Constructs and Methods for Delivering Molecules via Viral Vectors with Blunted Innate Immune Responses

A method for improving adeno-associated virus (AAV)-mediated gene expression, said method comprising:

• a) generating an AAV viral particle comprising a modified packaging insert, wherein said packaging insert comprises a nucleic acid molecule comprising two AAV inverted terminal repeat (ITR) and an exogenous gene sequence under the control of regulatory sequences which control expression of the gene product, wherein said sequences of said nucleic acid molecule are modified to reduce CpG di-nucleotides such that in immune response to the vector is reduced as compared to the unmodified AAV vector without significant reduction in expression of the gene product;
• and
• b) delivering the AAV to a subject.

A regimen for repeat administration of a gene product, said regimen comprising:

• a) delivering to a subject an adeno-associated viral (AAV) vector having an AAV capsid having packaged therein a nucleic acid molecule comprising two AAV inverted terminal repeats (ITR) and an exogenous gene sequence under the control of regulatory sequences which control expression of the gene product, wherein said sequences of said nucleic acid molecule are modified to reduce CpG di-nucleotides such that in immune response to the vector is reduced as compared to the unmodified AAV vector without significant reduction in expression of the gene product;
• and
• b) delivering to the subject a second vector comprising the exogenous gene sequence.