG1 protein in vitro and in vivo, with improvement of life span in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with low dose, setting the base for an improved therapeutic approach.
2022-04-01 | The effect of liver transplantation for argininemia—the largest experiences in a single center
Argininemia, a rare urea cycle disorder resulting from an arginase-1 deficiency, is characterized by a progressive spastic paraplegia. While advances in diagnosis and treatment have increased the management of this condition, not all symptoms are resolved in response to traditional therapies. Interestingly, there exist some rare reports on the use of liver transplantation (LT) for the treatment of argininemia.We conducted a retrospective study of eleven patients with argininemia receiving a LT as performed at our center over the period from January 2015 to November 2019. These patients were included due to their poor responses to protein restriction diets and alternative therapies of nitrogen scavengers. Detailed information on coagulation, liver function, histopathological and morphological examination of liver samples, and other clinical presentations were extracted from these patients. A grading scale was used for evaluating the neurological status, classification of physical growth and quality of life of these patients in response to the LT.Prior to LT, high levels of arginine were detected in all of argininemia patients and liver enzymes were elevated in nine of those patients. Nine patients presented with coagulation dysfunction without bleeding symptoms. Spastic paraplegia, irritability, intellectual developmental disability, and growth deficits were hallmarks of these nine patients, while four patients showed repeated, generalized tonic-clonic seizures before the operation. Seven novel mutations were found in these patients. The indication for LT in this series of patients was a presentation of progressive neurological impairments. After LT, the coagulation index and plasma arginine levels returned to normal and episodes of seizure were controlled in four patients. To date, all patients have survived and their LT has resulted a restoration of arginine metabolism and liver function, along with preventing further neurological deterioration, all of which provided an opportunity for future recuperation. Overall, the neurological status, growth deficits and quality of life were all significantly improved after LT with no evidence of severe complications.LT can serve as an effective treatment for argininemia in patients who respond poorly to traditional therapy. An early intervention of LT should be conducted in these patients to prevent neurological damage and improve their quality of life.
2021-07-01 | Neurophysiological characteristics in argininemia: a case report
: Argininemia is a rare inherited disorder characterized by progressive spastic paraplegia, leading by mutation of the ARG1 gene. Liver transplantation (LT) had been reported to prevent symptoms progression, while its pathophysiology is still unclear. A 13-year-old male patient with argininemia for progressive neurological impairment was admitted to our center. Plasma amino acid screening showed a high concentration of arginine, and gene sequencing showed heterozygous mutation of the ARG1 gene. Spastic Paraplegia Rating Scale (SPRS), motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs), F-wave, electromyography, nerve conduction velocity (NCV), and brain MRI were used to evaluate the patient. Herein, we describe the clinical characteristics of this patient, attempting a correlation between clinical, neurophysiological, and neuroimaging data in argininemia. Pyramidal tract dysfunction of lower limbs affected him, while only MEPs showed abnormalities among all neurophysiological evaluations, and mild cerebellum atrophy was observed. He responded poorly to traditional treatment such as a protein restriction diet and sodium benzoate. The symptoms of speech disorder, irritability, and dyskinesia were gradually deteriorating, so living-donor LT (LDLT) was done to prevent the progression. The symptoms improved significantly six months after LT, and the spasticity severity score decreased 50%. The findings suggest that LDLT is effective to argininemia, and the phenotypical similarities to other disorders that affect the urea cycle (HHH syndrome and pyrroline-5-carboxylate synthetase deficiency) suggest a common mechanism may contribute to maintaining the integrity of the corticospinal tract.
