IP Library › Granted Patent US 12,618,082
Granted Patent B2
US 12,618,082 · App. 17/707,944 · Granted May 5, 2026

Engineered muscle targeting compositions

Inventors: Pardis Sabeti (Cambridge, MA); Mohammadsharif Tabebordbar (Cambridge, MA); Simon Ye (Cambridge, MA); Kim Lagerborg (Cambridge, MA); Alexandra Stanton (Cambridge, MA); Amy Wagers (Cambridge, MA)
Assignees: The Broad Institute, Inc.; President and Fellows of Harvard College; Massachusetts Institute of Technology
C12N15/86A61P21/00A61K48/00C12N2750/14122C12N2750/14142C12N2750/14143C12N2750/14145C12N2750/14171C12N2830/008
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Quick Facts
Patent No.
US 12,618,082
App. No.
17/707,944
Filed
Mar 29, 2022
Granted
May 5, 2026
Kind
B2
Art Unit
1634
USPC
424/93.6
Abstract

Described herein are muscle-specific targeting moieties and compositions including the muscle specific targeting motifs. Also described herein are uses of the muscle-specific targeting motifs and compositions including the muscle specific targeting moieties. In some embodiments, the muscle-specific targeting moieties and compositions including the muscle specific targeting moieties can be used to direct delivery of a cargo to a muscle cell.

Claims (50)

1 . An engineered adeno-associated virus (AAV) capsid polypeptide comprising:

an n-mer motif inserted in a surface variable region VR-VIII of the engineered AAV capsid polypeptide,

wherein the n-mer motif comprises the amino acid sequence of any one of SEQ ID NOs: 2-7, 20-21, 28-33, 49, 51, 53, 55, 57, 59, 61, 64, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 91, 94, 96, 100, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 158, 160, 163, 166, 168, 170, 172, 174, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 199, 201, 203, 205, 207, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 282, 284, 286, 288, 290, 293, 295, 297, 299, 301, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 327, 329, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 401, 404, 406, 408, 411, 413, 418, 420, 423, 426, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 476, 478, 480, 482, 484, 487, 489, 492, 494, 497, 499, 501, 504, 506, 508, 510, 512, 514, 516, 519, 521, 523, 526, 529, 531, 533, 535, 538, 542, 544, 546, 548, 551, 553, 555, 558, 561, 563, 565, 567, 570, 572, 574, 576, 579, 582, 584, 586, 588, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 703, 707, 709, 711, 713, 715, 717, 720, 723, 726, 728, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 754, 756, 758, 760, 763, and 767.

2 . The engineered AAV capsid polypeptide of claim 1 , wherein the n-mer motif is inserted between any two amino acids in the surface variable region VR-VIII corresponding to amino acids 581-593 of an AAV9 capsid polypeptide of SEQ ID NO. 1 , or an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74 or an AAV rh.10 capsid polypeptide.

3 . The engineered AAV capsid polypeptide of claim 2 , wherein the first three amino acids of the n-mer motif replace 0, 1, 2, or 3 amino acids of the variable region VIII of the wild-type AAV9 VP1 capsid polypeptide or a wild-type AAV VP1 capsid polypeptide of a different serotype.

4 . The engineered AAV capsid polypeptide of claim 1 , wherein the engineered AAV capsid polypeptide is an engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh.74, or AAV rh.10 capsid polypeptide.

5 . The engineered AAV capsid polypeptide of claim 1 , wherein

(a) the amino acid at position 588 in an AAV9 capsid polypeptide of SEQ ID NO. 1 or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or an AAV rh.10 capsid polypeptide is glycine or alanine,

(b) the amino acid at position 592 in an AAV9 capsid polypeptide of SEQ ID NO. 1 or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or an AAV rh.10 capsid polypeptide is glutamine, or both (a) and (b).

