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Hematopoietic stem cells and methods of treatment of neovascular eye diseases therewith

a technology of hematopoietic stem cells and eye diseases, which is applied in the direction of biocide, drug composition, extracellular fluid disorder, etc., can solve the problems of insufficient epc targeting of neovasculature, no treatment is currently available to specifically treat ocular vascular disease, and significant loss of visual function, so as to stabilize the degeneration of retinal vasculature, and stabilize the effect o

Inactive Publication Date: 2007-05-24
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new type of stem cell that can be derived from bone marrow and has the ability to repair degenerating retinal vessels. These stem cells contain endothelial progenitor cells (EPC) that can target and stabilize neovasculature in the eye. The stem cells can also be genetically modified to inhibit new vessel formation and can be used for treating diseases associated with abnormal blood vessel growth. The isolated stem cells can rescue and stabilize retinal vasculature and maintain visual function in the eye. The invention also provides a method for isolating these stem cells from adult bone marrow.

Problems solved by technology

Since the retina consists of well-defined layers of neuronal, glial, and vascular elements, relatively small disturbances such as those seen in vascular proliferation or edema can lead to significant loss of visual function.
While significant progress has been made in identifying factors that promote and inhibit angiogenesis, no treatment is currently available to specifically treat ocular vascular disease.
Although these cells have been used in several experimental models of angiogenesis, the mechanism of EPC targeting to neovasculature is not known and no strategy has been identified that will effectively increase the number of cells that contribute to a particular vasculature.

Method used

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  • Hematopoietic stem cells and methods of treatment of neovascular eye diseases therewith
  • Hematopoietic stem cells and methods of treatment of neovascular eye diseases therewith
  • Hematopoietic stem cells and methods of treatment of neovascular eye diseases therewith

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example 1

Cell Isolation and Enrichment; Preparation of a Lin− HSC Populations A and B

[0041] General Procedure. All in vivo evaluations were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all evaluation procedures were approved by The Scripps Research Institute (TSRI, La Jolla, Calif.) Animal Care and Use Committee. Bone marrow cells were extracted from B6.129S7-Gtrosa26, Tie-2GFP, ACTbEGFP, FVB / NJ (rd / rd mice) or Balb / cBYJ adult mice (The Jackson Laboratory, Me.).

[0042] Monocytes were then separated by density gradient separation using HISTOPAQUE® polysucrose gradient (Sigma, St. Louis, Mo.) and labeled with biotin conjugated lineage panel antibodies (CD45, CD3, Ly-6G, CD 11, TER-119, Pharmingen, San Diego, Calif.) for Lin− selection. Lineage positive (Lin+) cells were separated and removed from Lin− HSC using a magnetic separation device (AUTOMACS™ sorter, Miltenyi Biotech, Auburn, Calif.). The resulting Lin− HSC population, containing endotheli...

example 2

Intravitreal Administration of Cells

[0046] An eyelid fissure was created with a fine blade to expose the P2 to P6 eyeball. Lineage negative HSC Population A of the present invention (approximately 105 cells in about 0.5 μl to about 1 μl of cell culture medium) was then injected intravitreally using a 33-gauge (Hamilton, Reno, Nev.) needled-syringe.

example 3

EPC Transfection

[0047] Lin− HSC (Population A) were transfected with DNA encoding the T2 fragment of TrpRS also enclosing a His6 tag (SEQ ID NO: 1, FIG. 7) using FUGENE™6 Transfection Reagent (Roche, Indianapolis, Ind.) according to manufacturer's protocol. Cells from a Lin− HSC composition (about 106 cell per ml) were suspended in opti-MEM® medium (Invitrogen, Carlsbad, Calif.) containing stem cell factor (PeproTech, Rocky Hill, N.J.). DNA (about 1 μg) and FuGENE reagent (about 3 μl) mixture was then added, and the mixtures were incubated at about 37° C. for about 18 hours. After incubation, cells were washed and collected. The transfection rate of this system was approximately 17% that was confirmed by FACS analysis. T2 production was confirmed by western blotting. The amino acid sequence of His6-tagged T2-TrpRS is shown as SEQ ID NO: 2, FIG. 8.

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Abstract

Isolated, mammalian, bone marrow-derived, hematopoietic stem cell populations contain endothelial progenitor cells (EPC) capable of forming retinal blood vessels. At least about 50% of the cells in the isolated cell population express CD31 and c-kit. Up to about 8% of the cells can express Sca-1, and up to about 4% of the cells can express Flk-1 / KDR. The cells can incorporate into the vasculature of the retina when intravitreally injected into the eye, and can thereby stabilize or rebuilt diseased or abnormal retinal blood vessels.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a division of U.S. Application for patent Ser. No. 10 / 628,783, which was filed on Jul. 25, 2003, now U.S. Pat. No. 7,153,501, which claims the benefit of Provisional Application for Patent Ser. No. 60 / 398,522, filed on Jul. 25, 2002, and Provisional Application for Patent Ser. No. 60 / 467,051, filed on May 2, 2003, each of which is incorporated herein by reference.STATEMENT OF GOVERNMENT INTEREST [0002] This invention was made with U.S. Government support under grant number CA92577 from the National Cancer Institute and under grants number EY11254, EY12598 and EY12599 from the National Institutes of Health. The United States Government has certain rights in this invention.FIELD OF THE INVENTION [0003] This invention relates to isolated, mammalian, lineage negative hematopoietic stem cells (Lin− HSC) derived from bone marrow. The invention also relates to treatment of vascular diseases of the eye by administering Lin− ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/14C12N5/06C12N5/08A01N63/00C12N15/09A61K35/12A61K35/28A61K48/00A61P9/10A61P27/02C12N5/00C12N5/02C12N5/071C12N5/078C12N5/0789C12N5/10
CPCA61K48/00A61K2035/124C12N5/0647C12N5/0692A61P27/02A61P7/06A61P9/10A61P9/14A61K35/12C12N5/0696
Inventor FRIEDLANDER, MARTINOTANI, ATSUSHISILVA, KAREN DA
Owner THE SCRIPPS RES INST
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