2021-05-27 | Characteristics of Argininemia and Effect of Liver Transplantation-the Largest Experience in China
Abstract Background: Argininemia is a rare urea cycle disorder due to arginase-1 deficiency, characterized by progressive spastic paraplegia. Coagulation dysfunction has been reported in few researches, and the pathophysiology is still unclear. Advances in diagnosis and treatment have increased the number of patients receiving effective management; however, not all symptoms are prevented under traditional treatments, and there is no consensus on liver transplantation (LT) for the treatment of patients with argininemia. Methods: We conducted a retrospective study of patients who had been done LT in our center between January 2015 and November 2019. Eleven patients with argininemia were included for their poor response to protein restriction dietary and alternative therapy of nitrogen scavengers. The details on coagulation, liver function, histopathological and morphological examination of liver samples, and other clinical presentations were extracted. The Grading Scale for evaluating neurological status and classification of physical growth and quality of life was used to assess the effect of LT. Results: All patients demonstrated hyperarginine, progressive neurological impairments, among whom nine patients presented coagulation dysfunction pre-oparation. After LT, the coagulation index and plasma arginine returned to normal in all patients, and neurological symptoms, growth deficit, and quality of life improved significantly without any severe complications. All patients survive to date. Conclusions: Our findings indicated that coagulation abnormality was a typical presentation of argininemia. LT can prevent progressive neurological impairment and restore metabolic disorders entirely.
2020-08-25 | Liver-transplantation-corrected coagulation dysfunction and neurological impairment in patients with argininemia
Abstract Background Argininemia is a rare disease caused by inborn errors of metabolism. Advances in diagnosis and treatment have increased the number of patients receiving effective management. Argininemia is characterized by progressive spastic paraplegia, mental retardation, failure to thrive and irritability, and patients with coagulopathy are paid more attention. We studied the changes in coagulation dysfunctions and neurodevelopment in patients with argininemia before and after liver transplantation(LT). Methods The data in this study were obtained from the Liver Transplantation Center of Beijing Friendship Hospital, Capital Medical University between January 2015 and November 2019. We identified data related to argininemia in all patients diagnosed with urea cycle disorder, and extracted the details on coagulation, liver function, neurodevelopmental outcomes, histopathological and morphological examination, and other clinical presentations. The patients were followed up by telephone and/or in the clinic. Results Nine patients with argininemia diagnosed by tandem mass spectrometry and symptoms, and confirmed by gene sequencing. The symptoms deteriorated after dietary restriction in all patients with argininemia. Coagulopathy manifested before surgery, and no significant correlation was detected with plasma ammonia concentration. The coagulation dysfunction was completely resolved and progressive neurological impairment was prevented in seven patients with LT. Conclusions Coagulation dysfunctions are common manifestations of patients with
proteins
2026-07-06 | Efficacy and safety of pegzilarginase in patients below 2 years of age with arginase 1 deficiency: a phase 3, open-label, multi-centre study.
Arginase 1 Deficiency (ARG1-D) is a rare metabolic disorder characterized by marked hyperargininaemia and progressive neurological impairment. Dietary protein restriction alone is often insufficient to normalize plasma arginine (pArg) or prevent disease progression. Pegzilarginase, a recombinant human ARG1 enzyme therapy, has demonstrated pArg normalization and improved clinical outcomes in patients ≥2 years. This study evaluated safety, pharmacokinetics (PK), and activity of pegzilarginase in patients <2 years. In this phase 3, open-label, single-arm study (NCT06582524, EU CT 2024-510797-25), conducted in United Kingdom, Austria and Portugal, patients received once-weekly subcutaneous pegzilarginase. As primary endpoint, change in pArg at 12 weeks was assessed. Secondary endpoints included safety, PK, plasma ornithine and Gross Motor Function Measure (GMFM-66). Descriptive analyses were performed on the Full Analysis Set. Three patients (mean age 20.3 months) were included between 30 August 2024 and 17 June 2025. After 12 weeks, mean (SD) pArg decreased by 221.5 (81.3) μmol/L, a 70.6% (4.3) reduction, reaching normal range by Visit 4 (114.1 [68.4] μmol/L). Plasma ornithine increased and plasma ammonia remained largely normal. GMFM-66 total scores improved by 21.0 (13.9) points (18.1% [5.8%]). Pegzilarginase exposure was consistent with previous studies; AUC and half-life were similar, whereas clearance and volume of distribution were lower, as expected in infants. No new safety findings were observed. In patients with ARG1-D <2 years of age, pegzilarginase demonstrated pharmacokinetic and pharmacodynamic responses comparable to older children and a favourable safety profile. Immedica Pharma AB.
