Messenger RNA as a personalized therapy: The moment of truth for rare metabolic diseases

Córdoba, Karol M.; Jericó, Daniel; Sampedro, Ana; Jiang, Lei; Iraburu, María J.; Martini, Paolo G.V.; Berraondo, Pedro; Ávila, Matías A.; Fontanellas, Antonio

doi:10.1016/bs.ircmb.2022.03.005

Cited by 8 publications

(8 citation statements)

References 149 publications

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“…There have been recent reports of serious hepatotoxicity following AAV gene delivery in X-linked myotubular myopathy and spinal muscular atrophy ( 54 – 57 ). In parallel, mRNA encapsulated in lipid nanoparticles is emerging as a promising therapy for liver monogenic diseases ( 58 – 60 ). This technology enables the delivery of a functional therapeutic protein to target cells with comparatively longer half-life and lower costs than protein replacement therapies.…”

Section: Discussionmentioning

confidence: 99%

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

Gurung,

Timmermand,

Perocheau

et al. 2024

Sci. Transl. Med.

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The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3- 18 F-fluoropropyl)- l -glutamate ([ 18 F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [ 18 F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.

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Section: Discussionmentioning

confidence: 99%

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

Gurung,

Timmermand,

Perocheau

et al. 2024

Sci. Transl. Med.

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show abstract

“…There have been recent reports of serious hepatotoxicity following AAV gene delivery, in XLMTM & SMN (54)(55)(56)(57). In parallel, lipid nanoparticles encapsulating mRNA is emerging as a promising therapy for liver monogenic diseases (58)(59)(60). Through encapsulation of mRNA in optimised LNPs, functional therapeutic protein can be delivered to target cells with comparatively longer half-life and lower costs than protein replacement therapies.…”

Section: Discussionmentioning

confidence: 99%

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Gurung

Timmermand

Perocheau

et al. 2022

Preprint

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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.

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“…Future prospects in the development of personalized gene therapies are promising due to the rapid manufacturing of these molecules. Personalized medicine strategies consider each patients' genotypic characteristics, which will allow the production of therapies specifically for cancer patients, rare metabolic disease patients and a range of other pathologies [27,28]. From a manufacturing perspective, these personalized medicines may require smaller infrastructure than that established throughout the COVID-19 pandemic due to the scale of production for individual patients rather than global populations.…”

Section: Current Therapeutic Applications Of Mrnamentioning

confidence: 99%

Enabling mRNA Therapeutics: Current Landscape and Challenges in Manufacturing

Youssef,

Hitti,

Puppin Chaves Fulber

et al. 2023

Biomolecules

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Recent advances and discoveries in the structure and role of mRNA as well as novel lipid-based delivery modalities have enabled the advancement of mRNA therapeutics into the clinical trial space. The manufacturing of these products is relatively simple and eliminates many of the challenges associated with cell culture production of viral delivery systems for gene and cell therapy applications, allowing rapid production of mRNA for personalized treatments, cancer therapies, protein replacement and gene editing. The success of mRNA vaccines during the COVID-19 pandemic highlighted the immense potential of this technology as a vaccination platform, but there are still particular challenges to establish mRNA as a widespread therapeutic tool. Immunostimulatory byproducts can pose a barrier for chronic treatments and different production scales may need to be considered for these applications. Moreover, long-term storage of mRNA products is notoriously difficult. This review provides a detailed overview of the manufacturing steps for mRNA therapeutics, including sequence design, DNA template preparation, mRNA production and formulation, while identifying the challenges remaining in the dose requirements, long-term storage and immunotolerance of the product.

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Messenger RNA as a personalized therapy: The moment of truth for rare metabolic diseases

Cited by 8 publications

References 149 publications

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Enabling mRNA Therapeutics: Current Landscape and Challenges in Manufacturing

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