Compositions and methods for ocular therapy
OwnerJeffrey O'CALLAGHAN, Thomas W. CHALBERG, Jr. +4inventors
InventorsJeffrey O'CALLAGHAN, Thomas W. CHALBERG, Jr., Matthew LAWRENCE, Annahita KERAVALA, Matthew CAMPBELL, Peter HUMPHRIES
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Abstract
Provided is a unit dose of recombinant adeno-associated virus (AAV) particles for expression of matrix metalloproteinase 3 (MMP-3). Further provided is a unit dose of recombinant MMP-3. Also provided are methods of use thereof, e.g., in transducing the corneal endothelium of a subject; reducing intraocular pressure in an eye of a subject; treating and/or preventing elevated intraocular pressure in a subject; and treating and/or preventing glaucoma in a subject. Subjects include primates.
Claims90
A unit dose comprising a plurality of recombinant adeno-associated virus of serotype 9 (rAAV9) particles,
- wherein each rAAV9 of the plurality of rAAV9 particles is non-replicating, and
- wherein each rAAV9 of the plurality of rAAV9 particles comprises a polynucleotide comprising, from 5′ to 3′:
- (a) a sequence encoding a 5′ inverted terminal repeat (ITR);
- (b) a sequence encoding a promoter;
- (c) a sequence encoding a human matrix metalloproteinase 3 (hMMP-3);
- (d) a sequence encoding a polyadenylation (polyA) signal;
- and
- (e) a sequence encoding a 3′ ITR;
- and
- wherein the unit dose comprises between 1×1010 vector genomes (vg) and 5×1012 vg, inclusive of the endpoints, of rAAV9 particles.
A unit dose comprising recombinant matrix metalloproteinase 3 (MMP-3) protein, wherein the unit dose comprises between 1 milligrams per milliliter (mg/mL) and 500 mg/mL, inclusive of the endpoints, of the recombinant MMP-3 protein;
- or between 0.1 nanograms (ng) and 10 ng, inclusive of the endpoints, of the recombinant MMP-3 protein.
A method of transducing the corneal endothelium of a subject, comprising administering an effective amount of a unit dose comprising a plurality of recombinant adeno-associated virus of serotype 9 (rAAV9) particles to the subject,
- wherein the subject is a primate;
- wherein each rAAV9 of the plurality of rAAV9 particles is non-replicating;
- wherein each rAAV9 of the plurality of rAAV9 particles is a single-stranded AAV (ssAAV);
- wherein each rAAV9 of the plurality of rAAV9 particles comprises a polynucleotide comprising, from 5′ to 3′:
- (a) a sequence encoding a 5′ inverted terminal repeat (ITR);
- (b) a sequence encoding a promoter;
- (c) a sequence encoding a matrix metalloproteinase 3 (MMP-3);
- (d) a sequence encoding a polyadenylation (polyA) signal;
- and
- (e) a sequence encoding a 3′ ITR;
- and
- wherein the unit dose comprises
- (i) between 1×1010 vector genomes (vg) and 5×1012 vg, inclusive of the endpoints, of rAAV9 particles;
- or
- (ii) about 1×1011 vector genomes (vg) per milliliter (mL) to 1×1014 vg/mL of rAAV9 particles;
- and
- wherein administering the effective amount of the unit dose results in expression of MMP-3 in the aqueous humor of an eye of the subject at a measured concentration of between 0.01 ng/mL and about 10 ng/mL, inclusive of the endpoints.
A method of transducing the corneal endothelium of a subject, comprising administering an effective amount of a unit dose comprising a plurality of recombinant adeno-associated virus of serotype 9 (rAAV9) particles to the subject,
- wherein the subject is a primate;
- wherein each rAAV9 of the plurality of rAAV9 particles is non-replicating;
- wherein each rAAV9 of the plurality of rAAV9 particles is a single-stranded AAV (ssAAV);
- wherein each rAAV9 of the plurality of rAAV9 particles comprises a polynucleotide comprising, from 5′ to 3′:
- (a) a sequence encoding a 5′ inverted terminal repeat (ITR);
- (b) a sequence encoding a promoter;
- (c) a sequence encoding a transgene;
- (d) a sequence encoding a polyadenylation (polyA) signal;
- a
- (e) a sequence encoding a 3′ ITR.
A gene therapy vector comprising an expression cassette comprising a transgene encoding a human matrix metalloproteinase 3 (hMMP-3) or a functional variant thereof, optionally operatively linked to a promoter, wherein the transgene is optimized for expression in a human host cell.
A polynucleotide, comprising a transgene encoding a human matrix metalloproteinase 3 (hMMP-3) or a functional variant thereof, wherein the transgene is optimized for expression in a human host cell.
Dependencies are inferred from the claim text.