2026-05-27 | Pegzilarginase in Arginase 1 Deficiency: Clinical and Biochemical Effects of Treatment Initiation, Discontinuation and Re-Initiation.
Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by hyperargininemia and progressive neurological impairment, including spasticity, loss of motor function, and reduced quality of life. Conventional management based on dietary protein restriction and ammonia scavengers rarely achieves adequate metabolic control or prevents neurological deterioration. Pegzilarginase, a recombinant human arginase 1 enzyme, is the first disease-modifying therapy for ARG1-D. We report the first Italian real-world experience with pegzilarginase in three pediatric patients with genetically confirmed ARG1-D enrolled in the phase 3 PEACE trial. Clinical, biochemical, functional, nutritional and quality-of-life data were retrospectively collected over a long-term follow-up (2003-2025). Outcomes were evaluated across three phases: treatment initiation (Start), a 13-month treatment interruption due to trial closure (Stop), and therapy re-initiation through an early access program (Restart). Pegzilarginase rapidly normalized plasma arginine levels and was associated with improvements in motor function, spasticity, walking endurance, dietary protein tolerance, bone mineral density, and quality of life. During treatment interruption, all patients experienced biochemical worsening and clinical deterioration, including increased spasticity, reduced mobility, and emotional distress. Re-initiation of pegzilarginase restored metabolic control and led to progressive neurological and functional recovery, including partial reversal of long-standing motor deficits. This real-world experience supports pegzilarginase as a disease-modifying therapy for ARG1-D. Sustained normalization of plasma arginine, rather than subthreshold biochemical control, correlates with functional and neurological improvement and may partially reverse non-lesional metabolic brain injury. Early initiation of pegzilarginase, including in newborn-screened patients, may further modify the natural history of ARG1-D.
2026-05-13 | Extracellular Vesicles Delivered a Functional ARG1 Enzyme and Restored Its Activity in a Mouse Model of ARG1-D Resulting in Improved Lifespan.
Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor's StealthXTM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1-/- mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthXTM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach.
2026-04-17 | Semi-Rational Engineering of rhArg1 via Non-Conserved Residue Mutagenesis for Enhanced Efficiency and Stability.
Arginase 1 deficiency is a rare inherited metabolic disorder characterized by progressive neurological dysfunction. Although recombinant human arginase 1 (rhArg1) has been investigated as a therapeutic enzyme, its clinical potential is limited by insufficient catalytic activity and stability. In this study, we applied an evolutionary conservation-guided design strategy to enhance rhArg1 activity by targeting low-conservation residues within the catalytic pocket. Seven candidate sites were identified, and 29 variants were generated by site-directed and combinatorial mutagenesis. Under 2 mM Mn2+ conditions, several mutants (N139K, Q143K, and Q143S) exhibited 1.4-1.6 fold increases in kcat relative to the wild type. Notably, under Mn2+-free conditions, the double mutant T136D/Q143V showed a 1.5-fold increase in kcat and a 73% improvement in kcat/KM. Molecular dynamics simulations revealed that these mutations enhance catalytic performance by promoting near-attack conformations. This work demonstrates an effective rational strategy for improving rhArg1 catalytic efficiency and stability, supporting its therapeutic development.
2025-07-28 | Long-Term Efficacy and Tolerability of Pegzilarginase in Arginase 1 Deficiency: Results of Two International Multicentre Open-Label Extension Studies.
