Restrictive inverted terminal repeats for viral vectors
AssigneeThe University of North Carolina at Chapel Hill
InventorsCurtis Hewitt, Richard Jude Samulski
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Abstract
This invention relates to modified parvovirus inverted terminal repeats (ITRs) that do not functionally interact with wild-type large Rep proteins, synthetic Rep proteins that functionally interact with the modified ITRs, and methods of using the same for delivery of nucleic acids to a cell or a subject. The modifications provide a novel Rep-ITR interaction that limits vector mobilization, increasing the safety of viral vectors.
Claims23
A method of delivering a nucleic acid to a cell, comprising contacting the cell with a recombinant parvovirus particle, under conditions sufficient for the recombinant parvovirus particle to enter the cell, wherein the recombinant parvovirus comprises a genome comprising the nucleic acid and at least one parvovirus inverted terminal repeat (ITR), wherein the ITR comprises:
- a) a first structural element that functionally interacts with a large Rep protein from a first adeno-associated virus (AAV) but does not functionally interact with a large Rep protein from a second AAV;
- and
- b) a second structural element that functionally interacts with the large Rep protein from the second AAV but does not functionally interact with the large Rep protein from the first AAV;
- wherein the ITR functionally interacts with a synthetic AAV large Rep protein, and wherein one of the structural elements is a nicking stem.
A method of administering a nucleic acid to a mammalian subject comprising administering to the subject a recombinant parvovirus particle comprising a genome comprising the nucleic acid and at least one parvovirus inverted terminal repeat (ITR), wherein the ITR comprises:
- a) a first structural element that functionally interacts with a large Rep protein from a first adeno-associated virus (AAV) but does not functionally interact with a large Rep protein from a second AAV;
- and
- b) a second structural element that functionally interacts with the large Rep protein from the second AAV but does not functionally interact with the large Rep protein from the first AAV;
- wherein the ITR functionally interacts with a synthetic AAV large Rep protein, and wherein one of the structural elements is a nicking stem.
Dependencies are inferred from the claim text.