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Arginase Deficiency

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0008814 Model: Edison Scientific Literature 31 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Arginase Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Arginase Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Arginase 1 Deficiency (Argininemia / Hyperargininemia): Molecular and Cellular Mechanisms, Disease Course, and 2023–2024 Translational Updates

Publication window prioritized: 2024 primary and review literature, plus ClinicalTrials.gov entries.

  1. Disease identity, key concepts, and definitions (current understanding)

Disease name and ontology - Arginase 1 deficiency (ARG1-D), also called argininemia or hyperargininemia, is an autosomal recessive urea cycle disorder caused by biallelic pathogenic variants in ARG1 (arginase 1), the final enzyme of the urea cycle. (russo2024efficacyandsafety pages 1-2, nteli2024argininemiapathophysiologyand pages 2-3) - MONDO: arginase deficiency = MONDO_0008814 (Open Targets output). (nteli2024argininemiapathophysiologyand pages 7-8)

Core biochemical definition - ARG1 catalyzes the final urea cycle step, “hydrolysis of L-arginine to ornithine and urea.” (nteli2024argininemiapathophysiologyand pages 2-3) - Loss of hepatic ARG1 activity leads to persistent hyperargininemia and accumulation of downstream nitrogenous metabolites, including guanidino compounds (GCs), with intermittent episodic hyperammonemia in some contexts. (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 3-5)

Key “pathophysiological driver” concept - In the 2024 phase 3 pegzilarginase PEACE trial paper, arginine is explicitly framed as the central driver: “Arginine: the key driver of patophysiology and progression in arginase 1 deficiency.” (russo2024efficacyandsafety pages 16-16)

  1. Core pathophysiology (molecular pathways and cellular processes)

2.1 Primary pathophysiological mechanism: impaired ureagenesis with hyperargininemia - ARG1 is predominantly a liver cytosolic enzyme, but is also present in erythrocytes, vasculature, and immune cells; it is described as a trimeric metalloprotein requiring Mn2+ for maximal activity and structural stabilization. (nteli2024argininemiapathophysiologyand pages 2-3) - ARG1 mutations reduce/ablate enzymatic activity, causing arginine accumulation and broader disruption of nitrogen disposal (“accumulation of arginine and other nitrogenous metabolites”), with hyperammonemia occurring less frequently than in many other urea cycle disorders but still clinically relevant during catabolic stress. (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 5-7)

Biomarker magnitudes and targets - Plasma arginine can be markedly elevated: “as high as four times the normal (>300 µmol/L),” and the “primary goal in argininemia is to reduce arginine concentration in plasma below 200 µmol/L.” (nteli2024argininemiapathophysiologyand pages 5-7)

2.2 Neurotoxicity: arginine-derivatives (guanidino compounds) and disrupted neurotransmission/ion homeostasis - The 2024 review emphasizes that accumulation of arginine, ammonia, and guanidino compounds act as neurotoxins contributing to neurological sequelae. (nteli2024argininemiapathophysiologyand pages 1-2, nteli2024argininemiapathophysiologyand pages 3-5) - Mechanistic neurotoxicity themes cited in the 2024 review include: - Inhibition of inhibitory neurotransmission: “Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture.” (russo2024efficacyandsafety pages 16-16) - Disruption of membrane ion pumps and cholinergic signaling via in vitro inhibitory effects on Na+,K+-ATPase and cholinesterases, and induction of oxidative stress in brain tissue models. (nteli2024argininemiapathophysiologyand pages 12-14)

2.3 White matter / myelination involvement (cellular and tissue pathology) - Central nervous system white matter pathology is supported by the review’s cited evidence of “dysmyelination” and corticospinal tract pathology, with oligodendrocyte degeneration/dysmyelination discussed as part of mechanistic interpretation for progressive spasticity. (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 3-5) - RNA-therapeutics review highlights preclinical evidence that addressing hepatic ARG1 deficiency can prevent CNS myelination defects in mice: “intermittent administration of LNPs carrying ARG1 mRNA significantly improved myelination in the central nervous system and managed ammonia and arginine levels in arginase-deficient mice.” (richard2024exploringrnatherapeutics pages 4-6)

