Inhibitor and stimulator of stem cell proliferation and uses thereof
AssigneeWellstat Therapeutics Corporation
InventorsStephen D. Wolpe, Irena Tsyrlova
Life of this patent
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Abstract
Disclosed and claimed are methods for the isolation and use of stem cell modulating factors for regulating stem cell cycle and for accelerating the post-chemotherapy peripheral blood cell recovery. Also disclosed and claimed are the inhibitors and stimulators of stem cell proliferation.
Claims90
A polypeptide comprising hemoglobin alpha chain wherein the C-terminal hydrophobic domain has been substituted or deleted.
A polypeptide comprising hemoglobin alpha chain wherein the C-terminal haptoglobin-binding domain has been substituted or deleted.
A polypeptide comprising amino acids 1-97 of the human alpha hemoglobin chain.
A pharmaceutical composition comprising a polypeptide consisting of amino acids 1-97 of the human alpha hemoglobin chain and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a polypeptide consisting of amino acids 1-94 of the human alpha hemoglobin chain and a pharmaceutically acceptable carrier.
A method for expressing alpha hemoglobin or substitution or deletion analogs thereof comprising expressing said alpha hemoglobin or substitution or deletion analogs as a ubiquitin fusion.
A peptide having the sequence selected from the group consisting of biotin-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, (iodo)Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val and (iodo)Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val.
A method of stimulating stem cell proliferation comprising contacting hematopoietic cells with a stem cell proliferation stimulating amount of INPROL and/or an opiate compound.
A method of stimulating stem cell proliferation comprising contacting hematopoietic cells with a compound capable of binding opiate receptors.
A method of stimulating or inhibiting stem cell proliferation comprising contacting hematopoietic cells with a compound capable of binding nociceptin receptors.
A method of stimulating or inhibiting stem cell proliferation comprising contacting hematopoietic cells with a compound capable of activating the Ginhibitory subclass of GTP binding proteins.
A method of stimulating or inhibiting stem cell proliferation comprising contacting hematopoietic cells with a compound capable of binding to an opiate-like receptor not including the classical mu, kappa or delta opiate receptors or ORL1, wherein said receptor (a) has stem cell stimulating and/or inhibiting properties and (b) has said stem cell stimulating and/or inhibiting ability antagonizable by naloxone.
A method of identifying a receptor for INPROL comprising contacting a material which contains said receptor with INPROL in a receptor-binding assay.
A method as in method 58 wherein said INPROL is selected from the group the alpha chain of hemoglobin, the beta chain of hemoglobin, the gamma chain of hemoglobin,
- the delta chain of hemoglobin, the epsilon chain of hemoglobin, the zeta chain of hemoglobin,
- a polypeptide having the sequence of amino acids 1-97 of the human alpha hemoglobin chain,
- a polypeptide having the sequence of amino acids 1-94 of the human alpha hemoglobin chain,
- 54 Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, biotin-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, (iodo)Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, (iodo)Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Cys-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val-Cys, and Asp-Ala-Leu-Thr-Asn-Ala-Val-Ala-His-Val-Asp-Asp-Met-Pro-Asn-Ala-Leu-Ser-Ala.
A method of identifying a receptor for INPROL comprising contacting a material which contains said receptor with INPROL in an adenylate cyclase assay.
A method as in method 60 wherein said INPROL is selected from the group the alpha chain of hemoglobin, the beta chain of hemoglobin, the gamma chain of hemoglobin, the delta chain of hemoglobin, the epsilon chain of hemoglobin, the zeta chain of hemoglobin
- a polypeptide having the sequence of amino acids 1-97 of the human alpha hemoglobin chain,
- a polypeptide having the sequence of amino acids 1-94 of the human alpha hemoglobin chain,
- 55 Phe-Pro-His-Phe-Asp-Leu- Ser-His-Gly-Ser-Ala-Gin-Val, biotin-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, (iodo)Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, (iodo)Phe-Pro-His-(iodo)Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Cys-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val-Cys, and Asp-Ala-Leu-Thr-Asn-Ala-Val-Ala-His-Val-Asp-Asp-Met-Pro-Asn-Ala-Leu-Ser-Ala.
