Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered ...DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
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•Engineered virus-like particles (eVLPs) overcome three bottlenecks to protein delivery•DNA-free eVLPs efficiently deliver gene editing proteins with minimal off-target editing•Base editor eVLPs reduced serum Pcsk9 levels 78% following 63% liver editing in mice•Base editor eVLPs improved visual function in a mouse model of genetic blindness
Engineered, DNA-free virus-like particles efficiently deliver gene editing proteins, have minimal off-target effects, can be applied in vivo to deliver base editors to multiple organs, and are used to improve visual function in a mouse model of genetic blindness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent evidence of high systemic absorption of sunscreen ingredients has raised concerns regarding the safety of sunscreen products. Oxybenzone (BP‐3) and octinoxate (OMC), two common sunscreen ...ingredients, were recently banned in Key West and Hawaii owing to their toxic effects on marine ecosystems. Their impact on human health requires a careful assessment. To summarize the current evidence on the association between the systemic level of BP‐3 or OMC and its health impact, a primary literature search was conducted using PubMed database in February 2019. There are 29 studies that address the impact of these ingredients on human health. Studies show that elevated systemic level of BP‐3 has no adverse effect on male and female fertility, female reproductive hormone level, adiposity, fetal growth, child's neurodevelopment, and sexual maturation. However, the association of BP‐3 level on thyroid hormone, testosterone level, kidney function, and pubertal timing has been reported and prompts further investigations to validate a true association. The systemic absorption of OMC has no reported effect on thyroid and reproductive hormone levels. In conclusion, current evidence is not sufficient to support the causal relationship between the elevated systemic level of BP‐3 or OMC and adverse health outcomes. There are either contradictory findings among different studies or an insufficient number of studies to corroborate the observed association. To accurately evaluate the long‐term risk of exposure to BP‐3 and OMC from sunscreen, a well‐designed longitudinal randomized controlled trial needs to be conducted.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
16.
Precision genome editing in the eye Suh, Susie; Choi, Elliot H; Raguram, Aditya ...
Proceedings of the National Academy of Sciences - PNAS,
09/2022, Volume:
119, Issue:
39
Journal Article
Peer reviewed
Open access
CRISPR-Cas-based genome editing technologies could, in principle, be used to treat a wide variety of inherited diseases, including genetic disorders of vision. Programmable CRISPR-Cas nucleases are ...effective tools for gene disruption, but they are poorly suited for precisely correcting pathogenic mutations in most therapeutic settings. Recently developed precision genome editing agents, including base editors and prime editors, have enabled precise gene correction and disease rescue in multiple preclinical models of genetic disorders. Additionally, new delivery technologies that transiently deliver precision genome editing agents in vivo offer minimized off-target editing and improved safety profiles. These improvements to precision genome editing and delivery technologies are expected to revolutionize the treatment of genetic disorders of vision and other diseases. In this Perspective, we describe current preclinical and clinical genome editing approaches for treating inherited retinal degenerative diseases, and we discuss important considerations that should be addressed as these approaches are translated into clinical practice.
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