# US 2025/0084408 A1 · Engineered rnas

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- Number: US 2025/0084408 A1
- Document ID: US20250084408A1
- Status: Published application
- Kind: A1
- Application number: 18/704,897
- Filed: 2022-10-27
- Published: 2025-03-13
- Earliest claimed: 2021-10-27
- Assignees: Shape Therapeutics Inc.
- Applicants: Shape Therapeutics Inc.
- Inventors: Susan BYRNE; Brian John BOOTH; Richard Thomas SULLIVAN; Adrian Wrangham BRIGGS; Yiannis SAVVA
- Web page: https://patentgrep.com/patent/US20250084408A1

## CPC

- C12N 15/11: DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/86: Viral vectors
- C12N 2310/11: Antisense
- C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR]
- C12N 2310/3519: Fusion with another nucleic acid
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2320/33: Alteration of splicing
- C12N 2320/34: Allele or polymorphism specific uses
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed herein are engineered RNAs and compositions comprising the same for treatment of diseases or conditions in a subject. Also disclosed herein are methods of treating diseases or conditions in a subject by administering engineered RNAs, polynucleotides encoding the described engineered RNAs, or pharmaceutical compositions described here.

## Claims

### Claim at position 1

-110. (canceled)

### Claim 111

An engineered RNA, comprising:
(a) a targeting sequence with complementarity to a target RNA;
(b) an RNA element that comprises:
(i) an engineered SmOPT variant sequence having at least 80% identity to SEQ ID NO: 87, SEQ ID NO: 84, SEQ ID NO: 85, or SEQ ID NO: 86; and
(ii) an engineered U7 hairpin variant sequence having SEQ at least 80% identity to SEQ ID NO: 96, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 98, or SEQ ID NO: 99.

### Claim 112 (depends on 111)

The engineered RNA of claim 111, wherein the engineered SmOPT variant sequence comprises the sequence of SEQ ID NO: 87, SEQ ID NO: 84, SEQ ID NO: 85, or SEQ ID NO: 86.

### Claim 113 (depends on 111)

The engineered RNA of claim 111, wherein the engineered U7 hairpin variant sequence comprises the sequence of SEQ ID NO: 96, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 98, or SEQ ID NO: 99.

### Claim 114 (depends on 111)

The engineered RNA of claim 111, wherein the targeting sequence, upon hybridization to the target RNA, forms a guide-target RNA scaffold comprising a structural feature selected from the group consisting of a mismatch, a bulge, an internal loop, a hairpin, and any combination thereof, wherein the structural feature substantially forms upon hybridization to the target RNA, and wherein the structural feature is not present within an engineered guide RNA prior to the hybridization of the engineered guide RNA to the target RNA.

### Claim 115 (depends on 111)

The engineered RNA of claim 111, further comprising a terminator.

### Claim 116 (depends on 115)

The engineered RNA of claim 115, wherein the terminator is a U7 box terminator or a truncated terminator.

### Claim 117 (depends on 111)

The engineered RNA of claim 111, wherein the RNA element comprises SEQ ID NO: 62, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 63; SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70.

### Claim 118 (depends on 111)

The engineered RNA of claim 111, wherein the target RNA is DUX4, MAPT, SNCA, ABCA4, ALAS1, APP, ATP7B, CFTR, DMD, DMPK, GAPDH, GBA, HEXA, HFE, LIPA, LRRK2, PCSK9 start site, PINK1, PMP22, SERPINA1, SCNN1A start site, SOD1, a fragment of any one of these, or combination thereof.

### Claim 119 (depends on 118)

The engineered RNA of claim 118, wherein the target RNA is SNCA, and wherein the SNCA comprises a mutation for RNA editing selected from the group consisting of: a translation initiation site (TIS) AUG to GTG in Codon 1, a TIS AUG in Codon 5, an AUG at position 265 in Exon 2, and any combination thereof.

### Claim 120 (depends on 119)

The engineered RNA of claim 119, wherein the engineered RNA is a circularized engineered RNA.

