mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Gurung, Sonam; Timmermand, Oskar V.; Perocheau, Dany; Gil-Martínez, Ana Luisa; Minnion, Magdalena; Touramanidou, Loukia; Fang, Sherry; Messina, Martina; Khalil, Youssef; Barber, A.; Edwards, Richard; Finn, Patrick F.; Cavedon, Alex; Siddiqui, Summar; Rice, Lisa; Martini, Paolo G.V.; Mills, Philippa; Waddington, Simon; Gissen, Paul; Eaton, Simon; Ryten, Mina; Feelisch, Martin; Frassetto, Andrea; Witney, Timothy H.; Baruteau, Julien

doi:10.1101/2022.10.19.512931

Cited by 7 publications

(6 citation statements)

References 77 publications

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“…Next, we wanted to determine if PCLS can be used for assessing gene therapies. mRNA encapsulated in lipid nanoparticles is an attractive therapeutic strategy, which is rapidly being developed for rare liver inherited metabolic diseases [51, 56] and is in phase I/II clinical trials for 2 inherited metabolic diseases i.e . ornithine trancarbamylase deficiency (NCT04442347), the most common urea cycle disorder, propionic acidaemia (NCT04899310), methylmalonic acidaemia (NCT04159103) and glycogen storage disease 1A (NCT05095727) [57].…”

Section: Resultsmentioning

confidence: 99%

“…The only cure is liver transplantation, which requires lifelong immunosuppression, has its own morbidity and is limited by organ shortage. Due to high unmet needs, novel therapies with small molecules [49] or gene therapies [50][51][52][53] are being developed. The ex vivo models rely on iPSC-derived hepatocytes with a relative inaccuracy in modelling the disease phenotype partially due to sub-optimal differentiation [3].…”

Section: Key Aspects For the Preparation And Culture Of Pclsmentioning

confidence: 99%

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Ex vivoprimary liver sections recapitulate disease phenotype and therapeutic rescue for liver monogenic diseases

Perocheau

Baruteau

Gurung

et al. 2023

Preprint

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In academic research and the pharmaceutical industry, in vitro single cell line cultures and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have limitations, with incomplete reproduction of pathophysiological characteristics and absence of 3-dimensional architecture with cell lines or the use of live animals brings ethical considerations, limiting the experimental scale and design. The use of precision-cut tissue slices can bridge the gap between these mainstream models as this technique combines the advantages of studying all cell sub-types whilst preserving the tissue-matrix architecture, thereby closely mimicking a mini-organ. Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers. We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Key Aspects For the Preparation And Culture Of Pclsmentioning

confidence: 99%

Ex vivoprimary liver sections recapitulate disease phenotype and therapeutic rescue for liver monogenic diseases

Perocheau

Baruteau

Gurung

et al. 2023

Preprint

Self Cite

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“…mRNA encapsulated in lipid nanoparticles is an emerging therapeutic strategy for rare liver inherited metabolic diseases 21,22 and PCLS present themselves as an attractive model to assess such therapies. PCLS generated from Asl Neo/Neo mice were therefore treated with either hASL mRNA or phosphate buffer saline (PBS).…”

Section: Resultsmentioning

confidence: 99%

Ex vivo precision-cut liver slices model disease phenotype and monitor therapeutic response for liver monogenic diseases

Perocheau,

Gurung,

Touramanidou

et al. 2023

F1000Res

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Background In academic research and the pharmaceutical industry, in vitro cell lines and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ. This approach can be used to replicate the biological phenotype of liver monogenic diseases using mouse models. Methods Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers, enabling its use as a reliable ex-vivo model to assess the therapeutic screening of inherited metabolic diseases Results We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects such as citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Conclusions Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.

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“…This has been successfully performed in OTC-deficient mice. 17,24 Non-viral gene therapy using repeated systemic injections of LNPs encapsulating mRNA has shown efficient liver targeting and phenotypic correction of mouse models of OTC deficiency, 37,38 argininosuccinate lyase deficiency 39,40 and arginase deficiency. 41,42…”

Section: Urea Cycle Disordersmentioning

confidence: 99%

Liver‐directed gene therapy for inherited metabolic diseases

Baruteau,

Brunetti‐Pierri,

Gissen

2024

J of Inher Metab Disea

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Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver‐directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver‐targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow‐up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver‐targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

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mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Cited by 7 publications

References 77 publications

Ex vivoprimary liver sections recapitulate disease phenotype and therapeutic rescue for liver monogenic diseases

Ex vivoprimary liver sections recapitulate disease phenotype and therapeutic rescue for liver monogenic diseases

Ex vivo precision-cut liver slices model disease phenotype and monitor therapeutic response for liver monogenic diseases

Liver‐directed gene therapy for inherited metabolic diseases

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