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2006.01) Kr, Kw, Kz, La, Lc, Lk, Lr, Ls, Lu, Ly, Ma, Md, Me, (21 ( (51) International Patent Classification: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, A61K 48/00 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 19/06 1701 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 15 November 2019 (15. 11.2019) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available) . ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/768,645 16 November 2018 (16. 11.2018) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 62/769,697 20 November 2018 (20. 11.2018) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 62/778,706 12 December 2018 (12. 12.2018) US MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, (71) Applicant: ASKLEPIOS BIOPHARMACEUTICAL, KM, ML, MR, NE, SN, TD, TG). INC. [US/US]; 20 T.W. Alexander Drive, Suite 110, Re¬ search Triangle Park, NC 27709 (US). Declarations under Rule 4.17: (72) Inventors: O'CALLAGHAN, Michael W.; c/o Asklepios — as to applicant's entitlement to apply for and be granted a Biopharmaceutical, Inc., 20 T.W. Alexander Drive, Suite patent (Rule 4.17(H)) 110, Research Triangle Park, NC 27709 (US). FRANCOIS, — as to the applicant's entitlement to claim the priority of the Achille; c/o Asklepios Biopharmaceutical, Inc., 20 T.W. earlier application (Rule 4.17(iii)) Alexander Drive, Suite 110, Research Triangle Park, NC Published: 27709 (US). — without international search report and to be republished (74) Agent: BENN, Susanna C. et al.; Nixon Peabody LLP, Ex¬ upon receipt of that report (Rule 48. 2(g)) change Place, 53 State Street, Boston, Massachusetts 02109 — with sequence listing part of description (Rule 5.2(a)) (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (54) Title: VECTORS COMPRISING A NUCLEIC ACID ENCODING LYSOSOMAL ENZYMES FUSED TO A LYSOSOMAL TARGETING SEQUENCE (57) Abstract: Vectors including viral vectors comprising a genome comprising a heterologous nucleic acid encoding a lysosomal targeting sequence, fused to a lysosomal storage enzyme, enabling the lysosomal enzyme to be targeted to the lysosomes. Particular embodiments relate to a recombinant viral vector, e.g., rAAV vector encoding a lysosomal enzyme, having a lysosomal targeting IGF2(V43) sequence that binds human cation-independent mannose-6-phosphate receptor (CI-MPR) orto the IGF2 receptor, permitting proper subcellular localization of the lysosomal enzyme polypeptide to lysosomes. Also encompassed are therapeutic fusion proteins encoded by the viral vector, non-viral vectors, cells, and methods to treat a glycogen storage disease, e.g., those listed in Table 4A or Table 5A with the viral vector. VECTORS COMPRISING A NUCLEIC ACID ENCODING LYSOSOMAL ENZYMES FUSED TO A LYSOSOMAL TARGETING SEQUENCE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This invention claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application 62/768,645 filed on November 16, 2018 and U.S. Provisional Application 62/769,697 filed on November 20, 2018, and U.S. Provisional Application 62/778,706 filed on December 12, 2018, the contents of each are incorporated herein in their entirety by reference. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 15, 2019 is named 046192-093910WOPT_SL and is 525,162 bytes in size. FIELD OF THE INVENTION [0003] The present invention relates to targeted vectors, including but not limited to adeno- associated virus (AAV) particles, virions and vectors for targeted translocation of lysosomal enzymes to lysosomes, and method of use for the treatment of lysosomal storage diseases. BACKGROUND [0004] Gene therapy has been shown to have the potential to not only cure genetic disorders, but to also facilitate the long-term non-invasive treatment of acquired and degenerative disease using a virus, such as an adeno-associated virus (AAV). AAV itself is a non-pathogenic-dependent parvovirus that needs helper viruses for efficient replication. AAV has been utilized as a virus vector for gene therapy because of its safety and simplicity. AAV has a broad host and cell type tropism capable of transducing both dividing and non-dividing cells. To date, 12 AAV serotypes and more than 100 variants have been identified. It has been shown that the different AAV serotypes can have differing abilities to infect cells of different tissues, either in vivo or in vitro and that these differences in infectivity are likely tied to the particular receptors and co-receptors located on the cell surface of each