# US 2016/0257952 A1 · Identification of structurally similar small molecules that enhance therapeutic exon skipping

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- Number: US 2016/0257952 A1
- Document ID: US20160257952A1
- Status: Published application
- Kind: A1
- Application number: 15/025,952
- Filed: 2014-09-30
- Published: 2016-09-08
- Earliest claimed: 2013-09-30
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Genevieve C. KENDALL; Stanley F. NELSON; M. Carrie MICELI
- Web page: https://patentgrep.com/patent/US20160257952A1

## CPC

- 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)}
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5415: ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- C12N 2310/11: Antisense
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/31: Combination therapy
- C12N 2320/33: Alteration of splicing
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates, e.g., to a method for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with an effective amount of a compound such as, for example, Perphenazine, Flupentixol DiHCl, Zuclopenthixol or Corynanthine HCl, or a compound which shares a similar 2-D structure and activity level with one of these compounds, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound, and, optionally, with an antisense oligonucleotide that is specific for a splicing sequence in the pre-mRNA Methods for treating Duchenne muscular dystrophy (DMD) are disclosed.

## Claims

### Claim 1

A composition for enhancing exon skipping in a pre-mRNA of interest, comprising:
(a) at least one of a compound having a structural similarity to Flupentixol diHCl of 0.65 or greater, wherein the structural similarity is calculated using the algorithm in the ChemmineR package as described in Cao et al. (2008) R. Bio informatics 24, 1733-1734, and
wherein the compound is at least as effective as Flupentixol diHCl in enhancing exon skipping in the pre-mRNA of interest when an effective amount of the compound is contacted with the pre-mRNA,
provided that the compound is not Fluphenazine HCl, Trifluoperazine HCl or Piperacetazine,
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound; and/or
(b) at least one of a compound having a structural similarity to Corynanthine HCl of 0.65 or greater, wherein the structural similarity is calculated using the algorithm in the ChemmineR package as described in Cao et al. (2008) R. Bio informatics 24, 1733-1734, and
wherein the compound is at least as effective as Corynanthine HCl in enhancing exon skipping in the pre-mRNA of interest when an effective amount of the compound is contacted with the pre-mRNA,
provided that the compound is not Yohimbinic Acid M, Yohimbine HCl or Rauwolscine HCl,
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound; and, in combination with the compound of (a) and/or (b),
(c) an antisense oligonucleotide (AO) that is specific for an exon that is to be skipped; and, optionally,
(d) a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The composition of claims 1,
wherein the compound in (a) is Perphenazine, Flupentixol DiHCl or Zuclopenthixol, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof,
or the compound in (b) is Corynanthine HCl. or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.

### Claim 3 (depends on 1)

A method for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with an effective amount of the composition of claim 1.

### Claim at position 4

-5. (canceled)

### Claim 6 (depends on 3)

The method of claim 3, wherein the mRNA is from the muscle dystrophin (DMD) gene, which encodes a muscle dystrophin protein.

### Claim 7 (depends on 6)

The method of claim 6, wherein the exon which is skipped is exon 23, 44, 45, 50, 51, 52 and/or 53 of the DMD gene.

### Claim 8 (depends on 3)

The method of claim 3, which is carried out in vitro, in a human subject that has Duchenne Muscular Dystrophy (DMD), in an animal model of DMD, or in another animal in which the exon skipping can be enhanced.

### Claim at position 8

-10. (canceled)

### Claim 11 (depends on 3)

The method of claim 3, wherein the compound is Perphenazine, Flupentixol DiHCl, Zuclopenthixol or Corynanthine HCl, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound.

### Claim 12

(canceled)

### Claim 13 (depends on 3)

The method of claim 3, further comprising wherein a subject that has Duchenne Muscular Dystrophy (DMD) is treated, or a non-human model of DMD is treated, and wherein the at least one compound of (a) and/or (b) is administered in conjunction with an AO which is specific for a splicing sequence of exon 23, 45, 44, 50, 51, 52 and/or 53 of the DMD gene.

### Claim 14 (depends on 13)

The method of claim 13, wherein the compound which is administered with the AO is Perphenazine, Flupentixol DiHCl, Zuclopenthixol or Corynanthine HCl.

