Phase changing formulations of nucleic acid payloads
AssigneeDicerna Pharmaceuticals, Inc.
InventorsBob Dale Brown, Sujit Kumar Basu
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Abstract
The present invention is based, at least in part, upon discovery of a process for identifying phase changing peptides. Such phase changing peptides are capable of enhancing in vitro and in vivo delivery of oligonucleotides (e.g., dsRNAs) in lipidic, vesicular, micellar and/or naked oligonucleotide formulations.
Claims60
A method of identifying a phase changing peptide based on a peptide's efficacy in delivering an oligonucleotide to the cytoplasm of a cell in a subject after administration of a formulation comprising said oligonucleotide and said peptide, comprising the steps of:
- (i) providing a test peptide, wherein said peptide is a charge-trapped peptide;
- (ii) preparing a formulation comprising said oligonucleotide and said test peptide;
- (iii) comparing the activity of said formulation with the activity of a control formulation which lacks said test peptide, in one or more of the following assays:
- (a) an assay measuring/evaluating internalization of said oligonucleotide into said cell,
- (b) an assay measuring/evaluating leakiness of said cell induced by said formulation of step (ii),
- (c) an assay measuring/evaluating in vitro target knockdown,
- (d) an assay measuring/evaluating in vivo target knockdown,
- (e) an assay measuring/evaluating in vivo efficacy;
- and
- (iv) identifying the test peptide as a phase changing peptide if the formulation of step (ii) displays an increased activity in at least one of the assays (a)-(e) relative to the control formulation.
A method of disrupting a formulation or particle comprising:
- preparing a formulation or particle comprising a cyclic charge-trapped peptide that is capable of linearizing when introduced into a reducing or low pH environment;
- introducing said formulation or particle to a sufficiently reductive or low pH environment to linearize said cyclic peptide, wherein said linearization of said cyclic peptide disrupts said formulation or particle,
- thereby disrupting said formulation or particle.
Dependencies are inferred from the claim text.