Lipid nanoparticle structure and delivery route during pregnancy dictates mRNA potency, immunogenicity, and health in the mother and offspring

Chaudhary, Namit; Newby, Alexandra N.; Arral, Mariah L.; Yerneni, Saigopalakrishna S.; LoPresti, Samuel T.; Doerfler, Rose; Petersen, Daria M. Strelkova; Fox, Bethany; Coon, Tiffany A.; Malaney, Angela; Sadovsky, Yoel; Whitehead, Kathryn A.

doi:10.1101/2023.02.15.528720

Cited by 6 publications

(4 citation statements)

References 73 publications

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“…The outlook for mRNA therapy in female reproductive health is encouraging, with new LNP formulations already being developed specifically for safety and efficacy during pregnancy. 177 Building on this, the future of mRNA LNP for application in female health is bright, and it will be exciting to see how these technologies continue to advance from the benchtop to the clinic in the coming years.…”

Section: Future Directions Of Research In Mrna Therapy For Female Rep...mentioning

confidence: 99%

“…The platformable nature of mRNA nanoparticle delivery systems allows for rapid gene therapy development for various diseases, including those associated with female reproductive health. The outlook for mRNA therapy in female reproductive health is encouraging, with new LNP formulations already being developed specifically for safety and efficacy during pregnancy . Building on this, the future of mRNA LNP for application in female health is bright, and it will be exciting to see how these technologies continue to advance from the benchtop to the clinic in the coming years.…”

Section: Future Directions Of Research In Mrna Therapy For Female Rep...mentioning

confidence: 99%

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Messenger RNA Therapy for Female Reproductive Health

VanKeulen-Miller,

Fenton

2024

Mol. Pharmaceutics

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Female reproductive health has traditionally been an underrepresented area of research in the drug delivery sciences. This disparity is also seen in the emerging field of mRNA therapeutics, a class of medicines that promises to treat and prevent disease by upregulating protein expression in the body. Here, we review advances in mRNA therapies through the lens of improving female reproductive health. Specifically, we begin our review by discussing the fundamental structure and biochemical modifications associated with mRNA-based drugs. Then, we discuss various packaging technologies, including lipid nanoparticles, that can be utilized to protect and transport mRNA drugs to target cells in the body. Last, we conclude our review by discussing the usage of mRNA therapy for addressing pregnancy-related health and vaccination against sexually transmitted diseases in women. Of note, we also highlight relevant clinical trials using mRNA for female reproductive health while also providing their corresponding National Clinical Trial identifiers. In undertaking this review, our aim is to provide a fundamental background understanding of mRNA therapy and its usage to specifically address female health issues with an overarching goal of providing information toward addressing gender disparity in certain aspects of health research.

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Section: Future Directions Of Research In Mrna Therapy For Female Rep...mentioning

confidence: 99%

Section: Future Directions Of Research In Mrna Therapy For Female Rep...mentioning

confidence: 99%

Messenger RNA Therapy for Female Reproductive Health

VanKeulen-Miller,

Fenton

2024

Mol. Pharmaceutics

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“…Flow cytometry and imaging data have been deposited in Zenodo ( https://zenodo.org/records/8342810 ) ( 72 ).…”

Section: Data Materials and Software Availabilitymentioning

confidence: 99%

Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes

Chaudhary,

Newby,

Arral

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages the use of existing medications and hinders new drug development. One potential solution is the use of lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, and lack of fetal accumulation. Here, we describe LNPs for efficacious mRNA delivery to maternal organs in pregnant mice via several routes of administration. In the placenta, our lead LNP transfected trophoblasts, endothelial cells, and immune cells, with efficacy being structurally dependent on the ionizable lipid polyamine headgroup. Next, we show that LNP-induced maternal inflammatory responses affect mRNA expression in the maternal compartment and hinder neonatal development. Specifically, pro-inflammatory LNP structures and routes of administration curtailed efficacy in maternal lymphoid organs in an IL-1β-dependent manner. Further, immunogenic LNPs provoked the infiltration of adaptive immune cells into the placenta and restricted pup growth after birth. Together, our results provide mechanism-based structural guidance on the design of potent LNPs for safe use during pregnancy.

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“…It is likely that systems to understand the LNP corona will be useful for the last three papers in the Special Feature, since all three report non-liver LNP delivery in vivo. In the first example, LNP delivery to maternal organs is demonstrated in pregnant mice via several routes of administration ( 18 ). The authors report delivery to trophoblasts, endothelial cells, and immune cells, also noting a relationship between the structure of the ionizable lipid and efficacy.…”

mentioning

confidence: 99%