ABCB5(+) stem cells for treating ocular disease
Inventors
Frank, Markus H. • Frank, Natasha Y. • Ksander, Bruce • Kolovou, Paraskevi Evi
Assignees
Boston Childrens Hospital • Schepens Eye Research Institute Inc • US Department of Veterans Affairs
Publication Number
US-9801912-B2
Publication Date
2017-10-31
Expiration Date
2034-02-19
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Abstract
Various aspects and embodiments of the present invention are directed to methods of treating a subject having an ocular condition, methods of isolating ocular stem cells, methods of selecting and/or producing ocular grafts for transplantation, and methods of promoting ocular cell regeneration as well as to grafts and preparations containing isolated ocular stem cells characterized by the expression of ABCB5 on their cell surface.
Core Innovation
The invention is directed to methods and compositions for treating ocular conditions by utilizing ABCB5(+) stem cells, which are ocular stem cells characterized by the expression of ABCB5 on their cell surface. These ABCB5(+) stem cells include limbal stem cells and retinal pigment epithelium (RPE) stem cells. The invention provides methods of isolating these cells, selecting ocular grafts enriched in these cells for transplantation, and promoting ocular cell regeneration through administration of such stem cells.
The problem addressed by the invention arises from the need to identify and isolate limbal stem cells (LSCs) which are essential for corneal epithelial homeostasis and regeneration. Loss of these cells, as in limbal stem cell deficiency (LSCD), leads to severe ocular diseases and blindness. Prior to this invention, no molecular marker was available to permit prospective enrichment and isolation of the LSC subset from mixed ocular cell populations, limiting the effectiveness of treatments.
The invention solves this problem by discovering that ABCB5 is a specific marker for LSCs and that ABCB5(+) stem cells are required for normal eye development and regeneration. Administration of isolated ABCB5(+) stem cells to subjects with ocular wounds or diseases can regenerate ocular cells and restore corneal and retinal structures. This is supported by experimental evidence demonstrating that ABCB5 expression identifies slow-cycling, label-retaining LSCs in mice and humans, that ABCB5 loss results in defective corneal development and regeneration, and that ABCB5(+) grafts can restore damaged corneas.
Claims Coverage
The patent contains multiple independent claims focusing on methods of treatment and methods of promoting ocular cell regeneration using isolated ABCB5(+) ocular stem cells, specifically limbal stem cells.
Treatment of corneal disease using isolated ABCB5(+) limbal stem cells
A method of treating a subject having a corneal disease by administering to the subject isolated ABCB5(+) ocular stem cells, where the ocular stem cells are limbal stem cells, in an amount effective to regenerate ocular cells.
Treatment of blindness due to limbal stem cell deficiency
The method specifically applicable to blindness caused by limbal stem cell deficiency (LSCD) by administering isolated ABCB5(+) limbal stem cells.
Administration of ABCB5(+) limbal stem cells as an ocular graft
Administering the isolated ABCB5(+) limbal stem cells as an ocular graft to the subject.
Use of allogeneic or syngeneic ABCB5(+) limbal stem cells
Administering isolated ABCB5(+) limbal stem cells that are either allogeneic or syngeneic stem cells to the subject.
Promotion of ocular cell regeneration by administering ABCB5(+) limbal stem cells
A method of promoting ocular (corneal) cell regeneration by identifying limbal stem cells as ABCB5(+) limbal stem cells and administering these cells in an amount effective to promote corneal cell regeneration.
Identification of ABCB5(+) limbal stem cells using specific antibodies
The identifying step involves the use of an antibody specific to ABCB5 to selectively recognize ABCB5(+) limbal stem cells for subsequent administration.
The independent claims cover methods of treating corneal diseases, including blindness due to LSCD, and promoting ocular cell regeneration using isolated ABCB5(+) limbal stem cells administered as ocular grafts, with variations covering the use of allogeneic or syngeneic cells and identifying ABCB5(+) cells by antibodies.
Stated Advantages
ABCB5 permits prospective enrichment and isolation of functionally essential limbal stem cells, improving outcomes in limbal stem cell transplantation.
Using ABCB5(+) stem cells enables restoration of corneal transparency and normal histology, reversing limbal stem cell deficiency.
ABCB5 expression identifies slow-cycling and ΔNp63α-positive limbal stem cells necessary for normal corneal development and repair.
Enrichment of ABCB5(+) stem cells within grafts significantly enhances therapeutic success in ocular diseases compared to unsegregated or ABCB5(−) cell grafts.
ABCB5 plays a novel in vivo physiological role in maintaining limbal stem cell quiescence, preserving stem cell pools, and regulating differentiation critical for corneal regeneration.
Documented Applications
Treatment of ocular conditions including corneal diseases such as blindness due to limbal stem cell deficiency (LSCD) and corneal epithelium wounding.
Treatment of retinal diseases including macular degeneration and retinitis/retinitis pigmentosa.
Use in treating ocular wounds and promoting ocular cell regeneration in subjects with damaged ocular tissue.
Production of ocular grafts containing isolated ABCB5(+) stem cells for transplantation to restore corneal tissue.
Isolation and selection of ocular grafts enriched in ABCB5(+) limbal stem cells for transplantation therapies.
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