6 . The engineered AAV capsid polypeptide of claim 1 , wherein the engineered AAV capsid polypeptide further comprises one or more mutations that result in a reduced or an eliminated uptake in a non-muscle cell as compared to an AAV capsid comprising an engineered AAV capsid polypeptide or a wild-type AAV capsid polypeptide that lack the one or more mutations, wherein the one or more mutations are in position 267, in position 269, in position 504, in position 505, in position 590, or any combination thereof in an AAV9 capsid polypeptide (SEQ ID NO: 1) or in one or more positions corresponding thereto in a non-AAV9 capsid polypeptide, wherein the non-AAV9 capsid polypeptide is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or AAV rh.10 capsid polypeptide.

7 . The engineered AAV capsid polypeptide of claim 6 , wherein the engineered AAV capsid polypeptide is an engineered AAV9 capsid polypeptide comprising a mutation at position 267, position 269 or both of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 267 is a G to A mutation and wherein the mutation at position 269 is an S to T mutation, wherein the engineered AAV capsid polypeptide is an engineered AAV9 capsid polypeptide comprising a mutation at position 590 of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 509 is a Q to A mutation, or wherein the engineered AAV capsid polypeptide is an engineered AAV9 capsid polypeptide comprising a mutation at position 504, position 505, or both of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 504 is a G to A mutation and wherein the mutation at position 505 is a P to A mutation.

8 . The engineered AAV capsid polypeptide of claim 6 , wherein the non-muscle cell is a liver cell.

9 . A cell, a pharmaceutical formulation, an engineered viral capsid, or an engineered viral particle comprising the engineered AAV capsid polypeptide of claim 1 .

10 . The cell, the pharmaceutical formulation, the engineered viral capsid, or the engineered viral particle of claim 9 , wherein the engineered viral capsid, the engineered viral particle, or both comprises modulated transduction via integrin heterodimer αVβ6, AAV receptor (AAVR), or both.

11 . The engineered AAV capsid polypeptide of claim 1 , wherein the n-mer motif is inserted between any two amino acids between amino acids 585 and 589 in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide.

12 . The engineered AAV capsid polypeptide of claim 1 , further comprising a cargo, wherein the cargo is coupled to or is otherwise associated with the engineered AAV capsid polypeptide.

13 . The engineered AAV capsid polypeptide of claim 12 , wherein the cargo is a morpholino, a peptide-linked morpholino, an antisense oligonucleotide, a PMO, a therapeutic transgene, a polynucleotide encoding a therapeutic polypeptide or peptide, a PPMO, one or more peptides, one or more polynucleotides encoding a CRISPR-Cas protein, a guide RNA, or both, a ribonucleoprotein, wherein the ribonucleoprotein comprises a CRISPR-Cas system molecule, a therapeutic transgene RNA, or other gene modifying or therapeutic RNA and/or protein, or any combination thereof.

14 . The engineered AAV capsid polypeptide of claim 12 , wherein the cargo treats or prevents a muscle disease or disorder selected from the group consisting of; an autoimmune disease, a cancer, a muscular dystrophy, a neuromuscular disease, a sugar or glycogen storage disease, an expanded repeat disease, a dominant negative disease, a cardiomyopathy, a viral disease, a progeroid disease, and a disease or disorder associated with a cell expressing both αVβ6 and AAVR; or any combination thereof.

15 . The engineered AAV capsid polypeptide of claim 14 , wherein the expanded repeat disease is Huntington's disease, a Myotonic Dystrophy, or Facioscapulohumeral muscular dystrophy (FSHD), wherein the muscular dystrophy is Duchene muscular dystrophy, Becker Muscular dystrophy, a Limb-Girdle muscular dystrophy, an Emery Dreifuss muscular dystrophy, a myotonic dystrophy, or FSH, wherein the myotonic dystrophy is Type 1 or Type 2, wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, DMD-associated cardiomyopathy, or Dannon disease, wherein the sugar or glycogen storage disease is a MPS type III disease or Pompe disease, wherein the MPS type III disease, is MPS Type IIIA, IIIB, IIIC, or IIID, wherein the neuromuscular disease is Charcot-Marie-Tooth disease or Friedreich's Ataxia, or any combination thereof.

16 . The engineered AAV capsid polypeptide of claim 12 , wherein the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, or wherein the cargo is a mini- or micro-dystrophin gene and comprises spectrin-like repeats 1, 2, 3, and 24.