2.4 Nitric oxide / polyamine pathway interface (dysregulated arginine utilization) - The 2024 review highlights pathway cross-talk: arginine is a common substrate for arginase and nitric oxide synthase (NOS), and cites work on the “Regulatory Role of Arginase I and II in Nitric Oxide, Polyamine, and Proline Syntheses in Endothelial Cells,” supporting the concept that ARG1 loss can perturb arginine partitioning into NO and polyamine-related pathways. (nteli2024argininemiapathophysiologyand pages 12-14)

  1. Key molecular players (genes/proteins, chemicals, cell types, anatomy)

3.1 Genes/proteins - Causal gene: ARG1 (arginase 1). (russo2024efficacyandsafety pages 1-2, nteli2024argininemiapathophysiologyand pages 2-3) - Disease genetics summary from 2024 review: ARG1 is on chromosome 6q23; “more than 43 pathogenic mutations have been identified.” (nteli2024argininemiapathophysiologyand pages 7-8)

3.2 Chemical entities / metabolites (with CHEBI-ready list) Key metabolites and small molecules implicated by the 2024 review and phase 3 trial: - L-arginine (CHEBI:29016) — primary elevated metabolite and disease driver. (russo2024efficacyandsafety pages 16-16, nteli2024argininemiapathophysiologyand pages 5-7) - Ornithine (CHEBI:15729) — reduced production due to impaired arginine hydrolysis; Arg/Orn ratio used diagnostically. (nteli2024argininemiapathophysiologyand pages 7-8) - Urea (CHEBI:16199) — reduced production due to impaired urea cycle output. (nteli2024argininemiapathophysiologyand pages 2-3) - Ammonia/ammonium (CHEBI:28938/CHEBI:7434) — episodic elevations during catabolic stress; less frequent than other UCDs. (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 5-7) - Guanidino compounds (group term; includes multiple guanidino-derivatives) — increased in ARG1-D; neurotoxic and measurable in blood/CSF/brain material. (russo2024efficacyandsafety pages 16-16, nteli2024argininemiapathophysiologyand pages 12-14)

Therapeutic chemical/biologic entities with real-world use - Nitrogen scavengers: benzoate, phenylbutyrate, phenylacetate. (nteli2024argininemiapathophysiologyand pages 5-7) - Pegzilarginase (pegylated recombinant human arginase 1 enzyme therapy). (russo2024efficacyandsafety pages 1-2)

3.3 Cell types (CL-ready examples supported by evidence) - Hepatocytes (liver is the central organ of ureagenesis; “hepatocyte arginase” deficiency is emphasized). (nteli2024argininemiapathophysiologyand pages 5-7) - Erythrocytes / red blood cells (ARG1 activity is measured in RBCs; ARG1 present in erythrocytes). (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 5-7) - Neurons (mouse neuron culture evidence for GABA/glycine response inhibition by increased guanidino compounds). (russo2024efficacyandsafety pages 16-16) - Oligodendrocytes (implicated by dysmyelination/white matter pathology discussed in review). (nteli2024argininemiapathophysiologyand pages 3-5) - Immune cells (ARG1 noted as present in immune cells such as M2-like macrophages). (nteli2024argininemiapathophysiologyand pages 2-3)

3.4 Anatomical locations (UBERON-ready examples) - Liver (UBERON:0002107) — primary site of ARG1-mediated urea cycle flux. (nteli2024argininemiapathophysiologyand pages 2-3) - Central nervous system / brain white matter (UBERON:0000955) — dysmyelination, corticospinal tract degeneration, and neuroimaging abnormalities. (nteli2024argininemiapathophysiologyand pages 2-3) - Cerebrospinal fluid (CSF) — arginine and guanidino compounds reported/assayed in CSF. (nteli2024argininemiapathophysiologyand pages 1-2, nteli2024argininemiapathophysiologyand pages 12-14)

