# US 2019/0167730 A1 · Methods and compositions for modulating angiogenesis and vasculogenesis

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- Number: US 2019/0167730 A1
- Document ID: US20190167730A1
- Status: Published application
- Kind: A1
- Application number: 16/269,000
- Filed: 2019-02-06
- Published: 2019-06-06
- Earliest claimed: 2012-01-27
- Assignees: SanBio, Inc.
- Applicants: SanBio, Inc.
- Inventors: Monique DAO; Ciara TATE; Casey C. CASE
- Web page: https://patentgrep.com/patent/US20190167730A1

## CPC

- A61K 35/34: Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes (vascular smooth muscle A61K35/44)
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 35/44: Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
- A61K 38/1866: {Vascular endothelial growth factor [VEGF]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61L 27/3834: {Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- C12N 5/0662: {Stem cells}
- C12N 5/0663: {Bone marrow mesenchymal stem cells (BM-MSC)}
- C12N 5/0668: {Mesenchymal stem cells from other natural sources}
- C12N 5/0697: {Artificial constructs associating cells of different lineages, e.g. tissue equivalents (blood vessels C12N5/0691)}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2501/42: Notch; Delta; Jagged; Serrate
- C12N 2502/1347: Smooth muscle cells
- C12N 2502/1352: Mesenchymal stem cells
- C12N 2502/28: Vascular endothelial cells
- C12N 2510/02: Cells for production
- C12N 2533/90: Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- 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

Disclosed herein are methods and compositions for stimulating angiogenesis, using cells descended from marrow adherent stromal cells that have been transfected with sequences encoding a Notch intracellular domain. Applications of these methods and compositions include treatment of ischemic disorders such as stroke.

## Claims

### Claim 1

Cells for use in providing angiogenin, angiopoietin-2 (ANG-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) to a subject or to a tissue, wherein the cells are made by a method comprising:
(a) providing a culture of mesenchymal stem cells (MSCs),
(b) contacting the cell culture of step (a) with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein said polynucleotide does not encode a full-length Notch protein,
(c) selecting cells that comprise the polynucleotide of step (b), and
(d) further culturing the selected cells of step (c) in the absence of selection and in the absence of trophic factors.

### Claim 2 (depends on 1)

The cells of claim 1, wherein the cells produce one or more additional factors selected from the group consisting of basic fibroblast growth factor, leptin, platelet-derived growth factor-BB, hepatocyte growth factor, vascular endothelial growth factor and placental growth factor.

### Claim 3 (depends on 1)

The cells of claim 1, wherein the subject has undergone an ischemic injury.

### Claim 4 (depends on 3)

The cells of claim 3, wherein the ischemic injury is selected from the group consisting of cerebral ischemia, cardiac ischemia, ischemia of the bowel, ischemia of the limb, cutaneous ischemia, ocular ischemia and cerebral palsy.

### Claim 5 (depends on 1)

The cells of claim 1, wherein the subject is a human.

### Claim 6 (depends on 1)

The cells of claim 1, wherein said cells have angiogenic activity upon contact with the subject or the tissue.

### Claim 7 (depends on 6)

The cells of claim 6, wherein the angiogenic activity is selected from the group consisting of prevention of endothelial cell death, enhancement of endothelial cell survival, stimulation of endothelial cell proliferation, enhancement of blood vessel branching and enhancement of sprouting of new blood vessels.

### Claim 8 (depends on 1)

The cells of claim 1, wherein the tissue is necrotic.

### Claim 9 (depends on 1)

The cells of claim 1, wherein the cells are selected, in step (c), by culturing in the presence of G418.

### Claim 10 (depends on 1)

The cells of claim 1, wherein the MSCs are obtained from a human.

### Claim 11 (depends on 1)

A method for providing one or more of angiogenin, angiopoietin-2 (ANG-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) to a subject or to a tissue, the method comprising implanting the cells of claim 1 into the subject or contacting the tissue with the cells of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the cells additionally provide one or more of basic fibroblast growth factor, leptin, platelet-derived growth factor-BB, hepatocyte growth factor, vascular endothelial growth factor and placental growth factor to the subject or the tissue.

### Claim 13 (depends on 11)

The method of claim 11, wherein the subject has an ischemic disorder.

### Claim 14 (depends on 13)

The method of claim 13, wherein the ischemic disorder is selected from the group consisting of cerebral ischemia, cardiac ischemia, ischemia of the bowel, ischemia of the limb, cutaneous ischemia, ocular ischemia and cerebral palsy.

### Claim 15 (depends on 11)

The method of claim 11, wherein the subject is a human.

### Claim 16 (depends on 11)

The method of claim 11, wherein said cells have angiogenic activity upon implantation.

### Claim 17 (depends on 16)

The method of claim 16, wherein the angiogenic activity is selected from the group consisting of prevention of endothelial cell death, enhancement of endothelial cell survival, stimulation of endothelial cell proliferation, enhancement of blood vessel branching and enhancement of sprouting of new blood vessels.

### Claim 18 (depends on 11)

The method of claim 11, wherein the tissue is necrotic.

### Claim 19 (depends on 1)

A method for repairing ischemic damage in a subject or in a tissue, the method comprising implanting the cells of claim 1 into the subject or contacting the tissue with the cells of claim 1.

### Claim 20 (depends on 19)

The method of claim 19, wherein the cells provide angiogenin, angiopoietin-2 (ANG-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) to the subject or the tissue.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cells additionally provide one or more of basic fibroblast growth factor, leptin, platelet-derived growth factor-BB, hepatocyte growth factor, vascular endothelial growth factor and placental growth factor to the subject or the tissue.

### Claim 22 (depends on 19)

The method of claim 19, wherein the ischemic damage results from cerebral ischemia, cardiac ischemia, ischemia of the bowel, ischemia of the limb, cutaneous ischemia, ocular ischemia or cerebral palsy.

### Claim 23 (depends on 19)

The method of claim 19, wherein the subject is a human.

### Claim 24 (depends on 19)

The method of claim 19, wherein said cells have angiogenic activity upon implantation.

### Claim 25 (depends on 24)

The method of claim 24, wherein the angiogenic activity is selected from the group consisting of prevention of endothelial cell death, enhancement of endothelial cell survival, stimulation of endothelial cell proliferation, enhancement of blood vessel branching and enhancement of sprouting of new blood vessels.

### Claim 26 (depends on 19)

The method of claim 19, wherein the tissue is necrotic.