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(12) United States Patent (10) Patent No.: US 7,867.484 B2 Samulski Et Al

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(12) United States Patent (10) Patent No.: US 7,867.484 B2 Samulski Et Al USOO7867484B2 (12) United States Patent (10) Patent No.: US 7,867.484 B2 Samulski et al. (45) Date of Patent: Jan. 11, 2011 (54) HEPARIN AND HEPARAN SULFATE BINDING WO WO 2005,106046 A1 11/2005 CHMERIC VECTORS (75) Inventors: Richard Jude Samulski, Chapel Hill, OTHER PUBLICATIONS NC (US); Zhijian Wu, Chapel Hill, NC Rutledge et al. J. Virol. 72:309-319; 1998.* (US); Aravind Asokan, Chapel Hill, NC International Search Report and Written Opinion of International (US) Application No. PCT/US07/02251, mailed Sep. 18, 2008 (13 pages). Opie et al. “Identification of Amino Acid Residues in the Capsid (73) Assignee: University of North Carolina at Proteins of Adeno-Associated Virus Type 2 That Contribute to Chapel Hill, Chapel Hill, NC (US) Heparan Sulfate Proteoglycan Binding” Journal of Virology 77(12):6995-7006 (2003). (*) Notice: Subject to any disclaimer, the term of this Wu et al. “Mutational Analysis of the Adeno-Associated Virus Type patent is extended or adjusted under 35 2 (AAV2) Capsid Gene and Construction of AAV2 Vectors with U.S.C. 154(b) by 58 days. Altered Tropism” Journal of Virology 74(18):8635-8647 (2000). Grimm et al. “Helper Virus-Free, Optically Controllable, and Two (21) Appl. No.: 11/698,505 Plasmid-Based Production of Adeno-associated Virus Vectors of Serotypes 1 to 6’ Molecular Therapy 7(6): 839-850 (Jun. 2003). (22) Filed: Jan. 26, 2007 Grimm et al. “Preclinical in vivo evaluation of pseudotyped adeno associated virus vectors for liver gene therapy” Blood 102(7): 2412 (65) Prior Publication Data 2419 (Oct. 1, 2003). Halbert etal. "Adeno-Associated Virus Type 6 (AAV6)Vectors Medi US 2007/O196338A1 Aug. 23, 2007 ate Efficient Transduction of Airway Epithethial Cells in Mouse Lungs Compared to That of AAV2 Vectors' Journal of Virology Related U.S. Application Data 75(14): 66.15-6624 (Jul 2001). (60) Provisional application No. 60/762,774, filed on Jan. Jooss et al. “Transduction of Dendritic Cells by DNA Viral Vectors 27, 2006. Directs the Immune Response to Transgene Products in Muscle Fibers” Journal of Virology 72(5): 4212-4223 (May 1998). Kern et al. “Identification of a Heparin-Binding Motif on Adeno (51) Int. Cl. Associated Virus Type2 Capsids”,Journal of Virology 77(20): 11072 CI2N 15/00 (2006.01) 11081 (Oct. 2003). CI2N 15/85 (2006.01) Vandenberghe et al. “Heparin binding directs activation of T cells CI2N 15/86 (2006.01) against adeno-associated virus serotype 2 capsid Nature Medicine: CI2N 5/64 (2006.01) 1-5 (Jul 16, 2006). (52) U.S. Cl. ................ 424/93.2:435/320.1; 435/252.3: 435/325; 435/455; 435/456; 435/471; 536/23.1 * cited by examiner (58) Field of Classification Search ................ 424/93.2: Primary Examiner Maria Leavitt 435/320.1, 252.3, 325,455, 456, 471; 536/23.1 (74) Attorney, Agent, or Firm Myers Bigel Sibley & See application file for complete search history. Sajovec, P.A. (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS 6.410,300 B1 6/2002 Samulski et al. The present invention is based on the finding that parvovirus 6,491,907 B1 12/2002 Rabinowitz et al. (including AAV) capsids can be engineered to incorporate 6,703,237 B2 * 3/2004 Samulski et al. ......... 435/320.1 7,172,893 B2 2/2007 Rabinowitz et al. Small, selective regions from other parvoviruses that confer 2003/0022870 A1 1/2003 Dzau et al. .................. 514,152 desirable properties. In some embodiments, a Substitution of 2006, O188483 A1 8, 2006 Rabinowitz et al. a single amino acid that is unique to the AAV6 capsid (Lys 2006, O188484 A1 8, 2006 Rabinowitz et al. 531) among other AAVs that have been characterized to date can confer one or more desirable properties to other AAVs. FOREIGN PATENT DOCUMENTS WO WOOO 28004 A1 5, 2000 35 Claims, 5 Drawing Sheets U.S. Patent Jan. 11, 2011 Sheet 1 of 5 US 7,867.484 B2 |3.Infil U.S. Patent Jan. 11, 2011 Sheet 2 of 5 US 7,867.484 B2 ****! 00A009 ( Wu)loeN Z?un61-I U.S. Patent Jan. 11, 2011 Sheet 3 of 5 US 7,867.484 B2 uobnpSueul effueuopio 100’0 ?un61-)© Sileo 6usseldx do 9% U.S. Patent US 7,867.484 B2 eun61-Iy U.S. Patent Jan. 11, 2011 Sheet 5 of 5 US 7,867.484 B2 US 7,867.484 B2 1. 