  1. Biological processes (GO-oriented annotations)

The following GO process categories are directly motivated by the evidence summarized in 2024 sources: - Urea cycle / ureagenesis / nitrogen compound metabolic process: disruption due to impaired ARG1-mediated conversion of arginine to urea and ornithine. (nteli2024argininemiapathophysiologyand pages 2-3) - Arginine catabolic process: primary enzymatic lesion (ARG1 loss). (nteli2024argininemiapathophysiologyand pages 2-3) - Amino acid homeostasis: persistent hyperargininemia and altered Arg/Orn ratio. (nteli2024argininemiapathophysiologyand pages 5-7, nteli2024argininemiapathophysiologyand pages 7-8) - Neurotransmitter receptor activity modulation / synaptic transmission (inhibitory): guanidino compounds inhibit GABA and glycine responses in neurons (mechanistic evidence cited within the 2024 trial paper). (russo2024efficacyandsafety pages 16-16) - Oxidative stress response: excess arginine can induce oxidative stress; guanidino compounds stimulate oxidative stress in brain tissue models (as cited in the 2024 review). (nteli2024argininemiapathophysiologyand pages 3-5, nteli2024argininemiapathophysiologyand pages 12-14) - Myelination / CNS development: dysmyelination and evidence that ARG1 mRNA therapy can improve myelination in arginase-deficient mice. (nteli2024argininemiapathophysiologyand pages 3-5, richard2024exploringrnatherapeutics pages 4-6)

  1. Cellular components (where processes occur)

  2. Cytosol: ARG1 is described as a liver cytosolic enzyme; enzymatic conversion of arginine to ornithine and urea is cytosolic in hepatocytes. (nteli2024argininemiapathophysiologyand pages 2-3)

  3. Extracellular space / plasma: clinically measured hyperargininemia; plasma arginine is the primary biochemical endpoint in trials. (russo2024efficacyandsafety pages 1-2)
  4. Cerebrospinal fluid: guanidino compounds and arginine-related metabolites measured in CSF in ARG1-D. (russo2024efficacyandsafety pages 16-16, nteli2024argininemiapathophysiologyand pages 12-14)

  5. Neuronal membrane/synaptic contexts: functional inhibition of neurotransmitter responses (GABA/glycine) by guanidino compounds implies synaptic receptor-level dysfunction. (russo2024efficacyandsafety pages 16-16)

  6. Disease progression (sequence of events)

A mechanistically anchored progression model consistent with 2024 evidence: 1) Genetic lesion: biallelic ARG1 variants → reduced/absent ARG1 activity (hepatic predominant). (russo2024efficacyandsafety pages 1-2, nteli2024argininemiapathophysiologyand pages 2-3) 2) Early biochemical phase: persistent hyperargininemia develops; newborn screening may miss cases because “plasma arginine levels may appear normal or near-normal due to the lingering effects of maternal arginase or due to arginase 2,” motivating Arg/Orn ratio approaches. (nteli2024argininemiapathophysiologyand pages 5-7) 3) Metabolite toxicity phase: arginine and guanidino compound accumulation contributes to neurotoxicity (inhibitory neurotransmission perturbation, oxidative stress, ion pump effects) and white matter injury/dysmyelination. (nteli2024argininemiapathophysiologyand pages 12-14, nteli2024argininemiapathophysiologyand pages 3-5) 4) Clinical neurologic phase: progressive spastic diplegia/paraparesis emerges, often beginning in early childhood/first decade; seizures and cognitive/developmental issues are common; catabolic stress may trigger episodic hyperammonemia with encephalopathy risk. (nteli2024argininemiapathophysiologyand pages 2-3) 5) Chronic disability phase: progressive motor impairment and mobility limitation; neuroimaging changes (cerebral/cerebellar atrophy, corticospinal tract degeneration, dysmyelination). (nteli2024argininemiapathophysiologyand pages 2-3)

  1. Phenotypic manifestations and mechanism linkage (HP-oriented)

Common phenotypes and frequencies (from 2024 review) - Progressive spastic diplegia/paraparesis (hallmark; onset often late infancy/early childhood). (nteli2024argininemiapathophysiologyand pages 2-3) - Upper motor neuron involvement in ~80% of patients. (nteli2024argininemiapathophysiologyand pages 2-3) - Seizures in ~60–75% of patients. (nteli2024argininemiapathophysiologyand pages 2-3) - Developmental delay, cognitive impairment, and hepatic pathology. (nteli2024argininemiapathophysiologyand pages 1-2)

