# US 10,765,706 B2 · Method of stem cell delivery into the brain during chronic disease using blood brain barrier permeabilizers

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- Number: US 10,765,706 B2
- Document ID: US10765706B2
- Status: Granted
- Kind: B2
- Application number: 15/257,315
- Filed: 2016-09-06
- Published: 2017-03-09
- Granted: 2020-09-08
- Earliest claimed: 2015-09-03
- Assignees: University of South Florida
- Applicants: Cesario Venturina Borlongan; Paul R. Sanberg
- Inventors: Cesario Venturina Borlongan; Paul R. Sanberg
- Web page: https://patentgrep.com/patent/US10765706B2

## CPC

- A61K 35/51: Umbilical cord; Umbilical cord blood; Umbilical stem cells
- 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 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- 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)

## Abstract

Blood brain barrier (BBB) permeabilizers, such as mannitol, can facilitate the entry of stem cells from the periphery to the stroke brain. It is unknown whether BBB permeation in the chronic stage of the disease still facilitates the entry of stem cells from the periphery to the injured brain. Evidence herein shows BBB permeation in the chronic stage of stroke assisted in the entry of stem cells from the periphery to the stroke brain. Stroke models treated with human umbilical cord stem cells (hUCBC) only (2 million viable cells), mannitol or a combination. Results revealed that hUCBC alone or combined with mannitol displayed significant behavioral and histological deficits compared to control animals, with the HUCBC-mannitol combined treatment showing improvements over hUCBC only treatments in brain cell survival in the peri-infarct area. BBB permeation in chronic stroke also lowers the effective stem cell dose necessary to improve functional outcomes.

## Claims

### Claim 1

A method of increasing neurogenesis in a patient having a chronic stroke comprising the steps:
identifying a patient suffering from chronic stroke wherein an initial stroke insult occurred at least one month prior;
obtaining umbilical cord blood stem cells; and
administering a therapeutically effective amount of the umbilical cord blood stem cells and a blood brain barrier permeabilizer to the patient after the acute and subacute phases of the stroke insult wherein the blood brain permeabilizer is selected from the group consisting of mannitol and lobradimil wherein the therapeutically effective amount of the umbilical cord blood stem cells is administered at one month post-stroke;
wherein administration of the therapeutically effective amount of the umbilical cord blood stem cells and the blood brain permeabilizer facilitates migration of the umbilical cord blood stem cells from periphery to stroke site and increases neurogenesis in the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the umbilical cord blood stem cells and the blood brain permeabilizer are administered concomitantly to the patient.

### Claim 3 (depends on 1)

The method of claim 1, wherein the umbilical cord blood stem cells and the blood brain permeabilizer are administered intra-arterially.

### Claim 4 (depends on 3)

The method of claim 3, wherein infusion rate of the umbilical cord blood stem cells and the blood brain permeabilizer is 1 μl per minute.

### Claim 5 (depends on 1)

The method of claim 1, wherein the umbilical cord blood stem cells are mononucleated cells.

### Claim 6 (depends on 1)

The method of claim 1, wherein the umbilical cord blood stem cells are administered separately from the blood brain permeabilizer with a temporal separation between the administration of the umbilical cord blood stem cells and the blood brain permeabilizer.

### Claim 7 (depends on 6)

The method of claim 6, wherein the temporal separation is less than a minute.

### Claim 8 (depends on 6)

The method of claim 6, wherein the temporal separation is at least one hour.

### Claim 9 (depends on 1)

The method of claim 1, wherein neurogenesis is increased about 175% as compared to a sham control.