# US 10,765,631 B2 · Liposomes for modulating Wiskott-Aldrich syndrome protein

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- Number: US 10,765,631 B2
- Document ID: US10765631B2
- Status: Granted
- Kind: B2
- Application number: 16/173,899
- Filed: 2018-10-29
- Published: 2019-02-14
- Granted: 2020-09-08
- Earliest claimed: 2013-06-03
- Assignees: Bar-Ilan University
- Applicants: Bar-Ilan University
- Inventors: Mira Barda-Saad
- Web page: https://patentgrep.com/patent/US10765631B2

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/415: 1,2-Diazoles
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/04: Immunostimulants
- 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)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12N 15/88: using microencapsulation, e.g. using {amphiphile} liposome vesicle
- C12N 2310/14: interfering nucleic acids [NA]
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Embodiments of the invention relate to liposomes comprising: a lipid bilayer having an internal cavity; a therapeutic agent within the internal cavity configured to modify expression or degradation of WASp in a cell; and a targeting moiety external to the lipid bilayer configured to target an extracellular domain of a cell. Embodiments of the invention relate to methods of treatment of disease comprising administering the liposomes. Novel pharmaceutical compositions are also disclosed.

## Claims

### Claim 1

A method for the treatment of a disease in a patient suffering from a condition selected from the group consisting of a hematopoietic malignancy, Wiskott-Aldrich syndrome (WAS), and X-linked thrombocytopenia (XLT) using a therapeutic agent that modifies expression or degradation of WASp in a cell, the method comprising: administering to said patient a liposome or a pharmaceutical composition comprising said liposome, wherein said liposome comprises a lipid bilayer having an internal cavity, a therapeutic agent within the internal cavity configured to modify expression or degradation of WASp in a cell, and a targeting moiety external to the lipid bilayer configured to target an extracellular domain of a cell and wherein said therapeutic agent is (a) a WASp specific-siRNA that, when contacted with a cell, reduces the expression of WASp or increases WASp degradation in said cell; or (b) a peptide that binds to WASp at lysine residues 76 or 81, thereby protecting WASp from ubiquitylation and subsequent degradation.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said targeting moiety is one that binds LFA-1.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said therapeutic agent of said liposome is an siRNA that, when contacted with a cell, reduces the expression of WASp or increases WASp degradation in said cell, said siRNA comprising an oligonucleotide of a sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6 SEQ ID NO. 7, and a duplex of said oligonucleotide with its complementary strand, or any mixture of said siRNAs.

### Claim 4 (depends on 3)

The method according to claim 3, for treating wherein said patient is one suffering from a hematopoietic malignancy.

### Claim 5 (depends on 1)

The method according to claim 1, wherein said targeting moiety is one that binds an integrin.

### Claim 6 (depends on 5)

The method according to claim 5, wherein said therapeutic agent of said liposome is a peptide that binds to WASp at lysine residues 76 or 81, thereby protecting WASp from ubiquitylation and subsequent degradation, said peptide comprising SEQ. ID NO. 13, 14 or 15.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said patient is one suffering from Wiskott-Aldrich syndrome or X-linked thrombocytopenia.

### Claim 8 (depends on 1)

The method according to claim 1, wherein said patient is one suffering from a hematopoietic malignancy, and wherein said therapeutic agent is an siRNA that, when contacted with a cell, reduces the expression of WASp or increases WASp degradation in said cell, said siRNA comprising an oligonucleotide of a sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6 SEQ ID NO. 7, and a duplex of said oligonucleotide with its complementary strand, or any mixture of said oligonucleotides.

### Claim 9 (depends on 1)

The method according to claim 1, wherein said patient is one suffering from Wiskott-Aldrich syndrome or X-linked thrombocytopenia and wherein said therapeutic agent is a peptide that binds to WASp at lysine residues 76 or 81, thereby protecting WASp from ubiquitylation and subsequent degradation.

### Claim 10 (depends on 1)

The method according to claim 1, wherein said patient is one suffering from Wiskott-Aldrich syndrome, and said WAS patient is further suffering from at least one condition selected from the group consisting of compromised immune system, eczema, autoimmunity and malignancy.

### Claim 11 (depends on 7)

The method according to claim 7, wherein said patient is one suffering from Wiskott-Aldrich syndrome, and said WAS patient is further suffering from at least one condition selected from the group consisting of compromised immune system, eczema, autoimmunity and malignancy.

### Claim 12 (depends on 9)

The method according to claim 9, wherein said patient is one suffering from Wiskott-Aldrich syndrome, and said WAS patient is further suffering from at least one condition selected from the group consisting of compromised immune system, eczema, autoimmunity and malignancy.