Lipid-like materials for low-dose in vivo gene silencing pdf

They found that dsrna was substantially more effective at gene silencing than either strand individually. Jan 23, 2012 in vivo delivery of sipkm2 additionally causes substantial tumor regression of established xenografts. Design of synthetic materials for intracellular delivery. May 25, 2010 the caption b luciferase should instead appear as b luciferase silencing at low doses of sirna s. Dna, sirna has a stiff structure and relatively low. Molecular therapy using small interfering rna sirna has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. Lipidlike materials for lowdose in vivo gene silencing. Lipidlike materials for lowdose, in vivo gene silencing pp. Interestingly, it was found that ineffective single lipidlike materials could be. Kt love, kp mahon, cg levins, ka whitehead, w querbes, jr dorkin, et al. Pdf rna interference therapeutics afford the potential to silence target gene expression. Efficiency of sirna delivery by lipid nanoparticles is limited by endocytic recycling.

Recent developments in nanoparticlebased sirna delivery for. Rna interference rnai is a gene regulation mechanism initiated by rna molecules that enables sequencespecific gene silencing by promoting degradation of specific mrnas. Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. Therapeutic sirna silencing in inflammatory monocytes. Pdf lipidlike materials for lowdose, in vivo gene silencing. A formulated control sirna was administered at a dose of 1 mg.

Such doses are comparable to those required by stable nucleic acid lipid particle snalp formulations, another delivery system which has shown utility for sirna delivery in nonhuman primates 14. While studies have demonstrated the potential of gene. Pdf development of lipidoidsirna formulations for systemic. Unlike lipid or lipidlike nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. Known as the warburg effect warburg 1956, this reprogramming of gene expression that alters glucose metabolism enables cells to suppress. Silencing tnf alpha with lipidoid nanoparticles downregulates both tnf alpha and mcp1 in an in vitro coculture model of diabetic foot ulcers. Reynolds 2, maixian liu 1, xin liu 1, guanying chen 1, folarin erogbogbo 1, lisa vathy 1, ravikumar aalinkeel 2, stanley a. Lipid like materials for low dose, in vivo gene silencing by kevin t. Lipidlike materials for lowdose in vivo gene silencing love et al.

Although much effort in the field of oncology has focused on canonical oncogenes and tumor suppressor genes, the importance of cancer cell metabolism is growing in appreciation deberardinis et al. Our results suggest that the inherent nucleotidelevel specificity of sirna can be harnessed to develop therapeutics that target isoformspecific exons in genes exhibiting differential splicing patterns in various cell types. Lipidlike materials for lowdose, in vivo gene silencing kevin t. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of rna interference. Lipid and lipidlike materials are currently the most wellstudied sirna delivery systems for. Lipid like materials for low dose, in vivo gene silencing. This corrects the article lipidlike materials for lowdose, in vivo gene silencing in volume 107 on page 1864. Ligand conjugated multimeric sirnas enable enhanced uptake. We formulated chemically distinct lipid nanoparticles lnps so.

Rna interference rnai has considerable potential as a therapeutic strategy, but the development of efficient in vivo rna delivery methods remains challenging. Lipid like materials for low dose, in vivo gene silencing kt love, kp mahon, cg levins, ka whitehead, w querbes, jr dorkin. Proceedings of the national academy of sciences 107. Preparation and optimization of lipidlike nanoparticles. To this end, we designed and synthesized chemically modified interfering nanoparticles inops composed of functionalized polyllysine dendrimers modified with reducible spacers to facilitate release of small interfering rnas sirnas. Overcoming cellular barriers for rna therapeutics nature. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables sirnadirected liver gene silencing in mice at doses below 0. We show that in vivo delivery efficacy is affected by many parameters, including the. Lipidlike materials for lowdose, in vivo gene silencing vol 107, pg 1864, 2010 article pdf available in proceedings of the national academy of sciences 10721. May 11, 2014 unlike lipid or lipid like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. The major challenges to application of sirna therapeutics include.

Lipid like materials for lowdose, in vivo gene silencing. Synthesisofepoxidederivedlipidoidlibraryaepoxideterminated alkyl chains and aminecontaining monomers were used in synthesis of com. In vivo gene silencing ability is provided in the form of relative fvii activity at a. In order to achieve this objective, we employed recently generated transcriptomes from myofibroblasts and their precursors in models of liver and kidney injury and fibrosis. The combination 86n1598o was first analyzed at a total sirna dose of 5. Lipidlike materials for lowdose, in vivo gene silencing by kevin t.