17 . A vector system comprising:

a vector comprising:

(a) one or more polynucleotides each encoding one or more engineered adeno-associated virus (AAV) capsid polypeptides, or

(b) one or more polynucleotides encoding one or more engineered AAV capsid polypeptides and a cargo,

wherein each of the one or more polypeptides of (a) and (b) comprises an n-mer motif inserted in a surface variable region VR-VIII of the one or more engineered AAV capsid polypeptides,

wherein the n-mer motif comprises the amino acid sequence of any one of SEQ ID NO: 2-7, 20-21, 28-33, 49, 51, 53, 55, 57, 59, 61, 64, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 91, 94, 96, 100, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 158, 160, 163, 166, 168, 170, 172, 174, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 199, 201, 203, 205, 207, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 282, 284, 286, 288, 290, 293, 295, 297, 299, 301, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 327, 329, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 401, 404, 406, 408, 411, 413, 418, 420, 423, 426, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 476, 478, 480, 482, 484, 487, 489, 492, 494, 497, 499, 501, 504, 506, 508, 510, 512, 514, 516, 519, 521, 523, 526, 529, 531, 533, 535, 538, 542, 544, 546, 548, 551, 553, 555, 558, 561, 563, 565, 567, 570, 572, 574, 576, 579, 582, 584, 586, 588, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 703, 707, 709, 711, 713, 715, 717, 720, 723, 726, 728, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 754, 756, 758, 760, 763, and 767; and

a regulatory element is operatively coupled to one or more polynucleotide(s), the cargo, or both.

18 . The vector system of claim 17 , wherein the cargo is a cargo polynucleotide and is operatively coupled to one or more of the one or more polynucleotides each encoding one or more engineered AAV capsid polypeptides.

19 . The vector system of claim 17 , wherein each of the one or more polypeptides of (a) and (b) comprise an engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh.74, or AAV rh.10 capsid polypeptides.

20 . The vector system of claim 17 , wherein a polynucleotide encoding the n-mer motif is inserted between two codons corresponding to any two amino acids between amino acids 581-593 in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide; or

is inserted between two codons corresponding to amino acids 588 and 589, in an AAV9 capsid polypeptide or in an analogous position thereto in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide, or

is inserted between two codons corresponding to any two amino acids between amino acids 585 and 589 in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, AAV rh.10 capsid polypeptide.

21 . The vector system of claim 17 , wherein the one or more engineered AAV capsid polypeptides comprise one or more mutations that result in reduced or eliminated uptake of an AAV capsid comprising the one or more engineered AAV capsid polypeptides in a non-muscle cell as compared to an AAV capsid lacking the one or more mutations, wherein the one or more mutations are in position 267, in position 269, in position 504, in position 505, in position 590, or any combination thereof in an AAV9 capsid polypeptide (SEQ ID NO: 1) or in one or more positions corresponding thereto in a non-AAV9 capsid polypeptide, wherein the non-AAV9 capsid polypeptide is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or AAV rh.10 capsid polypeptide.

22 . The vector system of claim 21 , wherein the one or more engineered AAV capsid polypeptides is/are engineered AAV9 capsid polypeptide(s) comprising a mutation at position 267, position 269 or both of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 267 is a G to A mutation and wherein the mutation at position 269 is an S to T mutation, wherein the engineered AAV capsid polypeptide is an engineered AAV9 capsid polypeptide comprising a mutation at position 590 of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 509 is a Q to A mutation, or wherein the engineered AAV capsid polypeptide is an engineered AAV9 capsid polypeptide comprising a mutation at position 504, position 505, or both of a wild-type AAV9 capsid polypeptide (SEQ ID NO: 1), wherein the mutation at position 504 is a G to A mutation and wherein the mutation at position 505 is a P to A mutation.