2 HEPARN AND HEPARAN SULEATE BINDING position 531 in an AAV1 capsid subunit or at the correspond CHMERIC VECTORS ing amino acid position in other AAV capsid subunits. In further aspects, the present invention provides a virus STATEMENT OF PRIORITY vector comprising an adeno-associated virus (AAV) capsid comprising an amino acid substitution that results in a cys This application claims the benefit, under 35 U.S.C. S 119 teine atamino acid position 531 in an AAV1 capsid subunit or (e), of U.S. Provisional Application No. 60/762,774, filed Jan. at the corresponding amino acid position in other AAV capsid 27, 2006, the entire contents of which are incorporated by Subunits. reference herein. In particular embodiments, the virus vector further com 10 prises a recombinant nucleic acid comprising a terminal FIELD OF THE INVENTION repeat (TR) sequence and a heterologous nucleic acid sequence; wherein the recombinant nucleic acid is packaged The present invention relates to novel viral vectors and within the AAV capsid. methods of purifying and administering the same. The invention also provides pharmaceutical formulations 15 comprising a virus vector of the invention in a pharmaceuti BACKGROUND OF THE INVENTION cally acceptable carrier. As a further aspect, the invention provides a method of Adeno-associated viral (AAV) vectors have been used delivering a nucleic acid to a cell comprising contacting the widely for therapeutic gene transfer to different cell types in cell with a virus vector or pharmaceutical formulation of the vitro and organs in vivo (Grimmetal. (2003) Curr. Gene Ther. invention. 3:281-304). The broad tissue tropisms exhibited by different The invention also provides a method of delivering a AAV serotypes can be attributed, at least in part, to the dis nucleic acid to a Subject comprising administering to the tribution of primary and secondary receptors on various cell subject a virus vector or pharmaceutical formulation of the types (Di Pasquale et al., (2003) Nat. Med. 9:1306-12: Kalu 25 invention. dov et al., (2001).J. Virol. 75:6884-93; Qing et al., (1999) Nat. As still another aspect, the invention provides a method of Med. 5:71-7: Summerford et al., (1999) Nat. Med. 5:78-82; purifying a virus vector of the invention from a sample, the Summerford et al., (1998) J. Virol. 72: 1438-45). In this method comprising: regard, initial cell Surface binding of the viral capsid is often mediated through complex cell Surface glycosaminoglycans (a) providing a solid Support comprising (i) a matrix and (Grimm et al., (2003) Curr. Gene. Ther. 3:281-304). For 30 (ii) heparin, wherein the heparin is bound to the matrix: example, AAV serotype 2 has been shown to utilize heparan (b) contacting the Solid Support with a sample comprising sulfate (HS) as a primary receptor for cell attachment (Sum the virus vector so as to bind the virus vector to the solid merford et al., (1998).J. Virol. 72:1438-45). AAV serotypes 4 Support; and and 5, which display different tropism with respect to AAV2. 35 (c) eluting the bound virus vector from the solid support. utilize sialic acid with different linkage specificities for cell As yet a further aspect, the invention provides the use of a surface binding and transduction (Kaludov et al., (2001) J. virus vector of the invention in the manufacture of a medica Virol. 75:6884-93). Similarly, transduction by AAV1, which ment for the treatment of disease. does not bind heparin, was inhibited by removal of cell sur These and other aspects of the invention are addressed in face sialic acid with sialidase (Chen et al., (2005) Hum. Gene 40 more detail in the description of the invention set forth below. Ther. 16:235-47). On the other hand, AAV6 which differs from AAV1 by only six amino acid residues (Rutledge et al., (1998).J. Virol. 72:309-19) and shares -85% homology with BRIEF DESCRIPTION OF THE DRAWINGS the AAV2 capsid sequence, binds heparan Sulfate and can be purified using heparin-affinity chromatography (Halbert et FIG. 1. List of AAV1 and AAV6 mutants generated by al., (2001).J. Virol. 75:6615-24). It is interesting to note that 45 Swapping amino acid residues using site-directed mutagen the AAV6 capsid does not possess the R585 and R588 resi esis. dues that are primarily responsible for HS binding by AAV2 FIGS. 2A-C. (a) Heparin binding profile of AAV6 mutants. (Kernet al., (2003).J. Virol. 77:11072-81: Opie et al., (2003) (b) Heparin binding profile of AAV1 mutants. (c) Elution J. Virol. 77:6995-7006). 50 profiles of AAV2, AAV6, and AAV1-E531 K at different salt Purification schemes for AAV2 based on heparin affinity concentrations. Mutants at the 531 position are shown in bold purification are well defined. Less streamlined are the purifi letters. cation parameters for other serotypes, which do not bind to FIGS. 3A-B. (a) Transduction profiles (GFP expression) of heparin. It would be desirable to engineer heparin-binding parental AAV-1 and AAV6 compared with mutants AAV1 properties into other AAV capsids to provide vectors with 55 E531 K and AAV6-K531 E. (b) Fold-decrease in transduction universal purification attributes for greater ease of purifica efficiencies of AAV1, AAV6, AAV1-E531 K, and AAV2 upon tion.
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