# US 11,304,911 B2 · Compositions and methods for organ specific delivery of nucleic acids

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- Number: US 11,304,911 B2
- Document ID: US11304911B2
- Status: Granted
- Kind: B2
- Application number: 17/473,863
- Filed: 2021-09-13
- Published: 2021-12-30
- Granted: 2022-04-19
- Earliest claimed: 2018-09-04
- Assignees: Board of Regents, The University of Texas System
- Applicants: The Board of Regents of the University of Texas System
- Inventors: Qiang Cheng; Tuo Wei; Daniel J. Siegwart
- Web page: https://patentgrep.com/patent/US11304911B2

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 48/0033: {the non-active part being non-polymeric}
- A61K 48/0091: {Purification or manufacturing processes for gene therapy compositions}
- C12N 9/226: {Class 2 CAS enzyme complex, e.g. single CAS protein}
- 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 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N 15/907: {in mammalian cells}
- A61K 48/0041: {the non-active part being polymeric}
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR]
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure provides compositions which shown preferential targeting or delivery of a nucleic acid composition to a particular organ. In some embodiments, the composition comprises a steroid or sterol, an ionizable cationic lipid, a phospholipid, a PEG lipid, and a permanently cationic lipid which may be used to deliver a nucleic acid.

## Claims

### Claim 1

A method for non-liver targeted delivery of a therapeutic agent, the method comprising:
administering to a subject in need thereof said therapeutic agent assembled with a selective organ targeting (SORT) lipid composition, which SORT lipid composition comprises:
(i) an ionizable cationic lipid, and
(ii) a SORT lipid separate from said ionizable cationic lipid, which SORT lipid is selected from the group consisting of a cationic SORT lipid, a zwitterionic SORT lipid, and an anionic SORT lipid;
wherein, upon said administering, a surface of said SORT lipid composition interacts with apolipoprotein E (Apo E) to a lesser degree than with an endogenous protein that is not Apo E in said subject, thereby providing a lesser amount or activity of said therapeutic agent in liver or a cell therein in said subject as compared to that achieved absent said SORT lipid.

### Claim 2 (depends on 1)

The method of claim 1, wherein, upon said administering, said endogenous protein binds to said surface of said SORT lipid composition in said subject at a greater amount than Apo E.

### Claim 3 (depends on 1)

The method of claim 1, wherein said endogenous protein is vitronectin, beta-2 glycoprotein 1, or apolipoprotein H (Apo H).

### Claim 4 (depends on 1)

The method of claim 1, wherein said endogenous protein is beta-2 glycoprotein 1 or apolipoprotein H (Apo H).

### Claim 5 (depends on 1)

The method of claim 1, wherein said endogenous protein is not beta-2 glycoprotein 1 or apolipoprotein H (Apo H); and wherein said surface of said SORT lipid composition interacts with Apo H to a lesser degree than with said endogenous protein in said subject.

### Claim 6 (depends on 5)

The method of claim 5, wherein said endogenous protein is vitronectin.

### Claim 7 (depends on 1)

The method of claim 1, wherein said administering comprises systemic administration.

### Claim 8 (depends on 1)

The method of claim 1, wherein said administering comprises intravenous administration.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method provides a greater amount or activity of said therapeutic agent in a non-liver organ or a cell therein in said subject as compared to that achieved absent said SORT lipid.

### Claim 10 (depends on 9)

The method of claim 9, wherein said non-liver organ or said cell therein comprises a lung, spleen, bone marrow, a lymph node, or a cell in any of the aforementioned organs.

### Claim 11 (depends on 10)

The method of claim 10, wherein said non-liver organ or said cell therein comprises a lung, or a cell therein.

### Claim 12 (depends on 10)

The method of claim 10, wherein said non-liver organ or said cell therein comprises spleen, bone marrow, a lymph node, or a cell in any of the aforementioned organs.

### Claim 13 (depends on 1)

The method of claim 1, wherein said SORT lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 65%.

### Claim 14 (depends on 1)

The method of claim 1, wherein said cationic SORT lipid is a permanently cationic SORT lipid or an ionizable cationic SORT lipid.

### Claim 15 (depends on 1)

The method of claim 1, wherein said cationic SORT lipid is a permanently cationic SORT lipid comprising a quaternary ammonium ion.

