Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-11-04
2004-10-26
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S631000, C514S632000, C514S665000, C514S563000
Reexamination Certificate
active
06809117
ABSTRACT:
BACKGROUND OF THE INVENTION
Organ development requires a tightly controlled program of cell proliferation followed by growth arrest and differentiation and, often, programmed cell death. The balance between the number of cell divisions and the extent of subsequent programmed cell death determines the final size of an organ (reviewed by Bryant and Simpson, Quart.
Rev. of Biol
. 59:387-415 (1984); Raft,
Nature
356:397-400 (1992)). Although much of the cellular machinery that determines the timing of onset and cessation of cell division per se is well understood (reviewed by Hunter and Pines,
Cell
79:573-582 (1994); Morgan,
Nature
374:131-134 (1995); Weinberg,
Cell
81:323-330 (1995)), little is known about the signals that cause discrete groups of cells and organs to terminate growth at the appropriate cell number and size. A better understanding of the signals involved provides possible targets for manipulating the cellular machinery resulting in therapeutic benefits for a number of conditions.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that nitric oxide (NO) is an important growth regulator in an intact developing organism. In particular, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells, including precursors to myeloid, lymphoid and erythroid cells, in bone marrow which are capable of undergoing normal hematopoiesis and differentiation, wherein the bone marrow is contacted with an inhibitor of NO, such as an inhibitor of nitric oxide synthase (NOS), thereby producing bone marrow having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis and differentiation. The method can be carried out in vivo or ex vivo. In addition, the method can be used to prevent differentiation of erythroid cells and/or myeloid cells in the mammal. The method can further comprise contacting the bone marrow with at least one agent (e.g., a hematopoietic growth factor) which induces differentiation of a selected hematopoietic stem cell population.
The present invention also relates to a method for treating a mammal to increase a population of hematopoietic stem cells in bone marrow of the mammal which are capable of undergoing normal hematopoiesis and differentiation. In the method, the bone marrow of the mammal is contacted with an inhibitor of NOS, thereby producing bone marrow having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis and differentiation. The method can further comprise contacting the bone marrow with at least one agent which induces differentiation of a selected hematopoietic stem cell population.
In one embodiment of the method for treating a mammal to increase a population of hematopoietic stem cells in bone marrow of the mammal which are capable of undergoing normal hematopoiesis and differentiation, bone marroow which is to be transplanted is obtained, wherein the bone marrow to be transplanted can be obtained from the mammal being treated (autologous transplantation) or from another mammal (heterologous transplantation). The bone marrow to be transplanted is contacted with an inhibitor of NOS. The bone marrow which is to be transplanted is transplanted into the mammal being treated, thereby providing the mammal with bone marrow having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis and differentiation. The method can further comprise treating the mammal with an inhibitor of NOS before or after transplanting the bone marrow. Alternatively, the method can further comprise treating the mammal with an enhancer of NOS before or after transplanting the bone marrow.
The present invention also relates to a method of increasing a population of dividing cells in a tissue of a mammal comprising contacting the cells with an inhibitor of nitric oxide. In one embodiment, the present invention also relates to a method of increasing a population of cells in S phase in a tissue of a mammal, comprising contacting the tissue with an inhibitor of NO, such as an inhibitor of NOS. In one embodiment, the method results in an increase in the size of an organ in which the tissue is occurs. Furthermore, as described herein the cells in S phase can be used in gene therapy.
The present invention also relates to a method of decreasing a population of cells in S phase in a tissue of a mammal and inducing differentiation of the cells, comprising contacting the tissue with an enhancer of NO, such as an enhancer of NOS. In one embodiment, the method results in a decrease in the size of an organ with which the tissue is associated.
The present invention also relates to a method of coordinating developmental decisions of a cell type in a mammal, comprising introducing NO into the cell type or a precursor of the cell type, thereby inhibiting proliferation of the cell type or a precursor of the cell type and inducing differentiation of the cell type or a precursor of the cell type.
A method of inducing differentiation in a mammalian cell population comprising contacting the cell population with NO or a NO enhancer is also encompassed by the present invention.
The invention also pertains to a method of regenerating tissue in an adult mammal comprising contacting a selected tissue (e.g., blood, skin, bone and digestive epithelium), or precursor cells of the selected tissue, with an inhibitor of NO, thereby inhibiting differentiation and inducing proliferation of cells of the tissue, then contacting the selected tissue with a compound (e.g., nitric oxide, a growth factor or a combination of both) which inhibits proliferation and induced differentiation. In one embodiment, the method involves repopulating an organ or tissue (e.g., muscle or nerve fiber) comprised of normally nondividing cells by contacting a selected organ or tissue, or precursor cells of the selected organ or tissue, with an inhibitor of NO, thereby inhibiting differentiation and inducing proliferation of cells of the organ or tissue, then contacting the selected organ or tissue with a compound which inhibits proliferation and induced differentiation.
The invention also encompasses a method of producing a subpopulation of hematopoietic cells. In the method, bone marrow is contacted with an inhibitor of NOS, thereby producing bone marrow having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis and differentiation; and at least one agent (e.g., a hematopoietic growth factor) selected to induce specific differentiation of the hematopoietic stem cell population, thereby producing a subpopulation of hematopoietic cells.
Identification of NO as an important growth regulator in an organism provides for various therapeutic applications in humans and other mammals.
DETAILED DESCRIPTION OF THE INVENTION
Results of the work described herein have shown that a transcellular messenger (nitric oxide (NO)) plays a critical role in tissue differentiation and organism development. NO regulates the balance between cell proliferation and cell differentiation in the intact developing organism. Increased production of NO permits cessation of cell division and subsequent differentiation of cell in a tissue, whereas removal of the NO-mediated growth arrest promotes cell division.
Accordingly, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells, including precursors to myeloid, lymphoid and erythroid cells, in bone marrow which are capable of undergoing normal hematopoiesis and differentiation, by contacting the bone marrow with an inhibitor of NO, such as an inhibitor of NOS. The present invention includes a method for treating a mammal to increase a population of hematopoietic stem cells in bone marrow of the mammal which are capable of undergoing normal hematopoiesis and differentiation, in which the bone marrow of the mammal is contacted with an inhibitor of NOS.
The present invention also relates to a met
Cline Hollis
Enikolopov Grigori N.
Kuzin Boris A.
Michurina Tatiyana
Peunova Natalia I.
Cold Spring Harbor Laboratory
Criares Theodore J.
Fish & Neave
Haley Jr. James F.
Li Z. Ying
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