AAV serotype or may be tied to the intracellular trafficking pathway itself. [0005] Accordingly, as an alternative or adjunct to enzyme therapy, the feasibility of gene therapy approaches to treat GSD-II have been investigated (Amalfitano, A., et al, (1999) Proc. Natl. Acad. Sci. USA 96:8861-8866, Ding, E., et al. (2002) Mol. Ther. 5:436-446, Fraites, T. L, et al., (2002) Mol. Ther. 5:571-578, Tsujino, S., et al. (1998) Hum. Gene Ther. 9:1609-1616). [0006] More than forty lysosomal storage diseases (LSDs) are caused, directly or indirectly, by the absence of one or more lysosomal enzymes in the lysosome Enzyme replacement therapy for LSDs is being actively pursued. Therapy generally requires that LSD proteins be taken up and delivered to the lysosomes of a variety of cell types in an M6P-dependent fashion. One possible approach involves purifying an LSD protein and modifying it to incorporate a carbohydrate moiety with M6P. This modified material may be taken up by the cells more efficiently than unmodified LSD proteins due to interaction with M6P receptors on the cell surface. [0007] However, viral or AAV delivery of genes, in particular lysosomal proteins and enzymes for treatment of lysosomal storage diseases has challenges. Normally, mammalian lysosomal enzymes are synthesized in the cytosol and traverse the ER where they are glycosylated with N-linked, high mannose type carbohydrate. In the golgi, the high mannose carbohydrate is modified on lysosomal proteins by the addition of mannose-6-phosphate (M6P) which targets these proteins to the lysosome. The M6P-modified proteins are delivered to the lysosome via interaction with either of two M6P receptors. However, recombinantly produced proteins used in enzyme replacement therapy often lack the addition of the M6P which is required for targeting them to the lysosomes, therefore, often requiring high doses of recombinantly produced enzymes to be administered to a patient and/or frequent infusions. [0008] Accordingly, there is a need in the art for improved methods of producing lysosomal polypeptides using gene therapy in vitro and in vivo, for example, to treat lysosomal polypeptide deficiencies. Further, there is a need for methods that result in systemic delivery of lysosomal polypeptides to affected tissues and organs. In particular, there remains a need for more efficient methods for administering lysosomal enzymes to subjects and targeting lysosomal proteins to patient lysosomes, while reducing any potential side effects. SUMMARY OF THE INVENTION [0009] The technology described herein relates generally to gene therapy constructs and more particularly to targeted viral vectors, e.g., viral vector, such as but not limited to lentivirus, adenovirus (Ad), adeno-associated viruses (AAV), HSV etc. for example, but not limited to adeno-associated virus (AAV) virions configured for delivering a lysosomal enzyme to a subject. In some instances, the vector can be non- viral such as naked “DNA” or DNA in a nanosphere or liposome. In an alternative embodiment, the vector is a therapeutic protein. The therapeutic protein can be any of the proteins encoded by the viral or non-viral vector. [0010] In particular, described herein are targeted viral vectors, e.g., using rAAV vectors as an exemplary example, that comprises a nucleotide sequence containing inverted terminal repeats (ITRs), a promoter, a heterologous gene, a poly-A tail and potentially other regulator elements for use to treat a lysosomal storage disease, such as those listed in Table 4A or Table 5A herein, wherein the heterologous gene is a lysosomal enzyme and wherein the vector, e.g., rAAV can be administered to a patient in a therapeutically effective dose that is delivered to the appropriate tissue and/ or organ for expression of the heterologous lysosomal enzyme gene and treatment of the disease. [0011] The technology described herein relates in general to a means of producing a lysosomal enzyme that is expressed in the liver using a vector, and more effectively targeted to the lysosomes of mammalian cells, for example, human cardiac and skeletal muscle cells. The present invention provides targeted vectors, including but not limited to rAAV vectors and viral genomes and isolated nucleic acids encoding lysosomal polypeptides (also referred to as lysosomal enzymes) that are fused to a lysosomal targeting peptide that enhances targeting of the polypeptide to the secretory pathway and to aid update into lysosomes.
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