23 . The engineered AAV capsid polypeptide of claim 21 , wherein

position 267 in the AAV9 capsid polypeptide (SEQ ID NO: 1), or position corresponding thereto in a non-AAV9 capsid polypeptide, is mutated to an A;

position 269 in the AAV9 capsid polypeptide (SEQ ID NO: 1) or position corresponding thereto in a non-AAV9 capsid polypeptide, is mutated to a T;

position 504 in the AAV9 capsid polypeptide (SEQ ID NO: 1), or position corresponding thereto in a non-AAV9 capsid polypeptide, is mutated to an A;

position 505 in the AAV9 capsid polypeptide (SEQ ID NO: 1), or position corresponding thereto in a non-AAV9 capsid polypeptide, is mutated to an A;

position 590 in the AAV9 capsid polypeptide (SEQ ID NO: 1), or position corresponding thereto in a non-AAV9 capsid polypeptide, is mutated to an A;

or any combination thereof.

24 . The vector system of claim 17 , wherein the cargo is capable of treating or preventing a muscle disease or disorder, wherein the muscle disease or disorder is optionally an auto immune disease; a cancer; a muscular dystrophy; a neuro-muscular disease; a sugar or glycogen storage disease; an expanded repeat disease; a dominant negative disease; a cardiomyopathy; a viral disease; a progeroid disease; a disease or disorder associated with a cell expressing both αVβ6 and AAVR, or any combination thereof, and wherein the cargo is optionally a morpholino, a peptide-linked morpholino, an antisense oligonucleotide, a PMO, a therapeutic transgene, a polynucleotide encoding a therapeutic polypeptide or peptide, a PPMO, one or more peptides, one or more polynucleotides encoding a CRISPR-Cas protein, a guide RNA, or both, a ribonucleoprotein, wherein the ribonucleoprotein comprises a CRISPR-Cas system molecule, a therapeutic transgene RNA, or other gene modifying or therapeutic RNA and/or protein, or any combination thereof.

25 . The vector system of claim 24 , wherein the expanded repeat disease is Huntington's disease, a Myotonic Dystrophy, or Facioscapulohumeral muscular dystrophy (FSHD), wherein the muscular dystrophy is Duchene muscular dystrophy, Becker Muscular dystrophy, a Limb-Girdle muscular dystrophy, an Emery Dreifuss muscular dystrophy, a myotonic dystrophy, or FSH, wherein the myotonic dystrophy is Type 1 or Type 2, wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, DMD-associated cardiomyopathy, or Dannon disease, wherein the sugar or glycogen storage disease is a MPS type III disease or Pompe disease, wherein the MPS type III disease, is MPS Type IIIA, IIIB, IIIC, or IIID, wherein the neuro-muscular disease is Charcot-Marie-Tooth disease or Friedreich's Ataxia, or any combination thereof.

26 . The vector system of claim 17 , wherein the cargo is capable of inducing exon skipping in a gene, optionally a dystrophin gene, or wherein the cargo is a mini- or micro-dystrophin gene and optionally comprises spectrin-like repeats 1, 2, 3, and 24, and optionally an nNOS domain.

27 . A cell or a pharmaceutical formulation comprising the vector system of claim 17 .

28 . An engineered AAV particle comprising

a cargo polynucleotide comprising a mini- or micro-dystrophin gene comprising spectrin-like repeats 1, 2, 3, and 24, and

an engineered AAV capsid polypeptide comprising

a muscle-specific targeting moiety comprising

an n-mer motif of any one of SEQ ID NOs: 28, 29, 30, 31, 32 and 33 inserted between any two amino acids between amino acids 581-593 in an AAV9 capsid polypeptide of SEQ ID NO: 1, or an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or an AAV rh.10 capsid polypeptide.

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 26, 2022
From: TABEBORDBAR, MOHAMMADSHARIF
To: THE BROAD INSTITUTE, INC.
Reel/Frame 061542/0888 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 4, 2022
From: LAGERBORG, KIM
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 060725/0646 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 4, 2022
From: STANTON, ALEXANDRA
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 060725/0658 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: SABETI, PARDIS
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 060671/0831 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: YE, SIMON
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 060672/0103 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: PARDIS SABETI, FOR HERSELF AND AS AGENT OF HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 060671/0964 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: WAGERS, AMY
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 060672/0063 →
Continuity (5)
Continuation 17614327
Provisional Application 63183038 · May 2, 2021
Provisional Application 63107394 · Oct 29, 2020
Provisional Application 63055265 · Jul 22, 2020
Related Publication 20220228173A1 · Jul 21, 2022
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