Mechanistic linkage - Spasticity/UMN signs are plausibly linked to corticospinal tract degeneration and dysmyelination described in the review. (nteli2024argininemiapathophysiologyand pages 2-3) - Seizures are linked in the review to “epileptogenic properties” of guanidino compounds. (nteli2024argininemiapathophysiologyand pages 3-5)

  1. Recent developments and latest research (2023–2024 prioritized)

8.1 Disease-modifying enzyme therapy: pegzilarginase (2024 phase 3 evidence) - PEACE phase 3 (eClinicalMedicine; publication Feb 2024; DOI: 10.1016/j.eclinm.2023.102405; URL: https://doi.org/10.1016/j.eclinm.2023.102405): randomized, double-blind, placebo-controlled, multi-centre trial; n=32 (21 pegzilarginase, 11 placebo). (russo2024efficacyandsafety pages 1-2) - Primary biochemical outcome: geometric mean plasma arginine decreased from 354.0 to 86.4 µmol/L at Week 24 on pegzilarginase, versus 464.7 to 426.6 µmol/L on placebo; normalization in 90.5% vs 0%. (russo2024efficacyandsafety pages 1-2) - Clinical outcomes: functional mobility improvements were reported and sustained, and hyperammonaemic events occurred less often in the pegzilarginase arm (36% placebo vs 14% pegzilarginase). (russo2024efficacyandsafety pages 15-16) - Visual evidence: Figure/Table region showing pArg reductions and mobility endpoints is available from the paper (Figure 2/Table 2). (russo2024efficacyandsafety media be435973, russo2024efficacyandsafety media f9206652)

8.2 RNA therapeutics for ARG1 deficiency (2024 JIMD review synthesis; preclinical) - Richard et al. (J Inherit Metab Dis; Oct 2024; DOI: 10.1002/jimd.12807; URL: https://doi.org/10.1002/jimd.12807) states: “mRNA therapies encapsulated in LNPs have emerged as promising treatments for various UCD,” and reports for ARG1 deficiency that “codon-optimized ARG1 mRNA encapsulated in LNPs led to 100% survival of arginase-deficient mice, restoring urea cycle activity and maintaining normal liver function without signs of hepatotoxicity.” (richard2024exploringrnatherapeutics pages 4-6) - The same review reports CNS benefit: “intermittent administration of LNPs carrying ARG1 mRNA significantly improved myelination in the central nervous system and managed ammonia and arginine levels in arginase-deficient mice.” (richard2024exploringrnatherapeutics pages 4-6)

8.3 Gene therapy and genome engineering (2024 JIMD review synthesis; preclinical) - Duff et al. (J Inherit Metab Dis; Apr 2024; DOI: 10.1002/jimd.12609; URL: https://doi.org/10.1002/jimd.12609) cites AAV-mediated ARG1 gene therapy studies in mice that achieved “Long-term survival of the juvenile lethal arginase-deficient mouse” and prevented neuropathology with normal cognitive development in a hyperargininemic mouse model. (duff2024genetherapyfor pages 11-12) - The same review cites CRISPR/Cas9 genomic addition approaches in patient-derived cellular models (“Restoring ureagenesis in hepatocytes by CRISPR/Cas9-mediated genomic addition to arginase-deficient induced pluripotent stem cells”). (duff2024genetherapyfor pages 11-12)

  1. Current applications and real-world implementations

9.1 Standard-of-care (implementation) - Standard-of-care is supportive and aims to lower arginine and reduce catabolic stress risk: “dietary protein restriction, essential amino acid supplementation, and symptomatic treatments,” with guideline target plasma arginine ≤200 µmol/L though “rarely achievable” with diet alone due to endogenous arginine sources. (russo2024efficacyandsafety pages 2-3) - The 2024 review also describes nitrogen scavenger use (benzoate, phenylbutyrate, phenylacetate), essential amino acid supplements, and supportive measures; liver transplantation can halt neurological deterioration. (nteli2024argininemiapathophysiologyand pages 5-7)

