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The 2023 Nobel Prize in Physiology / Medicine has been awarded to Katalin Karikó and Drew Weissman for their work on the development of mRNA vaccines against severe acute respiratory syndrome coronavirus 2. This article reviews the hard work of the biochemist Karikó in the research and development of mRNA drugs. The persistence and the right choice on the long journey of scientific research are important factors for her success. We envision that the mRNA modification technique will be more widely used in the future. [ABSTRACT FROM AUTHOR]

"Breaking through, my life in science" is an autobiography by Katalin Karikó, a scientist whose groundbreaking work on mRNA paved the way for the development of revolutionary vaccine technology. The book provides an insight into Karikó's career and her journey towards the Nobel Prize in Physiology or Medicine in 2023. It explores her experiences as a scientist, her dedication to understanding how the world works, and the challenges she faced along the way. Karikó's autobiography is a compelling read for anyone interested in the field of science, particularly those researching COVID-19 and mRNA therapies. [Extracted from the article]

Katalin Karikó, affiliated with Szeged University, Szeged, Hungary and University of Pennsylvania, Philadelphia, PA, USA, and Drew Weissman, affiliated with Penn Institute for RNA Innovations, University of Pennsylvania, Philadelphia, PA, USA, were awarded the 2023 Nobel Prize in Physiology or Medicine for their contributions to the foundational work of nucleoside base modifications that supported the development of effective mRNA vaccines against COVID-19. They identified modifications of nucleoside bases of in vitro mRNA that enabled efficient protein production without undesired inflammatory responses. Their work allowed for the advancement of future mRNA applications, including the COVID-19 vaccines. Following a general overview of mRNA modifications and mRNA vaccines is a bibliometric analysis of each of this year's laureates and their work. [ABSTRACT FROM AUTHOR]

Background Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.Methods We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.Results We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.Conclusion Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Dysfunction of the lymphatic system leads to secondary lymphedema and results in degradation of quality of life. Here, the authors show that delivery of nucleoside-modified Vascular Endothelial Growth Factor C (VEGFC) mRNA, encapsulated in lipid nanoparticles, induces organ-specific lymphatic growth and reverses experimental lymphedema.

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.