Method to enhance the efficiency of systemic AAV gene delivery to the central nervous system
The disclosure relates, in some aspects, to compositions and methods for enhanced delivery of a transgene to the central nervous system (CNS) of a subject. In some embodiments, the transgene is delivered by recombinant AAV (rAAV). In some embodiments, the method of enhancing transgene delivery comprises administering a blood brain barrier (BBB)-crossing molecule (e.g., K16ApoE) and an rAAV comprising a transgene to a subject.
1 . A method for delivering a transgene to CNS tissue in a subject, the method comprising co-administering to the subject:
(i) an effective amount of a targeting composition, wherein the targeting composition comprises a hydrophilic peptide comprising the amino acid sequence of SEQ ID NO: 17; and,
(ii) an effective amount of a recombinant adeno-associated virus (rAAV) comprising a nucleic acid comprising a promoter operably linked to a transgene and a capsid protein comprising an N-terminally grafted heterologous targeting peptide comprises or consists of a sequence selected from the group consisting of SEQ ID NOS: 15-17; wherein the co-administering comprises systemic co-injection.
2 . The method of claim 1 , wherein the capsid protein has a serotype selected from the group consisting of AAV1, AAV2, AAV2i8, AAV2.5, AAV6, AAV8, AAVrh8, AAV9, AAVrh10, AAV-B1, AAV9.45A-String, AAV9.45Angiopep, AAV9.47-Angiopep, and AAV9.47-AS.
3 . The method of claim 1 , wherein the capsid protein comprises or consists of a sequence selected from the group consisting of SEQ ID NOS: 10-14.
4 . The method of claim 1 , wherein the N-terminally grafted heterologous targeting peptide is expressed on the surface of the rAAV.
5 . The method of claim 1 , wherein the capsid protein is a VP2 capsid protein.
6 . The method of claim 1 , wherein the transgene is a CNS-associated transgene selected from the group consisting of ALS2, ANG, ATXN2, C9orf72, DCTN1, FIG. 4 , FUS, NEFH, OPTN, PFN1, PRPH, SETX, SIGMAR1, SMN1, SOD1, SPG11, TARDBP, UBQLN2, VAPB, VCP, Htt, Xbpls, CRAG, MAN2B1, MAN2B2, MAN2C1, AGA, CLN1, CLN2, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, MANBA, CTNS, LAMP2, GLA, ASAH1, FUCA1, CTSA, GBA, GALC, GLB1, HEXA, HEXB, ARSA, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, HYAL1, SMPD1, NPC1, NPC2, GAA, NAGA, SLCA17A5, and LAL.