9.2 Clinical development and implementation readiness: pegzilarginase programs ClinicalTrials.gov records (URLs provided by registry identifier format) - NCT03921541 (Phase 3; PEACE): “Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency” (Aeglea Biotherapeutics; initial posting 2019; URL: https://clinicaltrials.gov/study/NCT03921541). (NCT03921541 chunk 3) - NCT02488044 (Phase 1/2; open-label; n=16): registry specifies key PD outcomes including decreases in plasma arginine and plasma guanidino compound levels; participants continued prescribed diet. (NCT02488044 chunk 1) - NCT03378531 (Phase 2 extension; open-label; n=14; completed 2022): long-term safety/tolerability/immunogenicity/PK/PD follow-up for pegzilarginase. (NCT03378531 chunk 1) - NCT06582524 (Phase 3; <24 months; open-label; actual enrollment 3; status completed; start 2024-08-30): primary outcome is plasma arginine change from baseline to 12 weeks; secondary includes safety, PK, ADAs, arginine/ornithine, and feasible functional assessment (GMFM-66). URL: https://clinicaltrials.gov/study/NCT06582524. (NCT06582524 chunk 1)

  1. Expert opinions and analysis (authoritative synthesis)

  2. Mechanistic consensus in 2024 sources: persistent hyperargininemia and accumulation of neurotoxic metabolites (guanidino compounds; sometimes ammonia during stress) are central to neurological disease, with white-matter/myelination pathology a key substrate for progressive spasticity. (nteli2024argininemiapathophysiologyand pages 1-2, nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 3-5)

  3. Translational consensus in 2024 sources: correcting systemic arginine elevation is a rational disease-modifying approach; pegzilarginase demonstrates that sustained arginine normalization is achievable in a randomized controlled setting and is accompanied by functional mobility gains, supporting arginine lowering as a mechanism-linked therapeutic strategy. (russo2024efficacyandsafety pages 16-16, russo2024efficacyandsafety pages 1-2, russo2024efficacyandsafety pages 13-14)

  4. Future-facing consensus: non-viral LNP–mRNA approaches are positioned as promising, mutation-agnostic hepatic correction strategies with preclinical evidence of both survival benefit and CNS myelination improvement in arginase-deficient mice, but (per these excerpts) remain preclinical for ARG1 as of 2024. (richard2024exploringrnatherapeutics pages 4-6, richard2024exploringrnatherapeutics pages 1-2)

  5. Key statistics and recent data highlights (mechanistically relevant)

Epidemiology - From 2024 review: “Global birth prevalence of ARG1-D: 2.8 cases/1,000,000 live births” and “Population prevalence of ARG1-D: 1.4 cases/1,000,000 people.” (nteli2024argininemiapathophysiologyand pages 8-10) - The same review reports a median prevalence estimate of ~1:1,000,000 births (with wide study ranges). (nteli2024argininemiapathophysiologyand pages 1-2)

Natural history / phenotype frequencies - Upper motor neuron involvement ~80%. (nteli2024argininemiapathophysiologyand pages 2-3) - Seizures ~60–75%. (nteli2024argininemiapathophysiologyand pages 2-3)

Biomarkers - Plasma arginine can exceed 300 µmol/L and therapeutic target is <200 µmol/L. (nteli2024argininemiapathophysiologyand pages 5-7) - NBS support: Arg/Orn ratio ≥1.4 identified all arginase cases in the cited study; arginine alone may be near-normal in newborns due to maternal arginase or ARG2. (nteli2024argininemiapathophysiologyand pages 7-8, nteli2024argininemiapathophysiologyand pages 5-7)

Therapy effect size (phase 3) - PEACE trial: pArg reduction 354.0 → 86.4 µmol/L at Week 24; normalization 90.5% vs 0%. (russo2024efficacyandsafety pages 1-2) - Visual support for these endpoints is available in extracted Figure/Table region. (russo2024efficacyandsafety media be435973, russo2024efficacyandsafety media f9206652)

