Viral vectors exhibiting improved gene delivery properties
AssigneePresident and Fellows of Harvard College
InventorsGeorge M. CHURCH, Eric KELSIC, Pierce OGDEN, Sam SINAI
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Abstract
The technology described herein provides viral capsid polypeptides bearing mutations that alters tissue tropism of a virus comprising the viral capsid polypeptide. In various embodiments, tissue tropisim to the heart, kidney, liver, lung, spleen, or blood is altered.
Claims30
A viral capsid polypeptide, wherein the viral capsid polypeptide comprises:
- a mutation relative to SEQ ID NO:
- 1 (WT AAV2) that alters tissue tropism of a virus comprising the viral capsid polypeptide, wherein the mutation is selected from the mutations in any one of Tables 1-9;
- or
- a region corresponding to the amino acid sequence of SEQ ID NO:
- 2, wherein the region corresponding to the amino acid sequence of SEQ ID NO:
- 2 comprises a mutation relative to SEQ ID NO:
- 2 that alters tissue tropism of a virus comprising the viral capsid polypeptide, wherein the mutation is selected from the mutations in any one of Tables 10-15.
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-13. (canceled)
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A method of reducing tissue tropism of a virus comprising a viral capsid polypeptide corresponding to the viral capsid polypeptide of SEQ ID NO:
- 1, the method comprising introducing a mutation set out in any of Tables 7-9.
A method of increasing delivery of a nucleic acid to a cell of a kidney, heart, or lung, the method comprising;
- contacting a cell of a kidney, heart, or lung with a viral particle comprising a viral capsid polypeptide comprising a mutation that reduces delivery of a nucleic acid to a cell of a liver, blood, or spleen
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An AAV2 capsid polypeptide comprising a mutation in the region of amino acids selected the group consisting of:
- 440-460 of SEQ ID NO:
- 1, 475-505 of SEQ ID NO:
- 1, 518-532 of SEQ ID NO:
- 1, and 560-590 of SEQ ID NO:
- 1 that alters tissue tropism of a virus comprising the viral capsid polypeptide.
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An AAV2 capsid polypeptide, wherein the AAV2 capsid polypeptide comprises:
- a mutation in the region of amino acids 561-588 of SEQ ID NO:
- 1 that increases tissue tropism of a virus to the kidney, wherein the mutated region of amino acid 561-588 of SEQ ID NO:
- 1 has a sequence selected from the group consisting of:
- (SEQ ID NO:
- 3)
- DEEEIATTNPVATEQYGDVSENLMHFQN;
- (SEQ ID NO:
- 4)
- DEEEIRQTNPVATEGYGEVSTNLMHGNK;
- (SEQ ID NO:
- 5)
- DEEEIRTTNPVATEQYGIVnStTNLNEGNR;
- (SEQ ID NO:
- 6)
- DEEEIRTTNPVATECYGSVSTDLQSGNL;
- (SEQ ID NO:
- 7)
- DENEIRTTNPVATEIYGSVSTeNLQNnGdNR;
- (SEQ ID NO:
- 8)
- DEEEIRTTNPVATEQYGSVSeTNpLvQNGdDR;
- (SEQ ID NO:
- 9)
- DEEEIRTTNPVATEQYGDVSENLMHFQN;
- a mutation in the region of amino acids 561-588 of SEQ ID NO:
- 1 that increases tissue tropism of a virus to the liver, wherein the mutated region of amino acid 561-588 of SEQ ID NO:
- 1 has a sequence selected from the group consisting of:
- (SEQ ID NO:
- 10)
- DEEEIRTTNPVATEQYGVVSDNLQRGNR;
- (SEQ ID NO:
- 11)
- DECEIRTTNPVATEQYGSVGENLQRGNR;
- (SEQ ID NO:
- 12)
- DEEEIRTTNPVATEQYGVVSENLQRGNR;
- (SEQ ID NO:
- 13)
- DESEITTTNPVATEQYGWVSTNQQRGNR;
- (SEQ ID NO:
- 14)
- HELEIATTNPVATEQYGSASTNIQRGNR;
- (SEQ ID NO:
- 15)
- DEEEIATTNPVATEQYGGVSTNLQRGNR;
- or
- a mutation in the region of amino acids 561-588 of SEQ ID NO:
- 1 that increases tissue tropism of a virus to the lung, wherein the mutated region of amino acid 561-588 of SEQ ID NO:
- 1 has a sequence selected from the group consisting of:
- (SEQ ID NO:
- 16)
- DEEEIVTTNPVATEQYGNVSTNLQRGNR;
- (SEQ ID NO:
- 17)
- DEDEISTTNPVATEQYGSCSTNLQRGNR;
- (SEQ ID NO:
- 18)
- QEEEIRTTNPVATEQYGSVSTNLQRGDR;
- (SEQ ID NO:
- 19)
- NEEEIRTTNPCATEVYGSVSTNLQRGNR;
- (SEQ ID NO:
- 20)
- DEQEIVTTNPVATEVYGTVSTNLQRGNR.
-34. (canceled)
A viral capsid polypeptide bearing a mutation relative to SEQ ID NO:
- 1 (WT AAV2) that alters packaging efficiency of a virus comprising the viral capsid polypeptide, wherein the mutation is selected from the mutations in Table 16.
Dependencies are inferred from the claim text.