### Claim 16 (depends on 1)

The method of claim 1, wherein said cationic SORT lipid is a permanently cationic SORT lipid having a structure of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein, in Formula (I):
R1 and R2 are each independently alkyl(C8-C24), alkenyl(C8-C24), or a substituted version of either group;
R3, R3′, and R3″ are each independently alkyl(C≤6); or substituted alkyl(C≤6); and
X− is a monovalent anion; or
wherein, in Formula (II):
R4 and R4′ are each independently alkyl(C6-C24), alkenyl(C6-C24), or a substituted version of either group;
R4″ is alkyl(C≤24), alkenyl(C≤24), or a substituted version of either group;
R4′″ is alkyl(C1-C8), alkenyl(C2-C8), or a substituted version of either group; and
X2− is a monovalent anion; or
wherein, in Formula (III):
R1 and R2 are each independently alkyl(C8-C24), alkenyl(C8-C24), or a substituted version of either group;
R3, R3′, and R3″ are each independently alkyl(C≤6) or substituted alkyl(C≤6);
R4 is alkyl(C≤6) or substituted alkyl(C≤6); and
X− is a monovalent anion.

### Claim 17 (depends on 1)

The method of claim 1, wherein said zwitterionic SORT lipid is a zwitterionic phospholipid.

### Claim 18 (depends on 1)

The method of claim 1, wherein said anionic SORT lipid comprises a phosphate group.

### Claim 19 (depends on 1)

The method of claim 1, wherein said anionic SORT lipid has a structure of Formula (IV):
wherein, in Formula (IV):
R1 and R2 are each independently alkyl(C8-C24), alkenyl(C8-C24), or a substituted version of either group;
R3 is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6), or —Y1—R4, wherein:
Y1 is alkanediyl(C≤6) or substituted alkanediyl(C≤6); and
R4 is acyloxy(C≤8-24) or substituted acyloxy(C≤8-24).

### Claim 20 (depends on 1)

The method of claim 1, wherein said cationic SORT lipid is 1,2-dioleoyl-3-dimethylammonium-propane (DODAP).

### Claim 21 (depends on 1)

The method of claim 1, wherein said ionizable cationic lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 30%.

### Claim 22 (depends on 1)

The method of claim 1, wherein said ionizable cationic lipid is a dendrimer or dendron, or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The method of claim 1, wherein said SORT lipid composition further comprises a phospholipid, a polymer-conjugated lipid, a steroid or steroid derivative, or a combination thereof separate from said SORT lipid.

### Claim 24 (depends on 1)

The method of claim 1, wherein said SORT lipid composition further comprises a polymer-conjugated lipid separate from said SORT lipid.

### Claim 25 (depends on 24)

The method of claim 24, wherein said polymer-conjugated lipid comprises one or more hydrophobic moieties each comprising at least 6 carbon atoms.

### Claim 26 (depends on 24)

The method of claim 24, wherein said polymer-conjugated lipid comprises one or more hydrophobic moieties each comprising 6 to 24 carbon atoms.

### Claim 27 (depends on 24)

The method of claim 24, wherein said polymer-conjugated lipid comprises a polymer component having an average molecular weight from about 100 Daltons (Da) to about 15,000 Daltons.

### Claim 28 (depends on 24)

The method of claim 24, wherein said polymer-conjugated lipid is a polyethylene glycol (PEG) conjugated lipid.

### Claim 29 (depends on 1)

The method of claim 1, wherein said therapeutic agent comprises a small interfering ribonucleic acid (siRNA), a micro-ribonucleic acid (miRNA), a primary micro-ribonucleic acid (pri-miRNA), a messenger ribonucleic acid (mRNA), a clustered regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a CRISPR-RNA (crRNA), a single guide ribonucleic acid (sgRNA), a trans-activating CRISPR ribonucleic acid (tracrRNA), a plasmid deoxyribonucleic acid (pDNA), a transfer ribonucleic acid (tRNA), an antisense oligonucleotide (ASO), a guide ribonucleic acid, a double stranded deoxyribonucleic acid (dsDNA), a single stranded deoxyribonucleic acid (ssDNA), a single stranded ribonucleic acid (ssRNA), a double stranded ribonucleic acid (dsRNA), a protein, a CRISPR-associated (Cas) protein, or a combination thereof.

### Claim 30 (depends on 1)

The method of claim 1, wherein said therapeutic agent is present at a ratio to said SORT lipid composition of about 1:1 to about 1:100.