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mRNA formulated with lipid nanoparticles is a transformative technology that has enabled the rapid development and administration of billions of coronavirus disease 2019 (COVID-19) vaccine doses worldwide. However, avoiding unacceptable toxicity with mRNA drugs and vaccines presents challenges. Lipid nanoparticle structural components, production methods, route of administration and proteins produced from complexed mRNAs all present toxicity concerns. Here, we discuss these concerns, specifically how cell tropism and tissue distribution of mRNA and lipid nanoparticles can lead to toxicity, and their possible reactogenicity. We focus on adverse events from mRNA applications for protein replacement and gene editing therapies as well as vaccines, tracing common biochemical and cellular pathways. The potential and limitations of existing models and tools used to screen for on-target efficacy and de-risk off-target toxicity, including in vivo and next-generation in vitro models, are also discussed.The field of nucleic acid therapeutics is rapidly expanding, with mRNA drug and vaccine candidates now under development for diverse indications. However, various safety concerns are associated with the mRNA platform. This Review discusses key challenges and toxicities identified during the development of mRNA drugs and vaccines, assesses models and tools used to limit toxicity, highlighting knowledge gaps and future directions.

mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency. [Display omitted]

Propionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders. Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.

Intranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)–lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding (IgG and IgA) and neutralizing antibodies with similar robustness to intramuscular controls. Additionally, intranasal vaccination decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. This is the first study to demonstrate successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.Competing Interest StatementGBV, AC, CJH, AG, AJ, EJ, EA, CMG, XSF, JS, AC, DE, and KB are or were employees of Moderna, Inc., and hold stock/stock options from the company. MM, CAP, CEM, MAH, MEC, JMW, and AB have none to declare.

Besides their strong contribution to weather forecast improvement through data assimilation, thermal infrared sounders onboard polar-orbiting platforms are now playing a key role for monitoring atmospheric composition changes. The Infrared Atmospheric Sounding Interferometer (IASI) instrument developed by the French space agency (CNES) and launched by EUMETSAT onboard the Metop satellite series is providing essential inputs for weather forecasting and pollution/climate monitoring owing to its smart combination of large horizontal swath, good spectral resolution and high radiometric performance. EUMETSAT is currently preparing the next polar-orbiting program (EPS-SG) with the Metop-SG satellite series that should be launched around 2020. In this framework, CNES is studying the concept of a new instrument, the IASI-New Generation (IASI-NG), characterized by an improvement of both spectral and radiometric characteristics as compared to IASI, with three objectives: (i) continuity of the IASI/Metop series; (ii) improvement of vertical resolution; and (iii) improvement of the accuracy and detection threshold for atmospheric and surface components. In this paper, we show that an improvement of spectral resolution and radiometric noise fulfil these objectives by leading to (i) a better vertical coverage in the lower part of the troposphere, thanks to the increase in spectral resolution; and (ii) an increase in the accuracy of the retrieval of several thermodynamic, climate and chemistry variables, thanks to the improved signal-to-noise ratio as well as less interference between the signatures of the absorbing species in the measured radiances. The detection limit of several atmospheric species is also improved. We conclude that IASI-NG has the potential to strongly benefit the numerical weather prediction, chemistry and climate communities now connected through the European GMES/Copernicus initiative.

The Infrared Atmospheric Sounding Interferometer (IASI) forms the main infrared sounding component of the European Organisation for the Exploitation of Meteorological Satellites's (EUMETSAT's) Meteorological Operation (MetOp)-A satellite (Klaes et al. 2007), which was launched in October 2006. This article presents the results of the first 4 yr of the operational IASI mission. The performance of the instrument is shown to be exceptional in terms of calibration and stability. The quality of the data has allowed the rapid use of the observations in operational numerical weather prediction (NWP) and the development of new products for atmospheric chemistry and climate studies, some of which were unexpected before launch. The assimilation of IASI observations in NWP models provides a significant forecast impact; in most cases the impact has been shown to be at least as large as for any previous instrument. In atmospheric chemistry, global distributions of gases, such as ozone and carbon monoxide, can be produced in near–real time, and short-lived species, such as ammonia or methanol, can be mapped, allowing the identification of new sources. The data have also shown the ability to track the location and chemistry of gaseous plumes and particles associated with volcanic eruptions and fires, providing valuable data for air quality monitoring and aircraft safety. IASI also contributes to the establishment of robust long-term data records of several essential climate variables. The suite of products being developed from IASI continues to expand as the data are investigated, and further impacts are expected from increased use of the data in NWP and climate studies in the coming years. The instrument has set a high standard for future operational hyperspectral infrared sounders and has demonstrated that such instruments have a vital role in the global observing system.

The stability of the instrument is monitored routinely by the CNES Technical Expertise Centre, using onboard measurements, and by EUMETSAT, where stable, clear fields of view are compared with simulated radiances from numerical weather prediction model output. Since its launch, the instrument performance, which is discussed further in the next section, has been extremely stable.

Four years after launch, IASI has delivered significant advances in remote sensing capability for numerical weather prediction and atmospheric composition monitoring and promises an excellent dataset for climate studies. The Infrared Atmospheric Sounding Interferometer (IASI) forms the main infrared sounding component of EUMETSAT's Metop-A satellite (Klaes et al., 2007), which was launched in October 2006. This article presents the results of the first four years of the operational IASI mission. The performance of the instrument is shown to be exceptional in terms of calibration and stability the quality of the data has allowed the rapid use of the observations in operational numerical weather prediction (NWP) and the development of new products for atmospheric chemistry and climate studies, some of which were unexpected before launch. The assimilation of IASI observations in NWP models provides significant forecast impact; in most cases the impact has been shown to be at least as large as for any previous instrument. In atmospheric chemistry, global distributions of gases such as ozone and carbon monoxide can be produced in near-real time, and short-lived species such as ammonia or methanol can be mapped, allowing identification of new sources. The data have also shown the ability to track the location and chemistry of gaseous plumes and particles associated with volcanic eruptions and fires, providing valuable data for air quality monitoring and aircraft safety. IASI also contributes to the establishment of robust long term data records of several essential climate variables. The suite of products being developed from IASI continues to expand as the data are investigated, and further impacts are expected from increased use of the data in NWP and climate studies in the coming years. The instrument has set a high standard for future operational hyperspectral infrared sounders, and demonstrated that such instruments have a vital role in the global observing system.