Fusosome compositions and uses thereof
AssigneeFlagship Pioneering Innovations V, Inc.
InventorsGeoffrey A. von Maltzahn, Jacob Rosenblum Rubens, John Miles Milwid, Michael Travis Mee, Neal Francis Gordon, Jagesh Vijaykumar Shah
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Abstract
The present disclosure provides, at least in part, methods and compositions for in vivo fusosome delivery. In some embodiments, the fusosome comprises a combination of elements that promote specificity for target cells, e.g., one or more of a fusogen, a positive target cell-specific regulatory element, and a non-target cell-specific regulatory element. In some embodiments, the fusosome comprises one or more modifications that decrease an immune response against the fusosome.
Claims52
A fusosome comprising:
- a) a lipid bilayer comprising a fusogen;
- and
- b) a nucleic acid that comprises:
- (i) a payload gene encoding an exogenous agent;
- and
- (ii) a positive liver cell-specific regulatory element operatively linked to the payload gene, wherein the positive liver cell-specific regulatory element increases expression of the payload gene in a liver cell relative to an otherwise similar fusosome lacking the positive liver cell-specific regulatory element.
A fusosome comprising:
- a) a lipid bilayer comprising a fusogen;
- and
- b) a nucleic acid that comprises:
- (i) a payload gene encoding an exogenous agent;
- and
- (ii) a promoter operatively linked to the payload gene, wherein the promoter is chosen from an Apoa2, Cyp3a4, LP1B, MIR122, hemopexin, SERPINA1, or HLP promoter.
A fusosome comprising:
- a) a lipid bilayer comprising a fusogen;
- and
- b) a nucleic acid that comprises:
- (i) a payload gene encoding an exogenous agent;
- and
- (ii) a non-target cell-specific regulatory element (NTCSRE), operatively linked to the payload gene, wherein:
- the NTCSRE is a non-liver cell-specific miRNA recognition sequence, a non-liver cell-specific protease recognition site, a non-liver cell-specific ubiquitin ligase site, a non-liver cell-specific transcriptional repression site, or a non-liver cell-specific epigenetic repression site, and the NTCSRE decreases expression of the payload gene in a non-liver cell or tissue relative to an otherwise similar fusosome lacking the NTCSRE.
A fusosome comprising:
- a) a lipid bilayer comprising a fusogen;
- b) a nucleic acid that comprises a payload gene encoding an exogenous agent for treating a genetic deficiency;
- and
- c) one or both of:
- (i) a first exogenous or overexpressed immunosuppressive protein on the lipid bilayer;
- or
- (ii) a first immunostimulatory protein that is absent or present at reduced levels (e.g., reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) compared to a fusosome generated from an otherwise similar, unmodified source cell.
Dependencies are inferred from the claim text.