### Claim 121

A polynucleotide encoding an engineered RNA wherein the engineered RNA comprises:
(a) a targeting sequence with complementarity to a target RNA;
(b) an RNA element that comprises:
(iii) an engineered SmOPT variant sequence having at least 80% identity to SEQ ID NO: 87, SEQ ID NO: 84, SEQ ID NO: 85, or SEQ ID NO: 86; and
(iv) an engineered U7 hairpin variant sequence having SEQ at least 80% identity to SEQ ID NO: 96, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 98, or SEQ ID NO: 99.

### Claim 122 (depends on 121)

The polynucleotide of claim 121, wherein the engineered SmOPT variant sequence comprises the sequence of SEQ ID NO: 87, SEQ ID NO: 84, SEQ ID NO: 85, or SEQ ID NO: 86.

### Claim 123 (depends on 121)

The polynucleotide of claim 121, wherein the engineered U7 hairpin variant sequence comprises the sequence of SEQ ID NO: 96, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 98, or SEQ ID NO: 99.

### Claim 124 (depends on 121)

The polynucleotide of claim 121, comprising the sequence of SEQ ID NO: 51, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 59.

### Claim 125 (depends on 121)

The polynucleotide of claim 121, wherein the polynucleotide is operably linked to an RNA polymerase II-type promoter.

### Claim 126 (depends on 125)

The polynucleotide of claim 125, wherein the RNA polymerase II-type promoter is a U1 promoter, a U6 promoter, a U7 promoter, or a combination thereof.

### Claim 127 (depends on 111)

A delivery vehicle comprising the engineered RNA of claim 111.

### Claim 128 (depends on 121)

A delivery vehicle comprising the polynucleotide of claim 121.

### Claim 129 (depends on 128)

The delivery vehicle of claim 128, wherein the delivery vehicle is a viral vector, wherein the viral vector is an adeno-associated viral (AAV) vector or derivative thereof.

### Claim 130 (depends on 129)

The delivery vehicle of claim 129, wherein the AAV vector, derivative thereof, or a hybrid of any of these is selected from a group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PHP.B, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, AAV.HSC16, AAVhu68, a derivative of any of these, and a hybrid of any of these.

### Claim 131 (depends on 130)

The delivery vehicle of claim 130, wherein the AAV vector or derivative thereof is selected from a group consisting of: a recombinant AAV (rAAV) vector, a hybrid AAV vector, a chimeric AAV vector, a self-complementary AAV (scAAV) vector, and any combination thereof.

### Claim 132 (depends on 121)

A pharmaceutical composition, comprising the polynucleotide of claim 121 and a pharmaceutically acceptable: excipient, diluent, or carrier.

### Claim 133 (depends on 132)

A method of treating a disease or condition in a subject, the method comprising: administering to the subject an effective amount of the pharmaceutical composition of claim 132 to treat the disease or condition in the subject.

### Claim 134 (depends on 133)

The method of claim 133, wherein the disease or condition is selected from the group consisting of: a neurodegenerative disease or disorder, a muscular disease or disorder, a metabolic disease or disorder, an ocular disease or disorder, a liver disease or disorder, a cancer, and any combination thereof.

### Claim 135 (depends on 133)

The method of claim 133, wherein the disease or condition is selected from the group consisting of: Duchenne's Muscular Dystrophy (DMD), Becker muscular dystrophy, myotonic dystrophy, Facioscapulohumeral muscular dystrophy, Rett's syndrome, Charcot-Marie-Tooth disease, Alzheimer's disease, a tauopathy, Parkinson's disease, alpha-1 antitrypsin deficiency, cystic fibrosis-like disease, Wilson disease, and Stargardt's disease.

### Claim 136 (depends on 133)

The method of claim 133, wherein the disease or condition is associated with a mutation in a gene, or RNA encoded by DUX4, MAPT, SNCA, ABCA4, ALAS1, APP, ATP7B, CFTR, DMD, DMPK, GAPDH, GBA, HEXA, HFE, LIPA, LRRK2, PCSK9 start site, PINK1, PMP22, SERPINA1, SCNN1A start site, SOD1, a fragment of any one of these, or combination thereof.