IP Library › Granted Patent US 12,653,910
Granted Patent B2
US 12,653,910 · App. 17/778,783 · Granted Jun 16, 2026

Adeno-associated viral vector variants

Inventors: Beverly Davidson (Philadelphia, PA); Yonghong Chen (Philadelphia, PA); Paul T. Ranum (Philadelphia, PA); Xueyuan Liu (Philadelphia, PA)
Assignee: The Children's Hospital of Philadelphia
A61K48/0075A61P25/00C07K7/06C12N15/86C12N2750/14122C12N2750/14143C12N2750/14171
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Quick Facts
Patent No.
US 12,653,910
App. No.
17/778,783
Granted
Jun 16, 2026
Kind
B2
Abstract

Provided herein are targeting peptides and vectors containing a sequence that encodes the targeting peptides that deliver agents to specific substructures in the brain. Provided herein are viral vectors each comprising a modified capsid, wherein the modified capsid comprises at least one amino acid sequence that targets the viral vector to a distinct brain structure.

Claims (50)

1 . A modified adeno-associated (AAV) capsid protein comprising a targeting peptide that targets a viral vector comprising the modified AAV capsid protein to a distinct brain structure, wherein the targeting peptide is up to ten amino acids in length, wherein the targeting peptide comprises an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 110-137, wherein the modified AAV capsid protein is a modified AAV9 capsid protein having a sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 143 and the targeting peptide is inserted after residue 591 of the amino acid sequence of SEQ ID NO: 143.

2 . The modified AAV capsid protein of claim 1 , wherein the distinct brain structure is the brainstem, caudate, cerebellar cortex, cerebral cortex, deep cerebellar nuclei, ependyma, globus pallidus, hippocampus, meninges, motor cortex, optic nerve, prefrontal cortex, putamen, spinal cord, substantia nigra, subthalamic nuclei, temporal cortex, thalamus, or visual cortex.

3 . The modified AAV capsid protein of claim 1 , wherein the targeting peptide is flanked by linker sequences, wherein the linker sequences on each side of the targeting peptides are two or three amino acids long.

4 . The modified AAV capsid protein of claim 3 , wherein the linker sequences are AAA on the N-terminal side of the targeting peptide and AS on the C-terminal side of the targeting peptide.

5 . The modified AAV capsid protein of claim 1 , wherein the targeting peptide is seven amino acids in length.

6 . The modified AAV capsid protein of claim 1 , wherein the distance brain structure is the brainstem, caudate, cerebellar cortex, cerebral cortex, deep cerebellar nuclei, ependyma, globus pallidus, hippocampus, meninges, motor cortex, optic nerve, prefrontal cortex, putamen, spinal cord, substantia nigra, subthalamic nuclei, temporal cortex, thalamus, or visual cortex.

7 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the brainstem, and wherein the targeting peptide is selected from SEQ ID NOs: 110-117.

8 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the caudate, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 113, 115, 116, and 118-121.

9 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the cerebellar cortex, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 119, and 122-125.

10 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the cerebral cortex, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 114, 116, and 125-127.

11 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the ependyma, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 118-120 and 128.

12 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the globus pallidus, and wherein the targeting peptide is selected from SEQ ID NOs: 110-112, 114, 119, 120, and 129.

13 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the hippocampus, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 116, 123, 125, 129, and 130.

14 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the meninges, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 114, 118, 119, 122, and 131.

15 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the optic nerve, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 114, 115, 117, 129, and 132.

16 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the putamen, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 112, 113, 116, 123, 127, 133, and 134.

17 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the spinal cord, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 113, 119, 120, 122, 123, 128, 134.

18 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the substantia nigra, and wherein the targeting peptide is selected from SEQ ID NOs: 110-114, 117, and 129.

19 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the subthalamic nuclei, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 111, 113, 119, 120, 122, 132, and 135.

20 . The modified AAV capsid protein of claim 6 , wherein the distinct brain structure is the thalamus, and wherein the targeting peptide is selected from SEQ ID NOs: 110, 112-114, 125, 133, 136, and 137.

21 . The modified AAV capsid protein of claim 1 :

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 110 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 111 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 112 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 113 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 114 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 115 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 116 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 117 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 118 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 119 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 120 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 121 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 122 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 123 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 124 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 125 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 126 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 127 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 128 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 129 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 130 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 131 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 132 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 133 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 134 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 135 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143;

wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 136 or 137 and wherein the modified AAV capsid protein comprises the amino acid sequence of SEQ ID NO: 143.

22 . The modified AAV capsid protein of claim 1 , wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 110.