  1. Knowledge-base ready annotation tables (ontology-oriented)

12.1 Gene/protein - ARG1 (HGNC symbol: ARG1; protein: arginase 1). Evidence: causal biallelic variants; enzymatic role in urea cycle. (russo2024efficacyandsafety pages 1-2, nteli2024argininemiapathophysiologyand pages 2-3)

12.2 Candidate GO process annotations (evidence-motivated) - Nitrogen compound metabolic process / urea cycle / ureagenesis (ARG1 function loss). (nteli2024argininemiapathophysiologyand pages 2-3) - Arginine catabolic process (ARG1 catalytic lesion). (nteli2024argininemiapathophysiologyand pages 2-3) - Myelination / CNS development (dysmyelination; therapy-associated myelination rescue in mice). (nteli2024argininemiapathophysiologyand pages 3-5, richard2024exploringrnatherapeutics pages 4-6) - Response to oxidative stress (arginine excess; GC-linked oxidative stress). (nteli2024argininemiapathophysiologyand pages 3-5, nteli2024argininemiapathophysiologyand pages 12-14)

12.3 Phenotypes (HP term suggestions; evidence-backed concept level) - Spasticity / spastic paraplegia phenotype (progressive spastic diplegia/paraparesis). (nteli2024argininemiapathophysiologyand pages 2-3) - Seizures. (nteli2024argininemiapathophysiologyand pages 2-3) - Developmental delay / intellectual disability. (nteli2024argininemiapathophysiologyand pages 1-2) - Liver dysfunction / hepatic pathology. (nteli2024argininemiapathophysiologyand pages 1-2)

12.4 Cell types (CL term suggestions; evidence-backed concept level) - Hepatocyte; neuron; oligodendrocyte; erythrocyte; macrophage lineage (ARG1 expression noted). (nteli2024argininemiapathophysiologyand pages 2-3, russo2024efficacyandsafety pages 16-16, nteli2024argininemiapathophysiologyand pages 3-5)

12.5 Anatomy (UBERON term suggestions; evidence-backed concept level) - Liver; brain/CNS; CSF. (nteli2024argininemiapathophysiologyand pages 2-3, nteli2024argininemiapathophysiologyand pages 12-14)

  1. Evidence items (PMID-focused)

Important limitation: The 2024 full-text excerpts retrieved here provide strong mechanistic synthesis and clinical trial results, but they do not reproduce all underlying primary-study PMIDs inline in the extracted snippets. Where the excerpt explicitly references primary literature by concept but not PMID, the evidence is still attributable to the 2024 peer-reviewed sources above.

Primary 2024 anchor papers (with DOI/URL and publication month/year) - Nteli D et al. “Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease.” Applied Sciences. Feb 2024. DOI: 10.3390/app14041647. URL: https://doi.org/10.3390/app14041647. (nteli2024argininemiapathophysiologyand pages 1-2) - Russo RS et al. “Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3…” eClinicalMedicine. Feb 2024. DOI: 10.1016/j.eclinm.2023.102405. URL: https://doi.org/10.1016/j.eclinm.2023.102405. (russo2024efficacyandsafety pages 1-2) - Duff C et al. “Gene therapy for urea cycle defects: An update…” J Inherit Metab Dis. Apr 2024. DOI: 10.1002/jimd.12609. URL: https://doi.org/10.1002/jimd.12609. (duff2024genetherapyfor pages 11-12) - Richard E et al. “Exploring RNA therapeutics for urea cycle disorders.” J Inherit Metab Dis. Oct 2024. DOI: 10.1002/jimd.12807. URL: https://doi.org/10.1002/jimd.12807. (richard2024exploringrnatherapeutics pages 4-6)

Clinical trial registry evidence (URLs) - NCT03921541. https://clinicaltrials.gov/study/NCT03921541. (NCT03921541 chunk 3) - NCT02488044. https://clinicaltrials.gov/study/NCT02488044. (NCT02488044 chunk 1) - NCT03378531. https://clinicaltrials.gov/study/NCT03378531. (NCT03378531 chunk 1) - NCT06582524. https://clinicaltrials.gov/study/NCT06582524. (NCT06582524 chunk 1)

