US2022340929A1PendingUtilityA1
Engineered muscle targeting compositions
Est. expiryOct 16, 2039(~13.2 yrs left)· nominal 20-yr term from priority
C12N 2750/14143C07K 14/005C12N 15/86C07K 7/06C12N 15/11C12N 2810/405A61P 31/12A61K 48/0066C12N 2750/14145C12N 2750/14122C12N 2310/20C07K 14/47C12N 2830/008C12N 2800/80C12N 2810/6027C12N 2750/14123A61K 47/6435C07K 2319/01A61K 31/7088A61P 21/00C12N 9/22
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Claims
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
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A composition comprising:
a targeting moiety effective to target a muscle cell, wherein the targeting moiety comprises an n-mer motif; and a cargo, wherein the cargo is coupled to or is otherwise associated with the targeting moiety.
2 . The composition of claim 1 , wherein the n-mer motif comprises an RGD motif or a non-RGD n-mer motif.
3 . The composition of claim 2 , wherein the RGD motif has a formula of X m RGDX n , wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of: any amino acid.
4 . The composition of claim 3 , wherein the RGD motif has the formula RGDXn, wherein n is 4 or 5, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of: any amino acid.
5 . The compositions of claim 2 , wherein the n-mer motif is any one of SEQ ID NO: 13-50, 1277-2493, 3737-4979, 6647-8313, 8314-8502, or 8692-8889.
6 . The composition of claim 1 , wherein the targeting moiety comprises a polypeptide, a polynucleotide, a lipid, a polymer, a sugar, or a combination thereof.
7 . The composition of claim 1 , wherein the targeting moiety comprises a viral protein.
8 . The composition of claim 7 , wherein the viral protein is a capsid protein.
9 . The composition of claim 7 wherein the viral protein is an adeno associated virus (AAV) protein.
10 . The composition of claim 7 , wherein the n-mer motif is located between two amino acids of the viral protein such that the n-mer motif is external to a viral capsid of which the viral capsid protein is part.
11 . The composition of claim 10 , wherein the n-mer motif is inserted between any two contiguous 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.
12 . The composition of claim 11 , wherein the n-mer motif 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.
13 . The composition of claim 1 , wherein the composition is an engineered viral particle.
14 . The composition of claim 13 , wherein the engineered viral particle is an engineered AAV viral particle.
15 . The composition of claim 14 , wherein the engineered AAV viral particle is an engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh.74, or AAV rh.10 viral particle.
16 . The composition of claim 1 , wherein the cargo is capable of treating or preventing a muscle disease or disorder.
17 . The composition of claim 16 , wherein the muscle disease or disorder is
a. an auto immune disease; b. a cancer; c. a muscular dystrophy; d. a neuro-muscular disease; e. a sugar or glycogen storage disease; f. an expanded repeat disease; g. a dominant negative disease; h. a cardiomyopathy; i. a viral disease; j. a progeroid disease; or k. any combination thereof.
18 . The composition of claim 1 , wherein the cargo is
a. a morpholino; b. a peptide-linked morpholino; c. an antisense oligonucleotide; d. a PMO, a therapeutic transgene; e. a polynucleotide encoding a therapeutic polypeptide or peptide; f. a PPMO; g. one or more peptides or polypeptides; h. one or more polynucleotides encoding a CRISPR-Cas protein, a guide RNA, or both; i. a ribonucleoprotein, wherein the ribonucleoprotein comprises a CRISPR-Cas system molecule; j. a therapeutic transgene RNA, or other gene modifying or therapeutic RNA and/or protein; or k. any combination thereof.
19 . The composition of claim 1 , wherein the cargo is capable of inducing exon skipping in a gene.
20 . The composition of claim 1 , wherein the cargo is capable of inducing exon skipping in a dystrophin gene.
21 . The composition of claim 1 , wherein the cargo is a mini- or micro-dystrophin gene.
22 . The composition of claim 21 , wherein the mini- or micro-dystrophin gene comprises spectrin-like repeats 1, 1′, 2, 3, 16, 17, 20, 21, 22, 23, 24, or any combination thereof, and optionally an nNOS domain, an actin binding domain, one or more hinge regions, a dystroglycan binding domain, or any combination thereof.
23 . The composition of claim 1 , wherein the cargo is operably coupled to a muscle specific promoter.
24 . The composition of claim 17 , wherein the expanded repeat disease is Huntington's disease, a Myotonic Dystrophy, or Facioscapulohumeral muscular dystrophy (FSHD).
25 . The composition of claim 17 , 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 FSHD.
26 . The composition of claim 25 , wherein the myotonic dystrophy is a Type 1 or a Type 2 myotonic dystrophy.
27 . The composition of claim 17 , wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, Duchene muscular dystrophy-associated cardiomyopathy, or Dannon disease.
28 . The composition of claim 17 , wherein the sugar or glycogen storage disease is a MPS type III disease or Pompe disease.
29 . The composition of claim 28 , wherein the MPS type III disease, is MPS Type IIIA, IIIB, IIIC, or HID.
