Arginase I mRNA therapy – a novel approach to rescue arginase 1 enzyme deficiency

Asrani, Kirtika H.; Cheng, Lei; Cheng, Christopher J.; Subramanian, Romesh R.

doi:10.1080/15476286.2018.1475178

Cited by 45 publications

(15 citation statements)

References 30 publications

(30 reference statements)

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“…It draws attention to the importance of establishing specialized centers for metabolic disorders, which would increase the opportunity for early diagnosis and provide all the requirements for patients' care at an affordable cost. This will efficiently help decrease the disability as a consequence of potentially treatable causes in Sudanese children, especially with the advent of more advanced options of therapy like rescue mRNA therapy in addition to the existing treatment options (25,26).…”

Section: Discussionmentioning

confidence: 99%

Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

et al. 2020

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Background: Arginases catalyze the last step in the urea cycle. Hyperargininemia, a rare autosomal-recessive disorder of the urea cycle, presents after the first year of age with regression of milestones and evolves gradually into progressive spastic quadriplegia and cognitive dysfunction. Genetic studies reported various mutations in the ARG1 gene that resulted in hyperargininemia due to a complete or partial loss of arginase activity.Case Presentation: Five patients from an extended highly consanguineous Sudanese family presented with regression of the acquired milestones, spastic quadriplegia, and mental retardation. The disease onset ranged from 1 to 3 years of age. Two patients had epileptic seizures and one patient had stereotypic clapping. Genetic testing using whole-exome sequencing, done for the patients and a healthy parent, confirmed the presence of a homozygous novel missense variant in the ARG1 gene [GRCh37 (NM_001244438.1): exon 4: g.131902487T>A, c.458T>A, p.(Val153Glu)]. The variant was predicted pathogenic by five algorithms and affected a highly conserved amino acid located in the protein domain ureohydrolase, arginase subgroup. Sanger sequencing of 13 sampled family members revealed complete co-segregation between the variant and the disease distribution in the family in line with an autosomal-recessive mode of inheritance. Biochemical analysis confirmed hyperargininemia in five patients. Conclusion:This study reports the first Sudanese family with ARG1 mutation. The reported variant is a loss-of-function missense mutation. Its pathogenicity is strongly supported by the clinical phenotype, the computational functional impact prediction, the complete co-segregation with the disease, and the biochemical assessment.

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Section: Discussionmentioning

confidence: 99%

Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

et al. 2020

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“…For instance, β globin 5′- and 3′-UTRs, duplicating the β globin 3′-UTR, the 5′-UTR of tobacco etch virus, and a structure of the 5′-UTR of human heat shock protein 70 all enhanced mRNA translation in mammalian cells [ 158 , 183 , 188 , 189 ]. According to a very recent survey of a combinatorial UTR library, 5′-UTR sequences appear to be most critical for protein expression [ 190 ]. In contrast, 3′-UTRs seem to be the key driver for mRNA half-life as exemplified by the stabilizing effects of the α globin 3′-UTR as well as a duplication of the β globin 3′-UTR [ 183 , 191 ].…”

Section: Mrna As Therapeutic: Technological Considerations and First mentioning

confidence: 99%

mRNA as novel technology for passive immunotherapy

Schlake¹,

Theß²,

Thran³

et al. 2018

Cell. Mol. Life Sci.

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While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized with target-specific receptors. In either case, administration or expression of recombinant proteins plays a fundamental role. mRNA prepared by in vitro transcription (IVT) is increasingly appreciated as a drug substance for delivery of recombinant proteins. With its biological role as transient carrier of genetic information translated into protein in the cytoplasm, therapeutic application of mRNA combines several advantages. For example, compared to transfected DNA, mRNA harbors inherent safety features. It is not associated with the risk of inducing genomic changes and potential adverse effects are only temporary due to its transient nature. Compared to the administration of recombinant proteins produced in bioreactors, mRNA allows supplying proteins that are difficult to manufacture and offers extended pharmacokinetics for short-lived proteins. Based on great progress in understanding and manipulating mRNA properties, efficacy data in various models have now demonstrated that IVT mRNA constitutes a potent and flexible platform technology. Starting with an introduction into passive immunotherapy, this review summarizes the current status of IVT mRNA technology and its application to such immunological interventions.

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“…Exploiting this key feature of MRT could enable the treatment of many diseases, including those in which protein-based therapeutics are not currently possible, such as large transmembrane proteins 43 , 44 , 45 or proteins requiring cytoplasmic delivery. 46 , 47 , 48 Moreover, MRT could provide flexibility with respect to delivery within the body. The ultimate site of mRNA delivery and subsequent translation need not be within the target organ to achieve a therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy

et al. 2019

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Fabry disease is a lysosomal storage disorder caused by the deficiency of a-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human a-galactosidase protein in vivo via nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human a-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as $1,330-fold over normal physiological values.

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Arginase I mRNA therapy – a novel approach to rescue arginase 1 enzyme deficiency

Cited by 45 publications

References 30 publications

Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

mRNA as novel technology for passive immunotherapy

Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy

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