Appendix: Direct quotes captured (for knowledge-base curation) - “hydrolysis of L-arginine to ornithine and urea.” (ARG1 function) (nteli2024argininemiapathophysiologyand pages 2-3) - “Arginine: the key driver of patophysiology and progression in arginase 1 deficiency” (disease driver framing) (russo2024efficacyandsafety pages 16-16) - “as high as four times the normal (>300 µmol/L)” and “reduce arginine concentration in plasma below 200 µmol/L” (biomarker magnitude and target) (nteli2024argininemiapathophysiologyand pages 5-7) - “codon-optimized ARG1 mRNA encapsulated in LNPs led to 100% survival of arginase-deficient mice…” and “intermittent administration of LNPs carrying ARG1 mRNA significantly improved myelination…” (preclinical RNA-therapy efficacy) (richard2024exploringrnatherapeutics pages 4-6)

End of report.

References

  1. (russo2024efficacyandsafety pages 1-2): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  2. (nteli2024argininemiapathophysiologyand pages 2-3): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  3. (nteli2024argininemiapathophysiologyand pages 7-8): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  4. (nteli2024argininemiapathophysiologyand pages 3-5): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  5. (russo2024efficacyandsafety pages 16-16): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  6. (nteli2024argininemiapathophysiologyand pages 5-7): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  7. (nteli2024argininemiapathophysiologyand pages 1-2): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  8. (nteli2024argininemiapathophysiologyand pages 12-14): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.

  9. (richard2024exploringrnatherapeutics pages 4-6): Eva Richard, Ainhoa Martínez‐Pizarro, and Lourdes R. Desviat. Exploring rna therapeutics for urea cycle disorders. Journal of Inherited Metabolic Disease, 47:1269-1277, Oct 2024. URL: https://doi.org/10.1002/jimd.12807, doi:10.1002/jimd.12807. This article has 4 citations and is from a peer-reviewed journal.

  10. (russo2024efficacyandsafety pages 15-16): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  11. (russo2024efficacyandsafety media be435973): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  12. (russo2024efficacyandsafety media f9206652): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  13. (duff2024genetherapyfor pages 11-12): Claire Duff, Ian E. Alexander, and Julien Baruteau. Gene therapy for urea cycle defects: an update from historical perspectives to future prospects. Journal of Inherited Metabolic Disease, 47:50-62, Apr 2024. URL: https://doi.org/10.1002/jimd.12609, doi:10.1002/jimd.12609. This article has 28 citations and is from a peer-reviewed journal.

  14. (russo2024efficacyandsafety pages 2-3): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

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  19. (russo2024efficacyandsafety pages 13-14): Rossana Sanchez Russo, Serena Gasperini, Gillian Bubb, Linda Neuman, Leslie S. Sloan, George A. Diaz, and Gregory M. Enns. Efficacy and safety of pegzilarginase in arginase 1 deficiency (peace): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. eClinicalMedicine, 68:102405, Feb 2024. URL: https://doi.org/10.1016/j.eclinm.2023.102405, doi:10.1016/j.eclinm.2023.102405. This article has 21 citations and is from a peer-reviewed journal.

  20. (richard2024exploringrnatherapeutics pages 1-2): Eva Richard, Ainhoa Martínez‐Pizarro, and Lourdes R. Desviat. Exploring rna therapeutics for urea cycle disorders. Journal of Inherited Metabolic Disease, 47:1269-1277, Oct 2024. URL: https://doi.org/10.1002/jimd.12807, doi:10.1002/jimd.12807. This article has 4 citations and is from a peer-reviewed journal.

  21. (nteli2024argininemiapathophysiologyand pages 8-10): Despoina Nteli, Maria Nteli, Konstantinos Konstantinidis, Anastasia Foka, Foteini Charisi, Iliana Michailidou, Sotiria Stavropoulou De Lorenzo, Marina Boziki, Maria Tzitiridou-Chatzopoulou, Evangelia Spandou, Constantina Simeonidou, Christos Bakirtzis, and Evangelia Kesidou. Argininemia: pathophysiology and novel methods for evaluation of the disease. Applied Sciences, 14:1647, Feb 2024. URL: https://doi.org/10.3390/app14041647, doi:10.3390/app14041647. This article has 3 citations.