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Volume 11
Issue 6
10.3390/biomedicines11061735
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Article

ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model

by
Owen Daly
1,*,
Azita Josefine Mahiny
2,
Sara Majeski
1,
Kevin McClintock
1,
Julia Reichert
2,
Gábor Boros
2,
Gábor Tamás Szabó
2,
Jonas Reinholz
2,
Petra Schreiner
1,
Steve Reid
1,
Kieu Lam
1,
Marlen Lepper
2,
Melanie Adler
2,
Tracy Meffen
1,
James Heyes
1,
Katalin Karikó
2,
Pete Lutwyche
1 and
Irena Vlatkovic
2,*
1
Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada
2
BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany
*
Authors to whom correspondence should be addressed.
Biomedicines 2023, 11(6), 1735; https://doi.org/10.3390/biomedicines11061735
Submission received: 29 March 2023 / Revised: 5 June 2023 / Accepted: 11 June 2023 / Published: 16 June 2023
(This article belongs to the Special Issue Advanced Research in Nanomaterials for Biomedical Applications)
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Abstract

Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASLNeo/Neo mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
Keywords: lipid nanoparticle-mRNA (LNP-mRNA); mRNA optimization; mRNA therapeutic; rare disease; argininosuccinic aciduria (ASA); argininosuccinate lyase deficiency (ASLD) lipid nanoparticle-mRNA (LNP-mRNA); mRNA optimization; mRNA therapeutic; rare disease; argininosuccinic aciduria (ASA); argininosuccinate lyase deficiency (ASLD)
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MDPI and ACS Style

Daly, O.; Mahiny, A.J.; Majeski, S.; McClintock, K.; Reichert, J.; Boros, G.; Szabó, G.T.; Reinholz, J.; Schreiner, P.; Reid, S.; et al. ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model. Biomedicines 2023, 11, 1735. https://doi.org/10.3390/biomedicines11061735

AMA Style

Daly O, Mahiny AJ, Majeski S, McClintock K, Reichert J, Boros G, Szabó GT, Reinholz J, Schreiner P, Reid S, et al. ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model. Biomedicines. 2023; 11(6):1735. https://doi.org/10.3390/biomedicines11061735

Chicago/Turabian Style

Daly, Owen, Azita Josefine Mahiny, Sara Majeski, Kevin McClintock, Julia Reichert, Gábor Boros, Gábor Tamás Szabó, Jonas Reinholz, Petra Schreiner, Steve Reid, and et al. 2023. "ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model" Biomedicines 11, no. 6: 1735. https://doi.org/10.3390/biomedicines11061735

APA Style

Daly, O., Mahiny, A. J., Majeski, S., McClintock, K., Reichert, J., Boros, G., Szabó, G. T., Reinholz, J., Schreiner, P., Reid, S., Lam, K., Lepper, M., Adler, M., Meffen, T., Heyes, J., Karikó, K., Lutwyche, P., & Vlatkovic, I. (2023). ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model. Biomedicines, 11(6), 1735. https://doi.org/10.3390/biomedicines11061735

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