Rational polyploid aav virions that cross the blood brain barrier and elicit reduced humoral response

A population of rational polyploid AAV virions that allows repeat dosing, the population comprising:

• a rational polyploid AAV virion comprising at least one of AAV VP1 or VP2 viral structural proteins and a AAV VP3 viral structural protein;
• wherein the at least one of VP1 or VP2 viral structural proteins are each from any AAV viral serotype, and the VP3 viral structural protein is selected from a rhesus monkey AAV serotype;
• wherein the population of rational polyploid AAV virions elicits a reduced humoral response as compared to a humoral response elicited by the parental AAV serotype of the VP1 or VP2 viral structural proteins;
• wherein the at least one of VP1 or VP2 are not from a Rhesus AAV serotype, and
• wherein the repeat dosing comprises a first administration of the population of rational polyploid AAV virions and a second administration of a parental AAV serotype of the VP1 structural viral protein or VP2 structural viral protein.

A nucleic acid comprising, in a 5′ to 3′ direction:

• a. a first nucleic acid encoding an AAVrh10 VP3 capsid protein operatively linked to a first promoter;
• b. a first poly A sequence;
• c. a second nucleic acid encoding a rep protein;
• d. a third nucleic acid encoding AAV8 VP1 and VP2 viral structural proteins, the third nucleic acid sequence not being capable of expressing an AAV8 VP3 viral structural protein;
• and
• e. a second poly A sequence.

A nucleic acid comprising, in a 5′ to 3′ direction:

• a. a first nucleic acid encoding a AAVrh74 VP3 capsid protein operatively linked to a first promoter;
• b. a first poly A sequence;
• c. a second nucleic acid encoding a rep protein;
• d. a third nucleic acid encoding AAV8 VP1 and VP2 viral structural proteins, the third nucleic acid sequence not being capable of expressing a AAV8 VP3 viral structural protein;
• and
• e. a second poly A sequence.

A population of rational polyploid AAV virions that allow repeat dosing, the population comprising:

• at least one of AAV VP1 or VP2 viral structural proteins and a AAV VP3 viral structural protein;
• wherein the VP1 and VP2 viral structural proteins are each from any AAV viral serotype except for a Rhesus AAV serotype, and the VP3 viral structural protein is selected from a rhesus monkey AAV serotype;
• wherein the population of rational polyploid AAV virions evade neutralizing antibodies against a parental AAV rhesus monkey serotype of the VP3 viral structural protein,
• wherein the repeat dosing comprises a first administration of the parental AAV rhesus monkey serotype of the VP3 structural protein and a second administration of the population of rational polyploid AAV virions, and
• wherein the VP3 structural protein of the rational polyploid virions is a AAV rhesus monkey mutated viral structural protein VP3.