30 . The composition of claim 17 , wherein the neuro-muscular disease is Charcot-Marie-Tooth disease or Friedreich's Ataxia.
31 . The composition of claim 1 , wherein the composition has increased muscle cell potency, muscle cell specificity, reduced immunogenicity, or any combination thereof.
32 . A vector system comprising:
a vector comprising: one or more polynucleotides each encoding all or part of one or more targeting moieties effective to target a muscle cell, wherein each targeting moiety comprises one or more n-mer motifs, wherein each n-mer motif an RGD motif or a non-RGD n-mer motif, and wherein each polynucleotide at least encodes one or more of the one or more n-mer motifs; and optionally, a regulatory element operatively coupled to one or more of the one or more polynucleotides.
33 . The vector system of claim 32 , wherein the RGD motif has a formula of X m RGDX n , wherein m is 0-4 amino acids, wherein n is 0-15 amino acids, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of: any amino acid.
34 . The vector system of claim 33 , wherein the RGD motif has the formula RGDXn, wherein n is 4 or 5, wherein X is any amino acid, and wherein each X amino acid present is independently selected from the others from the group consisting of: any amino acid
35 . The vector system of claim 33 , wherein the n-mer motif is any one of SEQ ID NO: 13-50, 1277-2493, 3737-4979, 6647-8313, 8314-8502, or 8692-8889.
36 . The vector system of claim 32 , further comprising a cargo.
37 . The vector system of claim 36 , wherein the cargo is a cargo polynucleotide and is optionally coupled to one or more of the one or more polynucleotides encoding the targeting moiety, the regulatory element, or both.
38 . The vector system of claim 36 , wherein the cargo polynucleotide is present on the same vector or a different vector as the one or more polynucleotides encoding the targeting moiety.
39 . The vector system of claim 36 , wherein the vector system is capable of producing virus particles that contain the cargo.
40 . The vector system of claim 32 , wherein the vector system is capable of producing a viral capsid polypeptide comprising one or more of the targeting moieties.
41 . The vector system of claim 32 , wherein the vector system is capable of producing AAV virus particles.
42 . The vector system of any of claim 41 , wherein AAV viral particles are engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh.74, or AAV rh.10 viral particle.
43 . The vector system of claim 40 , wherein the capsid polypeptide is an engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh.74, AAV rh.10 capsid polypeptide.
44 . The vector system of claim 39 , wherein at least one of the one or more polynucleotides encoding the n-mer motif(s) is inserted between two codons corresponding to two amino acids of the viral protein such that at least one of the n-mer motifs is external to the viral capsid.
45 . The vector system of claim 44 , wherein the two codons correspond to any two contiguous 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.
46 . The vector system of claim 45 , wherein the two codons correspond to amino acid 588 and 589 in the AAV9 capsid polynucleotide or in an analogous position in an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh.74, or AAV rh.10 capsid polypeptide.
47 . The vector system of any of claim 32 , wherein the vector comprising the one or more polynucleotides each encoding all or part of one or more targeting moieties does not comprise splice regulatory elements.
48 . The vector system of claim 32 , further comprising a polynucleotide encoding a viral rep protein.
49 . The vector system of claim 48 , wherein the viral rep protein is an AAV rep protein.
50 . The vector system of claim 48 , wherein the polynucleotide encoding the viral rep protein is on the same vector or different vector as the one or more polynucleotides each encoding all or part of one or more targeting moieties.
51 . The vector system of claim 48 , wherein the viral rep protein is operatively coupled to a regulatory element.
52 . A polypeptide produced by expressing a vector system as in any one of claims 32 - 51 .
53 . The polypeptide of claim 52 , wherein the polypeptide is a viral polypeptide.
54 . The polypeptide of claim 53 , wherein the viral polypeptide is an AAV polypeptide.
55 . A particle produced by expressing a vector system as in any one of claims 32 - 51 .
56 . The particle of claim 55 , wherein the particle is a viral particle.
57 . The particle of claim 56 , wherein the viral particle is an adeno-associated virus (AAV) particle.
58 . The particle of claim 56 , wherein the viral particle has a muscle-specific tropism.
59 . The vector system of any one of claims 36 - 51 , a polypeptide as in any one of claims 52 - 54 , or a particle as in any one of claims 55 - 58 , wherein the cargo is capable of treating or preventing a muscle disease or disorder.
60 . The vector system, the polypeptide, or the particle of claim 59 , wherein the muscle disease or disorder is
a. an auto immune disease; b. a cancer; c. a muscular dystrophy; d. a neuro-muscular disease; e. a sugar or glycogen storage disease; f. an expanded repeat disease; g. a dominant negative disease; h. a cardiomyopathy; i. a viral disease; j. a progeroid disease; or k. any combination thereof.
