CD34 stem cell-related methods and compositions

• US 7,998,472 B2
• Filed: 05/20/2008
• Issued: 08/16/2011
• Est. Priority Date: 05/24/2007
• Status: Active Grant

• Current Assignee: Apceth GmbH & Co. KG (Resonac Holdings Corp.)
• Original Assignee: Apceth GmbH & Co. KG (Resonac Holdings Corp.)
• Inventors: Nelson, Peter C, Raggi, Matthias C, Stangl, Manfred J, Huss, Ralf
• Primary Examiner(s): SCHULTZ, JAMES
• Application Number:
  US12/154,059
• Publication Number:
  US 20090041735A1
• Time in Patent Office: 1,183 Days
• Field of Search: None
• US Class Current: 424/93.2
• CPC Class Codes: A61K 2035/122 for inducing tolerance or supression of immune responses
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/49 : Platelet-derived growth factor [PDGF]
• CPC Class Codes: C12N 5/0663 : Bone marrow mesenchymal stem cells (BM-MSC)

Abstract

This invention provides novel stem cell-based methods for treating a number of conditions. These methods employ CD34⁻ stem cells, and have a tremendous advantage in that they do not require myeloablation in the subject being treated. The CD34⁻ stem cells used in the instant methods can be genetically modified or not, depending on the disorder treated.

Claims

1. A method for treating a subject afflicted with a tumor comprising introducing into the subject'"'"'s bloodstream a therapeutically effective number of genetically modified CD34⁻

stem cells, wherein (a) each of the genetically modified CD34⁻

stem cells contains an exogenous nucleic acid comprising (i) a cytotoxic protein-encoding region operably linked to (ii) a promoter or promoter/enhancer combination, whereby the cytotoxic protein is selectively expressed when the genetically modified CD34⁻

stem cells come into proximity with, and differentiate into endothelial-like cells in proximity with, tumor tissue undergoing angiogenesis, directly and/or indirectly causing tumor tissue death, and (b) the introduction of the genetically modified CD34⁻

stem cells is not preceded, accompanied or followed by myeloablation.

2. The method of claim 1, wherein the subject is human.

3. The method of claim 2, wherein the tumor is selected from the group consisting of a prostate tumor, a pancreatic tumor, a squamous cell carcinoma, a breast tumor, a melanoma, a basal cell carcinoma, a hepatocellular carcinoma, testicular cancer, a neuroblastoma, a glioma or a malignant astrocytic tumor such as glioblastma multiforme, a colorectal tumor, an endometrial carcinoma, a lung carcinoma, an ovarian tumor, a cervical tumor, an osteosarcoma, a rhabdo/leiomyosarcoma, a synovial sarcoma, an angiosarcoma, an Ewing sarcoma/PNET and a malignant lymphoma.

4. The method of claim 2, wherein the promoter/enhancer combination is the Tie2 promoter/enhancer, the cytotoxic protein is Herpes simplex viral thymidine kinase, and the subject is treated with ganciclovir in a manner permitting the Herpes simplex viral thymidine kinase to render the ganciclovir cytotoxic.

5. The method of claim 2, wherein the genetically modified CD34⁻

stem cells are allogenic with respect to the subject.

6. The method of claim 2, wherein the genetically modified CD34⁻

stem cells are autologous with respect to the subject.

7. The method of claim 2, wherein the therapeutically effective number of genetically modified CD34⁻

stem cells is from about 1×

10³ to about 1×

10⁷ cells/kg body weight.