Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency

Khoja, Shariq; Liu, Xiaobo; Truong, Brian; Nitzahn, Matthew; Lambert, Jenna; Eliav, Adam; Nasser, Eram; Randolph, Emma; Burke, Kristine; White, Rebecca A.; Zhu, Xinwen; Martini, Paolo G.V.; Nissim, Itzhak; Cederbaum, Stephen D.; Lipshutz, Gerald S.

doi:10.1016/j.omtn.2022.04.012

Cited by 16 publications

(10 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on previous proof of concept studies performed in arginase deficiency, another UCD (65, 66), the therapeutic dose of 1 mg/kg of hASL mRNA delivered weekly through systemic routes of administration was tested in the Asl Neo/Neo mouse. The treatment of animals from birth showed remarkable effects by normalising the macroscopic phenotype, biomarkers, in vivo ureagenesis, liver ASL expression and activity to physiological levels.…”

Section: Discussionmentioning

confidence: 99%

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Gurung

Timmermand

Perocheau

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which is required for ammonia detoxification, and the citrulline-nitric oxide (NO) cycle for NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease with hyperammonaemia and a chronic systemic phenotype with neurocognitive impairment and chronic liver disease. ASL deficiency as an inherited model of systemic NO deficiency, shows enhanced nitrosative and oxidative stress. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics andin vivopositron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG). Upregulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways.hASLmRNA encapsulated in lipid nanoparticles corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis and glutathione metabolism and ameliorating chronic liver disease. We further present [18F]FSPG PET as a novel non-invasive diagnostic tool to assess liver disease and therapeutic efficacy in ASA. These findings support clinical translation of mRNA therapy for ASA.

show abstract

Section: Discussionmentioning

confidence: 99%

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Gurung

Timmermand

Perocheau

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…46 Normalization of plasma arginine and reductions in guanidino compounds were achieved in the mice receiving lipid nanoparticle/Arg1 mRNA compared with untreated knockouts and wild-type controls; these biochemical changes were associated with a dramatic recovery of myelin density, increased myelin sheath thickness, and normal growth and survival. 46 This evidence of abnormal neurophysiology and dysmyelination is consistent with the limited available observations reported in children with ARG1-D. In one patient with toe walking and spastic paraplegia, among other signs of pyramidal tract dysfunction affecting his lower limbs, neurophysiologic assessment revealed prolonged latency of motor evoked potentials, indicating involvement of the corticospinal tract.…”

Section: Empirical Studies Implicate Arginine In Development and Prog...mentioning

confidence: 95%

“…Finally, in a more recent mouse model also spearheaded by the Lipshutz group, a lipid nanoparticle carrying human Arg1 mRNA was administered intermittently to constitutive Arg1 knockout mice to restore their hepatic arginase 1 activity. 46 Normalization of plasma arginine and reductions in guanidino compounds were achieved in the mice receiving lipid nanoparticle/ Arg1 mRNA compared with untreated knockouts and wild‐type controls; these biochemical changes were associated with a dramatic recovery of myelin density, increased myelin sheath thickness, and normal growth and survival. 46 …”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

“…Furthermore, there is little to no increase in brain arginase 2 in Arg1 knockout animals, and little to no increase in brain arginase 1 in genetically corrected Arg1 knockouts. Finally, in a more recent mouse model also spearheaded by the Lipshutz group, a lipid nanoparticle carrying human Arg1 mRNA was administered intermittently to constitutive Arg1 knockout mice to restore their hepatic arginase 1 activity 46 . Normalization of plasma arginine and reductions in guanidino compounds were achieved in the mice receiving lipid nanoparticle/ Arg1 mRNA compared with untreated knockouts and wild‐type controls; these biochemical changes were associated with a dramatic recovery of myelin density, increased myelin sheath thickness, and normal growth and survival 46 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role and control of arginine levels in arginase 1 deficiency

Diaz

Bechter²,

Cederbaum

2022

J of Inher Metab Disea

Self Cite

View full text Add to dashboard Cite

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.arginase deficiency, guanidino compounds, hyperargininemia, inborn error of metabolism, urea cycle disorder Synopsis ARG1-D is a distinct urea cycle disorder with a progressive neurologic phenotype. This review presents a comprehensive discussion of evidence from genetically manipulated mouse models and observations from clinical practice that implicate high arginine levels directly in disease pathophysiology.

show abstract

Liver gene transfer for metabolite detoxification in inherited metabolic diseases

D'Alessio,

Boffa,

De Stefano

et al. 2024

FEBS Letters

View full text Add to dashboard Cite

Inherited metabolic disorders (IMDs) are a growing group of genetic diseases caused by defects in enzymes that mediate cellular metabolism, often resulting in the accumulation of toxic substrates. The liver is a highly metabolically active organ that hosts several thousands of chemical reactions. As such, it is an organ frequently affected in IMDs. In this article, we review current approaches for liver‐directed gene‐based therapy aimed at metabolite detoxification in a variety of IMDs. Moreover, we discuss current unresolved challenges in gene‐based therapies for IMDs.

show abstract

Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency

Cited by 16 publications

References 48 publications

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

The role and control of arginine levels in arginase 1 deficiency

Liver gene transfer for metabolite detoxification in inherited metabolic diseases

Contact Info

Product

Resources

About