{"id":175357,"date":"2023-11-03T14:23:54","date_gmt":"2023-11-03T19:23:54","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2023\/11\/lipid-nanoparticle-mediated-hit-and-run-approaches-yield-efficient-and-safe-in-situ-gene-editing-in-human-skin"},"modified":"2023-11-03T14:23:54","modified_gmt":"2023-11-03T19:23:54","slug":"lipid-nanoparticle-mediated-hit-and-run-approaches-yield-efficient-and-safe-in-situ-gene-editing-in-human-skin","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2023\/11\/lipid-nanoparticle-mediated-hit-and-run-approaches-yield-efficient-and-safe-in-situ-gene-editing-in-human-skin","title":{"rendered":"Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin"},"content":{"rendered":"<p><a class=\"blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/lipid-nanoparticle-mediated-hit-and-run-approaches-yield-efficient-and-safe-in-situ-gene-editing-in-human-skin3.jpg\"><\/a><\/p>\n<p>Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for <i>in situ<\/i> gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10\u201316%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a p <i>K<\/i><sub>a<\/sub> \u223c 7.1 yielded superior gene editing rates (55%\u201372%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%\u201312% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of \u223c5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an <i>in situ<\/i> correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal [\u2026]<\/p>\n","protected":false},"author":511,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1902,11,412,4],"tags":[],"class_list":["post-175357","post","type-post","status-publish","format-standard","hentry","category-bioengineering","category-biotech-medical","category-genetics","category-nanotechnology"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/175357","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/511"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=175357"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/175357\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=175357"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=175357"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=175357"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}