Proceedings of the national academy of sciences 107 5, 18641869, 2010. Pyruvate kinase m2specific sirna induces apoptosis and tumor. Lipid like materials for low dose, in vivo gene silencing created date. We proposed reducing constitutive gene and protein expression of lrp2 megalin in order to understand its molecular regulation in mice. As a result of the highly efficient gene silencing achieved by c12200, we hypothesized that silencing of multiple genes in the liver with a single i. Lipidlike materials for lowdose, in vivo gene silencing article pdf available in proceedings of the national academy of sciences 1075.

Surface depegylation controls nanoparticlemediated sirna. Efficiency of sirna delivery by lipid nanoparticles is limited by endocytic. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of rna interference therapeutics. Gene silencing by rna interference rnai is attracting increasing attention as a potential therapeutic strategy. Ubr2 mediates transcriptional silencing during spermatogenesis via. In vivo sirna delivery and rebound of renal lrp2 in mice. Preparation and optimization of lipidlike nanoparticles for. Maximizing the potency of sirna lipid nanoparticles for hepatic gene silencing in vivo. At the two lower doses, all formulations were well. Robert dorkin, d june qin, d william cantley, d liu liang qin, d timothy racie, d maria frankkamenetsky, d ka ning yip, a rene alvarez, d dinah w. Identification of novel fibrosis modifiers by in vivo. Lipidlike materials for lowdose, in vivo gene silencing core. Dual hela cells were transfected with sirna against rab8a, rab27a.

Lipidbased colloidal carriers for targeted sirna delivery. Targeting by polyvalent display of a compact ligand for the asialoglycoprotein receptor. Lipidlike materials for lowdose, in vivo gene silencing. Recent developments in nanoparticlebased sirna delivery. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Clinical advances of sirna therapeutics hu 2019 the. Applied biological sciences correction for lipidlike materials for lowdose, in vivo gene silencing, by kevin t. Lipid like materials for low dose, in vivo gene silencing proc natl acad sci usa, 107 2010, pp. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. Degradable lipid nanoparticles with predictable in vivo. Rna sirna delivery studies, very few materials have been reported to. During rnai, small interfering rna sirna duplexes are introduced into the cell and assemble in the rnainduced silencing complex risc, a multiprotein complex that cleaves the complementary targeted mrna or blocks its translation.

Jul 21, 2017 love kt, mahon kp, levins cg et al 2010 lipidlike materials for lowdose, in vivo gene silencing. Nov 23, 2012 12 love kt, mahon kp, levins cg et al. Lowdose efficacy enables multiple gene silencing in vivo. Lipidlike materials for lowdose, in vivo gene silencing created date. Polydopaminebased surface modification of novel nanoparticleaptamer bioconjugates for in vivo breast cancer targeting and enhanced therapeutic effects. Hepatocytespecific delivery of sirnas conjugated to novel nonnucleosidic trivalent nacetylgalactosamine elicits robust gene silencing in vivo. In vivo endothelial sirna delivery using polymeric. A method for concentrating lipid peptide dna and sirna. Lipidoid nanoparticles containing pdl1 sirna delivered in.

Systemic rnaimediated gene silencing in nonhuman primate and rodent myeloid cells. Design of synthetic materials for intracellular delivery of. Full text a method for concentrating lipid peptide dna and. Pyruvate kinase m2specific sirna induces apoptosis and. Levins, kathryn ann whitehead, william querbes, joseph robert dorkin, june qin, william cantley, liu liang qin, timothy racie, maria frankkamenetsky, ka yip, rene alvarez, dinah w. Functional nanostructures for effective delivery of small interfering. Love kt, mahon kp, levins cg, whitehead ka, querbes w, dorkin jr, et al. Barcoded nanoparticles for high throughput in vivo. Lipidlike materials for lowdose, in vivo gene silencing pnas.

Low dose efficacy enables multiple gene silencing in vivo. Identification of novel fibrosis modifiers by in vivo sirna. Inflammatory monocytesbut not the noninflammatory subsetdepend on the chemokine. High s values correlated well with higher levels of gene silencing, and low s values. A variety of nanomaterials have been developed for the effective in vivo delivery of short small rnas, messenger rnas, and rnas required for gene editing technologies including clustered regularly interspaced palindromic repeat crisprcas. While promising, delivery with these materials requires sirna doses greater than 1 mgkg to achieve high levels of gene silencing in vivo. Lipidlike materials for lowdose, in vivo gene silencing proc natl acad sci usa, 107 2010, pp. Prior sirna efforts have successfully prevented upregulation of mrna in response to injury. Sep 26, 2019 lipidlike materials for lowdose, in vivo gene silencing. Love kt, mahon kp, levins cg et al 2010 lipidlike materials for lowdose, in vivo gene silencing. Jun 16, 2017 the comparatively weaker effect of col1a1 silencing in vitro.