Arginase 1 deficiency (ARG1-D) is an autosomal recessive urea cycle disorder characterised by chronic hyperargininaemia, progressive spasticity, loss of mobility, and cognitive dysfunction. Standard of care (SOC), based on dietary protein restriction, rarely prevents progression. Pegzilarginase, a recombinant human enzyme, is the first approved disease-modifying therapy. We report outcomes from Study 102A (n = 14; up to 5 years) and the PEACE long-term extension (LTE) (n = 31; up to 3 years). Weekly pegzilarginase was administered with SOC. Outcomes included functional mobility (2-/6-minute walk tests [2MWT/6MWT], Gross Motor Function Measure [GMFM] D/E), spasticity (Modified Ashworth Scale [MAS]), plasma arginine, guanidino compounds, and safety. In PEACE, LTE arms were named according to initial 24-week double-blind treatment: placebo-pegzilarginase or pegzilarginase-pegzilarginase. Of 39 evaluable participants, 37 (95%) met composite response or achieved maximum score in ≥ 1 motor function domain. In 102A, mean 6MWT improved to 68.2 m (+19%; n = 12); GMFM-D/E increased by 2.7/3.7. In PEACE (pegzilarginase-pegzilarginase; placebo-pegzilarginase), 2MWT improved to 16.5 m (+25%; n = 6) and 13.5 m (+16%; n = 2); GMFM-D/E improved by 4.3/6.0 (n = 6) and 5.3/11.3 (n = 3). Spasticity improved in 21/25 (84%), with 12 reaching MAS 0 (no spasticity). Pegzilarginase sustained plasma arginine control: in 102A, means were 118 μmol/L at Week 192 (n = 9); in PEACE, < 115 μmol/L through Week 96 (n = 11). Guanidinoacetic acid normalised; N-acetylarginine approached normal; argininic acid and α-keto-δ-guanidinovaleric acid declined by > 50%. Most adverse events were mild/moderate; no treatment-related discontinuations or persistent antibodies occurred. Pegzilarginase produced sustained improvements in mobility, spasticity and biochemical control, supporting early intervention, long-term use and disease modification in ARG1-D.
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2024-10-25 | Exploring RNA therapeutics for urea cycle disorders.
RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.
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.
2018-07-03 | Arginase I mRNA therapy – a novel approach to rescue arginase 1 enzyme deficiency
Arginase I (ARG1) deficiency is an autosomal recessive urea cycle disorder, caused by deficiency of the enzyme Arginase I, resulting in accumulation of arginine in blood. Current Standard of Care (SOC) for ARG1 deficiency in patients or those having detrimental mutations of ARG1 gene is diet control. Despite diet and drug therapy with nitrogen scavengers, ~25% of patients suffer from severe mental deficits and loss of ambulation. 75% of patients whose symptoms can be managed through diet therapy continue to suffer neuro-cognitive deficits. In our research, we demonstrate in vitro and in vivo that administration of ARG1 mRNA increased ARG1 protein expression and specific activity in relevant cell types, including ARG1-deficient patient cell lines, as well as in wild type mice for up to 4 days. These studies demonstrate that ARG1 mRNA treatment led to increased functional protein expression of ARG1 and subsequently an increase in urea. Hence, ARG1 mRNA therapy could be a potential treatment option to develop for patients.
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Drug Discovery Landscape
9 orphan drug designations for Argininemia, including 3 approved therapies.
9 orphan drug designations for Argininemia, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated vector expressing human codon-optimized arginase 1 under a liver-specific promoter | gene therapies | FDA | 2024-11-12 | — | Ronald Reagan UCLA Medical Center |
Sodium benzoate, sodium phenylacetate | small molecules | EMA | 2019-06-28 | — | Dipharma B.V. |
Sodium benzoate | small molecules | EMA | 2016-07-14 | — | Lucane Pharma SA |
Poly(oxy-1,2-ethanediyl), alpha-(carboxymethyl)-omega-methoxy-,amide with arginase 1 [cobalt cofactor] (synthetic human) (1:10), trimer [Loargys] | proteins | EMA | 2016-07-14 | 2023-12-18 | Immedica Pharma AB |
Sodium benzoate | small molecules | EMA | 2016-01-11 | — | Syri Pharma Limited |
pegzilarginase-nbln [Loargys] | proteins | FDA | 2015-03-16 | 2026-02-23 | Immedica Pharma AB |
Heterologous human adult liver-derived progenitor cells | cell therapies | EMA | 2013-07-17 | — | Cellaion |
Human heterologous liver cells (for infusion) | cell therapies | EMA | 2010-12-17 | — | Promethera Biosciences |
Glyceryl tri-(4-phenylbutyrate) [Ravicti] | small molecules | EMA | 2010-06-10 | 2015-12-01 | Immedica Pharma AB |
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