A method of treating cancer in a mammal suffering therefrom comprising the steps of:
- a) administering radiotherapy and/or chemotherapy, and
- b) administering a stem cell proliferation stimulatory amount of INPROL and/or an opiate compound.
A method of stimulating stem cell division in a mammal exposed to an agent which damages or destroys stem cells comprising administering a stem cell proliferation stimulating amount of INPROL and/or an opiate compound.
A method of maintaining mammalian hematopoietic stem cells ex vivo comprising contacting hematopoietic cells with a stem cell proliferation stimulating amount of INPROL and/or an opiate compound.
A method of treating a myeloproliferative disease, hematopoieitic or epithelial stem cell hypoproliferation in a mammal suffering therefrom comprising administering a stimulatory amount of INPROL and/or an opiate compound.
A method for treating or preventing stem cell exhaustion comprising administering a stem cell proliferation inhibitory amount of INPROL and/or an opiate compound.
A method for differentially protecting normal stem cells in a mammal from chemotherapy or radiation comprising administering a stem cell protecting amount of an opiate compound.
A method of conducting gene therapy in a mammal comprising:
- a) removing hematopoietic cells from said mammal,
- b) treating said hematopoietic cells ex vivo with a stem cell stimulatory amount of INPROL and/or an opiate compound,
- c) transfecting or infecting said hematopoietic cells with a predetermined gene,
- d) contacting said transfected hematopoietic cells ex vivo with a stem cell inhibitory amount of INPROL and/or an opiate compound,
- e) transplanting into said mammal the hematopoietic cells of step d
- f) optionally treating said mammal in vivo with a stem cell inhibitory or stimulatory quantity INPROL and/or an opiate compound.
A method for conducting ex vivo stem cell expansion comprising contacting hematopoietic cells with a stem cell stimulatory amount of INPROL and/or an opiate compound.
A pharmaceutical composition comprising (a) an opiate compound and (b) at least one inhibitory compound selected from the group consisting of MIP-1α, TGFβ, TNFα, INFα, INFβ, INFγ, the pentapeptide pyroGlu-Glu-Asp-Cys-Lys, the tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro, and the tripeptide glutathione (Gly-Cys-γGlu).
A pharmaceutical composition comprising (a) an opiate compound and (b) at least one stimulatory compound selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-13, IL-14, IL-15, G-CSF, GM-CSF, M-CSF, erythropoietin, thrombopoietin, stem cell factor, and flk2/flt3 ligand.
A method of treating pain in a mammal comprising administering to said mammal an analgesia-inducing amount of INPROL.
A method of treating immune deficiency in a mammal comprising administering to said mammal an immunostimulatory amount of INPROL.
A method as in method 87 wherein said INPROL is selected from the group the alpha chain of hemoglobin, the beta chain of hemoglobin, the gamma chain of hemoglobin, the delta chain of hemoglobin, the epsilon chain of hemoglobin, the zeta chain of hemoglobin,
- a polypeptide having the sequence of amino acids 1-97 of the human alpha hemoglobin chain,
- a polypeptide having the sequence of amino acids 1-94 of the human alpha hemoglobin chain,
- 56 Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Cys-Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val-Cys, and Asp-Ala-Leu-Thr-Asn-Ala-Val-Ala-His-Val-Asp-Asp-Met-Pro-Asn-Ala-Leu-Ser-Ala.
A method as in method 87 wherein said INPROL is selected from the group the alpha chain of hemoglobin, the beta chain of hemoglobin, the gamma chain of hemoglobin, the delta chain of hemoglobin, the epsilon chain of hemoglobin, the zeta chain of hemoglobin,
- a polypeptide having the sequence of amino acids 1-97 of the human alpha hemoglobin chain,
- a polypeptide having the sequence of amino acids 1-94 of the human alpha hemoglobin chain,
- 57 Phe-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val, Cys-Peh-Pro-His-Phe-Asp-Leu-Ser-His-Gly-Ser-Ala-Gln-Val-Cys, and Asp-Ala-Leu-Thr-Asn-Ala-Val-Ala-His-Val-Asp-Asp-Met-Pro-Asn-Ala-Leu-Ser-Ala.
Dependencies are inferred from the claim text.