# US 2021/0275597 A1 · Mitochondrial augmentation therapy of ocular diseases

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- Number: US 2021/0275597 A1
- Document ID: US20210275597A1
- Status: Published application
- Kind: A1
- Application number: 17/256,527
- Filed: 2019-07-22
- Published: 2021-09-09
- Earliest claimed: 2018-07-22
- Assignees: Minovia Therapeutics Ltd.
- Applicants: Minovia Therapeutics Ltd.
- Inventors: Natalie Yivgi Ohana; Uriel Halavee; Shmuel Bukshpan; Noa Sher; Moriya Blumkin
- Web page: https://patentgrep.com/patent/US20210275597A1

## CPC

- A61K 35/50: Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
- C12N 5/0647: {Haematopoietic stem cells; Uncommitted or multipotent progenitors}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 35/14: Blood; Artificial blood (perfluorocarbons A61K31/02; umbilical cord blood A61K35/51; haemoglobin A61K38/42)
- A61K 35/15: Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells (presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00)
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 35/18: Erythrocytes (haemoglobin A61K38/42)
- A61K 35/19: Platelets; Megacaryocytes
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 35/33: Fibroblasts
- A61K 35/35: Fat tissue; Adipocytes; Stromal cells; Connective tissues (adipose-derived stem cells A61K35/28; collagen A61K38/39)
- A61K 35/38: Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
- A61K 35/51: Umbilical cord; Umbilical cord blood; Umbilical stem cells
- A61K 35/545: Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 27/02: Ophthalmic agents
- C12N 2502/11: blood or immune system cells
- C12N 2510/00: Genetically modified cells
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides stem cells enriched with healthy functional mitochondria, pharmaceutical compositions comprising these cells and methods of use thereof for treating ocular diseases, disorders and symptoms thereof where the disease may or may not be associated with acquired mitochondrial dysfunction.

## Claims

### Claim at position 1

-3. (canceled)

### Claim 4 (depends on 32)

The method of claim 32, wherein the human exogenous mitochondria are syngeneic or allogeneic.

### Claim at position 3

-6. (canceled)

### Claim 7 (depends on 32)

The method of claim 32, wherein the disease or disorder is selected from the group consisting of Chronic Progressive External Ophthalmoplegia (CPEO), dominant optic atrophy (DOA), Kjer optic neuropathy, Retinitis Pigmentosa, age-related macular degeneration (AMD), diabetic retinopathy, cataracts, glaucoma and Pigmentary Retinopathy.

### Claim 8

(canceled)

### Claim 9 (depends on 32)

The method of claim 32, wherein the symptom is selected from the group consisting of ptosis, tunnel vision, reduced eye motility, severe external ophthalmoplegia, strabismus, nystagmus, low visual acuity, refractive error, photophobia, partial or total optic atrophy, night blindness, cataracts, blindness, central vision loss, light sensitivity, death of retinal ganglion cells or retinal epithelial cells, optic atrophy, optic neuropathy, retinopathy and blurring and clouding of vision.

### Claim 10

(canceled)

### Claim 11 (depends on 32)

The method of claim 32, wherein said pharmaceutical composition is administered directly to the eye, to the ocular system or by systemic administration.

### Claim at position 9

-15. (canceled)

### Claim 16 (depends on 32)

The method of claim 32, wherein the mitochondrially-enriched human stem cells have at least one of:
(i) an increased mitochondrial DNA content;
(ii) an increased level of citrate synthase (CS) activity;
(iii) an increased content of at least one mitochondrial protein selected from SDHA and COX1;
(iv) an increased rate of O2 consumption;
(v) an increased rate of ATP production; or
(vi) any combination thereof,
relative to the corresponding level in the stem cells prior to mitochondrial enrichment.

### Claim at position 11

-19. (canceled)

### Claim 20 (depends on 32)

The method of claim 32, wherein the human stem cells are hematopoietic stem cells, mesenchymal stem cells, pluripotent stem cells (PSCs), induced pluripotent stem cells (iPSCs), or CD34+ cells.

### Claim at position 13

-24. (canceled)

### Claim 25 (depends on 32)

The method of claim 32, wherein the human stem cells are isolated, derived or obtained from cells of the bone marrow, adipose tissue, oral mucosa, skin fibroblasts, blood or umbilical cord blood.

### Claim 26 (depends on 32)

The method of claim 32, wherein the human exogenous mitochondria are isolated or obtained from placenta, placental cells grown in culture or blood cells.

### Claim 27

(canceled)

### Claim 28 (depends on 32)

The method of claim 32, wherein the human exogenous mitochondria constitute at least 1-30% of the total mitochondria in the mitochondrially-enriched human stem cells.

### Claim 29 (depends on 28)

The method of claim 28, wherein the human exogenous mitochondria constitute at least 1%, 3%, 5%, 9%, 10%, 15%, 20%, 25% or 30% of the total mitochondria in the mitochondrially enriched human stem cells.

### Claim 30 (depends on 32)

The method of claim 32, wherein the composition further comprises non-enriched stem cells, megakaryocytes, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, monocytes, macrophages, natural killer (NK) cells, small lymphocytes, T lymphocytes, B lymphocytes, plasma cells, reticular cells, or any combination thereof.

### Claim 31

(canceled)

### Claim 32

A method for treating an ocular disease or an ocular disorder or a symptom thereof in a patient in need thereof, comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising at least about 104 to 108 human stem cells, wherein the human stem cells are enriched with human exogenous mitochondria, and wherein the ocular disease or disorder is not a mitochondrial disease or disorder caused by a pathogenic mutation in mitochondrial DNA or by a pathogenic mutation in nuclear DNA encoding a mitochondrial protein.

### Claim at position 22

-35. (canceled)

### Claim 36 (depends on 32)

The method of claim 32, wherein the human stem cells are obtained or derived from the patient before enrichment with the exogenous mitochondria.

### Claim 37 (depends on 32)

The method of claim 32, wherein the human stem cells are obtained or derived from a donor different than the patient before enrichment with the exogenous mitochondria.

### Claim 38 (depends on 37)

The method of claim 37, wherein the donor is at least partly HLA-matched with the patient.

### Claim 39 (depends on 37)

The method of claim 37, further comprising a step of administering to the patient an agent which prevents, delays, minimizes or abolishes an adverse immunogenic reaction between the patient and the mitochondrially-enriched human stem cells.

### Claim 40 (depends on 39)

The method of claim 39, wherein the adverse immunogenic reaction is a graft-versus-host disease (GvHD).

### Claim 41 (depends on 32)

The method of claim 32, further comprising administering to the subject non-enriched stem cells, megakaryocytes, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, monocytes, macrophages, natural killer (NK) cells, small lymphocytes, T lymphocytes, B lymphocytes, plasma cells, reticular cells, or any combination thereof.

### Claim 42 (depends on 16)

The method of claim 16, wherein increased mitochondrial DNA content is from endogenous and/or exogenous mitochondria.

### Claim 43 (depends on 29)

The method of claim 29, wherein the human exogenous mitochondria constitute at least 1% of the total mitochondria in the mitochondrially enriched human stem cells.