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

By Kevin T. Lovea, Kerry P. Mahonb, Christopher G. Levinsb, Kathryn A. Whiteheadb, William Querbesd, J. Robert, Dorkind, June Qind, William Cantleyd, L. Qind and 11 more. Proceedings of the National Academy of Sciences of the United States of America, 2010

923 citations recorded by the source corpus.

Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. 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. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/481acd6889dd04f2fd6524c8a3bf40d4b951f1d1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Molecular Biology

Citations in the corpus

Advanced Materials and Processing for Drug Delivery: The Past and the Future (2012, background): “A follow-up study used improved chemistry to synthesize another library of lipid-like polymers to reduce dosage of siRNA required for in vivo study [107].”
Nanoparticles in the clinic (2016, methodology): “Recent research efforts have described methods to test numerous nanoparticle formulations for specific biological functions or in vitro release profiles, and through selective iterations arriving at a single optimized formulation for a single specific function (Figure 4a).(91,127,128) The most advan”
Nanoparticles for Cancer Therapy: Current Progress and Challenges (2021, methodology): “To overcomes this, we can use certain methods that can test numerous nano-formulation and by selective iterations selecting a single optimized formulation [190-192].”
Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine (2017, background): “These vesicles prevent the drugs from being filtered by the kidneys and improve intracellular delivery.(81,82,84)”
Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling (2013, positive): “16 When HeLa-GFP cells were incubated with LNPs containing Alexa-647-labelled siRNA against GFP for 3 hrs, the particles appear to localize at the perinuclear region within 1 hour post exposure (Fig S1 a-b).”