### Claim at position 13

-19. (canceled)

### Claim 20

A method for enhancing exon skipping in a pre-mRNA from the muscle dystrophin (DMD) gene, comprising contacting the pre-mRNA with a composition comprising (a) an agent that inhibits the Ryanodine Receptor (RyR1) and (b) an agent that inhibits calmodulin (CaM) and, optionally, (c) an AO which is specific for a splicing sequence in the pre-mRNA.

### Claim 21

A composition for enhancing exon skipping in a pre-mRNA of interest, comprising
(a) at least one of clemizole hydrocholoride, probucol, N6-methyladenosine, isoflupredone acetate, succinylsulfathiazole, ondansetron hydrochloride, metoclopramide monohydrochloride, propoxycain hydrochloride, sulfasalazine, cefalonium, methyldopa (L,−), hydroquinine hydrobromide hydrate, tetramisole hydrochloride, flumequine, pipenzolate bromide, procainamide hydrochloride, tocopherol (R,S), phentolamine hydrochloride, clemastine fumarate, 1DA, 3AD, 9DI, AD3, ADY, FM1, FM2, FMB, RPP, AE2, ANB, AND, ANO, AOM, ASD, DEX, DHT, PDN, STR, TES, ZK5, SAS, DTY, IPO, ISA, IYR, PHI, TPQ, and/or VIT, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer of the compound,
(b) an antisense oligonucleotide (AO) that is specific for an exon that is to be skipped, and, optionally,
(c) a pharmaceutically acceptable carrier.

### Claim 22 (depends on 21)

The composition of claim 21, wherein the at least one compound of (a) is clemizole hydrocholoride, probucol, N6-methyladenosine, isoflupredone acetate, succinylsulfathiazole, ondansetron hydrochloride, metoclopramide monohydrochloride, propoxycain hydrochloride, sulfasalazine, cefalonium, methyldopa (L,−), hydroquinine hydrobromide hydrate, tetramisole hydrochloride, flumequine, pipenzolate bromide, procainamide hydrochloride, tocopherol (R,S), phentolamine hydrochloride, clemastine fumarate, 1DA, 3AD, 9DI, AD3, ADY, FM1, FM2, FMB, RPP, AE2, ANB, AND, ANO, AOM, ASD, DEX, DHT, PDN, STR, TES, ZK5, SAS, DTY, IPO, ISA, IYR, PHI, TPQ, or VIT.

### Claim 23 (depends on 21)

A method for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with an effective amount of the composition of claim 21.

### Claim 24 (depends on 23)

The method of claim 23, wherein the mRNA is from the muscle dystrophin (DMD) gene, which encodes a muscle dystrophin protein.

### Claim 25 (depends on 23)

The method of claim 23, wherein the exon which is skipped is exon 23, 44, 45, 50, 51, 52 and/or 53 of the DMD gene.

### Claim 26 (depends on 23)

The method of claim 23, which is carried out in vitro, in a subject that has Duchenne Muscular Dystrophy (DMD), is an animal model of DMD, or in another animal in which the exon skipping can be enhanced.

### Claim 27 (depends on 23)

The method of claim 23, further comprising wherein a subject that has Duchenne Muscular Dystrophy (DMD) is treated, or a non-human model of DMD is treated, and wherein the at least one compound is administered in conjunction with an AO which is specific for a splicing sequence of exon 23, 45, 44, 50, 51, 52 and/or 53 of the DMD gene.

### Claim 28 (depends on 27)

The method of claim 27, wherein the at least one compound is at least one of clemizole hydrocholoride, probucol, N6-methyladenosine, isoflupredone acetate, succinylsulfathiazole, ondansetron hydrochloride, metoclopramide monohydrochloride, propoxycain hydrochloride, sulfasalazine, cefalonium, methyldopa (L,−), hydroquinine hydrobromide hydrate, tetramisole hydrochloride, flumequine, pipenzolate bromide, procainamide hydrochloride, tocopherol (R,S), phentolamine hydrochloride, clemastine fumarate, 1DA, 3AD, 9DI, AD3, ADY, FM1, FM2, FMB, RPP, AE2, ANB, AND, ANO, AOM, ASD, DEX, DHT, PDN, STR, TES, ZK5, SAS, DTY, IPO, ISA, IYR, PHI, TPQ, and/or VIT.