61 . The vector system, the polypeptide, or the particle of claim 60 , wherein the cargo is a morpholino;
a. a peptide-linked morpholino; b. an antisense oligonucleotide; c. a PMO, a therapeutic transgene; d. a polynucleotide encoding a therapeutic polypeptide or peptide; e. a PPMO; f. one or more peptides or polypeptides; g. one or more polynucleotides encoding a CRISPR-Cas protein, a guide RNA, or both; h. a ribonucleoprotein, wherein the ribonucleoprotein comprises a CRISPR-Cas system molecule; i. a therapeutic transgene RNA, or other gene modifying or therapeutic RNA and/or protein; or j. any combination thereof.
62 . The vector system, the polypeptide, or the particle of claim 59 , wherein the cargo is capable of inducing exon skipping in a gene.
63 . The vector system, the polypeptide, or the particle of claim 59 , wherein the cargo is capable of inducing exon skipping in a dystrophin gene.
64 . The vector system, the polypeptide, or the particle of claim 59 , wherein the cargo is a mini- or micro-dystrophin gene.
65 . The vector system, the polypeptide, or the particle of claim 64 , wherein the mini- or micro-dystrophin gene comprises spectrin-like repeats 1, 1′, 2, 3, 16, 17, 20, 21, 22, 23, 24, or any combination thereof, and optionally an nNOS domain, an actin binding domain, one or more hinge regions, a dystroglycan binding domain, or any combination thereof.
66 . The vector system, the polypeptide, or the particle of claim 60 , wherein the expanded repeat disease is Huntington's disease, a Myotonic Dystrophy, or Facioscapulohumeral muscular dystrophy (FSHD).
67 . The vector system, the polypeptide, or the particle of claim 60 , 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 FSHD.
68 . The vector system, the polypeptide, or the particle of claim 67 , wherein the myotonic dystrophy is Type 1 or Type 2.
69 . The vector system, the polypeptide, or the particle of claim 60 , wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, DMD-associated cardiomyopathy, or Dannon disease.
70 . The vector system, the polypeptide, or the particle of claim 60 , wherein the sugar or glycogen storage disease is a MPS type III disease or Pompe disease.
71 . The vector system, the polypeptide, or the particle of claim 70 , wherein the MPS type III disease, is MPS Type IIIA, IIIB, IIIC, or IIID.
72 . The vector system, the polypeptide, or the particle of claim 60 , wherein the neuro-muscular disease is Charcot-Marie-Tooth disease or Friedreich's Ataxia.
73 . The polypeptide or the particle of any one of claims 52 - 58 , wherein the polypeptide, the particle, or both have increased muscle cell potency, muscle cell specificity, reduced immunogenicity, or any combination thereof.
74 . A cell comprising:
a. a composition as in any of claims 1 - 31 ; b. a vector system as in any one of claim 32 - 51 or 59 - 72 ; c. a polypeptide as in any one of claim 52 - 54 or 59 - 73 ; d. a particle as in any one of claims 55 - 73 ; or e. a combination thereof.
75 . The cell of claim 74 , wherein the cell is prokaryotic.
76 . The cell of claim 74 , wherein the cell is eukaryotic.
77 . A pharmaceutical formulation comprising:
a. a composition as in any of claims 1 - 31 ; b. a vector system as in any one of claim 32 - 51 or 59 - 72 ; c. a polypeptide as in any one of claim 52 - 54 or 59 - 73 ; d. a particle as in any one of claims 55 - 73 ; e. a cell as in any one of claims 74 - 76 ; or f. a combination thereof; and a pharmaceutically acceptable carrier.
78 . A method comprising:
administering, to a subject in need thereof, a
a. composition as in any of claims 1 - 31 ;
b. vector system as in any one of claim 32 - 51 or 59 - 72 ;
c. polypeptide as in any one of claim 52 - 54 or 59 - 73 ;
d. particle as in any one of claims 55 - 73 ;
e. cell as in any one of claims 74 - 76 ;
f. pharmaceutical formulation as in claim 77 ; or
g. combination thereof.
79 . The method of claim 78 , wherein the subject in need thereof has a muscle disease or disorder.
80 . The method of claim 79 , wherein the muscle disease or disorder is
a. an auto immune disease; b. a cancer; c. a muscular dystrophy; d. a neuro-muscular disease; e. a sugar or glycogen storage disease; f. an expanded repeat disease; g. a dominant negative disease; h. a cardiomyopathy; i. a viral disease; j. a progeroid disease; or k. any combination thereof.
81 . The method of claim 80 , wherein the expanded repeat disease is Huntington's disease, a Myotonic Dystrophy, or Facioscapulohumeral muscular dystrophy (FSHD).
82 . The method of claim 80 , 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 FSHD.
83 . The method of claim 82 , wherein the myotonic dystrophy is Type 1 or Type 2.
84 . The method of claim 80 , wherein the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, DMD-associated cardiomyopathy, or Dannon disease.
85 . The method of claim 80 , wherein the sugar or glycogen storage disease is a MPS type III disease or Pompe disease.
86 . The method of claim 85 , wherein the MPS type III disease, is MPS Type IIIA, IIIB, IIIC, or HID.
87 . The method of claim 80 , wherein the neuro-muscular disease is Charcot-Marie-Tooth disease or Friedreich's Ataxia.Join the waitlist — get patent alerts
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