23 . The modified AAV capsid protein of claim 1 , wherein the targeting peptide comprises the amino acid sequence of SEQ ID NO: 113.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 23, 2022
From: DAVIDSON, BEVERLY; RANUM, PAUL; CHEN, YONGHONG; LIU, XUEYUAN
To: THE CHILDREN'S HOSPITAL OF PHILADELPHIA
Reel/Frame 060872/0348 →
Continuity (3)
Provisional Application 63084709 · Sep 29, 2020
Provisional Application 62939315 · Nov 22, 2019
Related Publication 20230346981A1 · Nov 2, 2023
References Cited (63)
US 8299215B2 · Davidson et al. · 2012 [cited by applicant]
US 8691948B2 · Davidson et al. · 2014 [cited by applicant]
US 9585971B2 · Deverman · 2017 [cited by applicant]
US 10472650B2 · Davidson et al. · 2019 [cited by applicant]
US 20040031072A1 · La Rosa et al. · 2004 [cited by applicant]
US 20130224836A1 · Muramatsu · 2013 [cited by applicant]
US 20130330335A1 · Bremel et al. · 2013 [cited by applicant]
US 20170029464A1 · Körbelin et al. · 2017 [cited by applicant]
US 20190175763A1 · Shapiro et al. · 2019 [cited by applicant]
KR 1020170086537 · 2017 [cited by applicant]
KR 1020180097629 · 2018 [cited by applicant]
KR 1020190034239 · 2019 [cited by applicant]
WO WO2003052051 · 2003 [cited by applicant]
WO WO2006105392 · 2006 [cited by applicant]
WO WO2012057363 · 2012 [cited by applicant]
WO WO2015038958 · 2015 [cited by applicant]
WO WO2016081811 · 2016 [cited by applicant]
WO WO2017100671 · 2017 [cited by applicant]
WO WO2018022905 · 2018 [cited by applicant]
WO WO2018152333 · 2018 [cited by applicant]
WO WO2018209317 · 2018 [cited by applicant]
WO WO2019060454 · 2019 [cited by applicant]
WO WO2019067840 · 2019 [cited by applicant]
WO WO2019222329 · 2019 [cited by applicant]
WO WO2020014471A1 · 2020 [cited by examiner]
WO WO2021163556 · 2021 [cited by applicant]
Chen X et al. Fusion Protein Linkers: Property, design, and functionality. 2013. Advanced Drug Delivery Reviews. 65, 1357-1369. ( Year: 2013). [cited by examiner]
Pham Q et al. Chemical approaches to probe and engineer AAV vectors. 2024. Nanoscale. 16. 13820-13833. (Year: 2024). [cited by examiner]
Singh RK et al. Protein Engineering Approaches in the Post-Genomic Era. 2017. Current Protein and Peptide Science. 18, 1-11. ( Year: 2017). [cited by examiner]
Zhang M et al. Propagated Perturbations from a Peripheral Mutation Show Interactions Supporting WW Domain Thermostability. 2018. Structure. 26, 1474-1485. (Year: 2018). [cited by examiner]
Chen et al., Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Nat Med, 2009. 15(10): p. 1215-8. [cited by applicant]
Chen et al., Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy. Mol Ther, 2018. 26(4): p. 1118-1126. [cited by applicant]
Deverman et al., Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol, 2016. 34(2): p. 204-9. [cited by applicant]
Hartz et al., Isolation of Cerebral Capillaries from Fresh Human Brain Tissue. J Vis Exp, 2018(139). [cited by applicant]
Hordeaux et al., The Neurotropic Properties of AAV-PHP.B are Limited to C57BL/6J Mice. Mol Ther, 2018. 26(3): p. 664-668. [cited by applicant]
International Preliminary Report on Patentability issued in Patent Application No. PCT/US20/61464, dated May 27, 2022. [cited by applicant]
International Search Report issued in Patent Application No. PCT/US20/61464, dated Apr. 9, 2021. [cited by applicant]
Katz et al., AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Sci Transl Med, 2015. 7(313): p. 313ra180. [cited by applicant]
Keiser et al., Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. Brain, 2015. 138(Pt 12): p. 3555-66. [cited by applicant]
Koerber et al., DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther, 2008. 16(10): p. 1703-9. [cited by applicant]
Matsuzaki et al., Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci Lett, 2018. 665: p. 182-188. [cited by applicant]
McBride et al., Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Mol Ther, 2011. 19(12): p. 2152-62. [cited by applicant]
Monteys et al., CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo. Mol Ther, 2017. 25(1): p. 12-23. [cited by applicant]
Muller et al., Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors. Nat Biotechnol, 2003. 21(9): p. 1040-6. [cited by applicant]
Schaffer & Maheshri, Directed evolution of AAV mutants for enhanced gene delivery. Conf Proc IEEE Eng Med Biol Soc, 2004. 5: p. 3520-3. [cited by applicant]
Zhong et al., Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci U S A, 2008. 105(22): p. 7827-32. [cited by applicant]
Chekhonin et al., “Targeted Transport of Genetic Material into Brain” [cited by applicant]
Dalton et al., “Multiple Myeloma” [cited by applicant]
Lundberg et al., “Direct delivery of leptin to the hypothalamus using recombinant adeno-associated virus vectors results in increased therapeutic efficacy”, [cited by applicant]
Muller et al., “Spliceosomal Peptide P140 for Immunotherapy of Systemic Lupus Erythematosus” [cited by applicant]
Pires et al. “Old and new challenges in Parkinson's disease therapeutics”, [cited by applicant]
Schwab et al., “Dopamine and Huntington's disease”, [cited by applicant]
Smirnova et al., “Structure of the nervous system”, [cited by applicant]
Zhou et al., “Mitochondria-homing peptide functionalized nanoparticles performing dual extracellular/intracellular roles to inhibit aminoglycosides induced ototoxicity”, [cited by applicant]
Zvěřová “Clinical aspects of Alzheimer's disease”, [cited by applicant]
Extended European Search Report for EP Application No. 20890214.8 dated Dec. 11, 2023, 9 pages. [cited by applicant]
Lee et al. “Adeno-Associated Virus (AAV) Vectors: Rational Design Strategies for Capsid Engineering”, [cited by applicant]
Stover et al., “Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer”, [cited by applicant]
Office Action for Korean Application No. 10-2022-7021143 dated Sep. 19, 2025; 8 pages, inclusive of machine translation to English. [cited by applicant]
Office Action for Columbian Application No. NC2022/0008507 dated Aug. 8, 2025; 20 pages, inclusive of machine translation to English. [cited by applicant]
Office Action for Singapore Application No. 11202205339R dated Sep. 19, 2025, 13 pages. [cited by applicant]
Büning et al., “Capsid Modifications for Targeting and Improving the Efficacy of AAV Vectors”, [cited by applicant]
Office Action for Canadian Application No. 3,159,113 dated Mar. 24, 2026, 8 pages. [cited by applicant]