Granted Patent
B2
US 12,410,447 · App. 18/915,537 · Granted Sep 9, 2025
Engineered muscle targeting compositions
Inventors:
Pardis Sabeti (Cambridge, MA); Mohammadsharif Tabebordbar (Cambridge, MA); Simon Ye (Cambridge, MA)
Assignees:
The Broad Institute, Inc.; President and Fellows of Harvard College; Massachusetts Institute of Technology
C12N15/86A61K31/7088A61K47/6435A61K48/0066C07K7/06C07K14/005C07K14/47C12N9/22C12N15/11C07K2319/01C12N2310/20C12N2750/14122C12N2750/14123C12N2750/14143C12N2750/14145C12N2800/80C12N2810/405C12N2810/6027C12N2830/008
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Abstract
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.
Claims (45)
1. A composition comprising a targeting moiety effective to target a muscle cell, wherein the targeting moiety comprises an n-mer motif comprising X m RGDYX 1 X 2 L,
wherein X is selected from any amino acid, and wherein m is 0-4.
2. The composition of claim 1 , wherein X 1 is S and X 2 is G.
3. The composition of claim 2 , wherein m is 3.
4. The composition of claim 3 , wherein the first three amino acids of the n-mer motif are ESR, NNG, NT, SNN, SSN, or TDK.
5. The composition of claim 1 , wherein X 1 is R and X 2 is E.
6. The composition of claim 5 , wherein m is 3.
7. The composition of claim 6 , wherein the first three amino acids of the n-mer motif are AAA, ATT, NNN, NNS, NSN, SNG, TAG, TAT, TNT, or TTI.
8. The composition of claim 1 , wherein the targeting moiety is an engineered adeno associated virus (AAV) capsid polypeptide.
9. The composition of claim 8 , wherein the n-mer motif is inserted into a surface variable region of the engineered AAV capsid polypeptide.
10. The composition of claim 9 , wherein the surface variable region is selected from VR-IV, VR-V, or VR-VIII.
11. The composition of claim 8 , wherein the n-mer motif is inserted between any two amino acids between amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 704-714, or any combination thereof, in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or AAV rh.10 capsid polypeptide; or is inserted between amino acids 588 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, or AAV rh.10 capsid polypeptide.
12. The composition of claim 1 , further comprising a cargo.
13. The composition of claim 12 , wherein the cargo is
(a) capable of treating or preventing a muscle disease or disorder;
(b) 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 or polypeptides; 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; or
(c) both (a) and (b).
14. The composition of claim 13 , wherein the muscle disease or disorder is 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; or any combination thereof.
15. An engineered particle comprising composition of claim 1 .
16. The engineered particle of claim 15 , wherein the wherein the targeting moiety is an engineered adeno associated virus (AAV) capsid polypeptide.
17. The engineered particle of claim 16 , wherein the n-mer motif is inserted into a surface variable region of the engineered AAV capsid polypeptide.
18. The engineered particle of claim 17 , wherein the surface variable region is selected from VR-IV, VR-V, or VR-VIII.
19. The engineered particle of claim 16 , wherein the n-mer motif is inserted between any two amino acids between amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 704-714, or any combination thereof, in an AAV9 capsid polypeptide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or AAV rh.10 capsid polypeptide; or is inserted between amino acids 588 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, or AAV rh.10 capsid polypeptide.
20. The engineered particle of claim 15 , wherein the engineered particle is an adeno associated virus (AAV) capsid.
21. The engineered particle of claim 15 , further comprising a cargo.
22. The engineered particle of claim 21 , wherein the cargo is
(a) capable of treating or preventing a muscle disease or disorder;
(b) 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 or polypeptides; 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; or
(c) both (a) and (b).
23. The engineered particle of claim 22 , wherein the muscle disease or disorder is 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; or any combination thereof.
24. A vector system comprising:
a polynucleotide encoding the composition of claim 1 .
25. The vector system of claim 24 , further comprising a cargo polynucleotide.
26. The vector system of claim 25 , wherein the cargo polynucleotide
(a) is capable of treating or preventing a muscle disease or disorder;
(b) is or encodes 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 or polypeptides; 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; or
(c) both (a) and (b).
27. A method of treating or preventing a muscle disease or disorder in a subject in need thereof, comprising:
administering a composition of claim 1 or an engineered particle comprising the composition to a subject in need thereof.
28. The method of claim 27 , wherein the composition or the engineered particle comprises a cargo.
29. The method of claim 28 , wherein the cargo is
(a) capable of treating or preventing the muscle disease or disorder;
(b) 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 or polypeptides; 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; or
(c) both (a) and (b).
30. The method of claim 27 , wherein the muscle disease or disorder is 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; or any combination thereof.
Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 21, 2024
From: SABETI, PARDIS
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 068959/0407 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 21, 2024
From: SABETI, FOR HERSELF AND AS AGENT OF HOWARD HUGHES MEDICAL INSTITUTE, PARDIS
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 068959/0556 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 21, 2024
From: TABEBORDBAR, MOHAMMADSHARIF
To: THE BROAD INSTITUTE, INC.
Reel/Frame 068959/0771 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 21, 2024
From: YE, SIMON
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 068960/0022 →
Continuity (6)
Continuation
17764509
Provisional Application
63055252
· Jul 22, 2020
Provisional Application
63018454
· Apr 30, 2020
Provisional Application
62916207
· Oct 16, 2019
Provisional Application
62916221
· Oct 16, 2019
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