Delivery of therapeutic biologicals from implantable tissue matrices

• US 20040086497A1
• Filed: 10/21/2003
• Published: 05/06/2004
• Est. Priority Date: 01/27/2000
• Status: Active Grant

• Current Assignee: David T MacLaughlin, Joseph P. Vacanti, Patricia K. Donahoe, Peter T. Masiakos
• Original Assignee: David T MacLaughlin, Joseph P. Vacanti, Patricia K. Donahoe, Peter T. Masiakos
• Inventors: Vacanti, Joseph P., Masiakos, Peter T., Donahoe, Patricia K., MacLaughlin, David T.
• Granted Patent: US 7,078,032 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• 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: B33Y 10/00 Processes of additive manufacturing
• CPC Class Codes: B33Y 30/00 Apparatus for additive manufacturing; Details thereof or accessories therefor
• CPC Class Codes: B33Y 70/00 Materials specially adapted for additive manufacturing
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C12N 2510/02 Cells for production
• CPC Class Codes: C12N 5/0656 Adult fibroblasts

Abstract

Normal cells, such as fibroblasts or other tissue or organ cell types, are genetically engineered to express biologically active, therapeutic agents, such as proteins that are normally produced in small amounts, for example, MIS, or other members of the TGF-beta family Herceptin™, interferons, andanti-angiogenic factors. These cells are seeded into a matrix for implantation into the patient to be treated. Cells may also be engineered to include a lethal gene, so that implanted cells can be destroyed once treatment is completed. Cells can be implanted in a variety of different matrices. In a preferred embodiment, these matrices are implantable and biodegradable over a period of time equal to or less than the expected period of treatment, when cells engraft to form a functional tissue producing the desired biologically active agent. Implantation may be ectopic or in some cases orthotopic. Representative cell types include tissue specific cells, progenitor cells, and stem cells. Matrices can be formed of synthetic or natural materials, by chemical coupling at the time of implantation, using standard techniques for formation of fibrous matrices from polymeric fibers, and using micromachining or microfabrication techniques. These devices and strategies are used as delivery systems via standard or minimally invasive implantation techniques for any number of parenterally deliverable recombinant proteins, particularly those that are difficult to produce in large amounts and/or active forms using conventional methods of purification, for the treatment of a variety of conditions that produce abnormal growth, including treatment of malignant and benign neoplasias, vascular malformations (hemangiomas), inflammatory conditions, keloid formation, abdominal or plural adhesions, endometriosis, congenital or endocrine abnormalities, and other conditions that can produce abnormal growth such as infection. Efficacy of treatment with the therapeutic biologicals is detected by determining specific criteria, for example, cessation of cell proliferation, regression of abnormal tissue, or cell death, or expression of genes or proteins reflecting the above.

Claims

1. A method for treating a disorder characterized by excessive proliferation of tissue comprising

implanting a cell-matrix structure comprising a matrix having attached thereto an effective amount of cells stably expressing a gene encoding at least one biological modifier to stop or regress the excessive tissue proliferation,

wherein the cells are either genetically engineered to produce the biological modifier or of a different cell type than the tissue that has proliferated excessively.

2. The method of claim 1 wherein the disorder is selected from the group consisting of malignant and benign neoplasias, vascular, inflammatory conditions causing excessive proliferation of cells, keloid formation, intraperitoneal or intrathoracic adhesions, endometriosis, congenital or endocrine abnormalities, and infections causing excessive proliferation of cells.

3. The method of claim 1 wherein the matrix is selected from the group consisting of fibrous scaffolds, polymeric hydrogels, and micromachine or micromolded substrates.

4. The method of claim 1 wherein the cells are selected from the group consisting of tissue specific cells, progenitor cells, and stem cells.

5. The method of claim 4 wherein the cells are genetically engineered to produce the biological modifier.

6. The method of claim 5 wherein the biological modifier is a protein.

7. The method of claim 1 wherein the biological modifier is selected from the group consisting of angiogenesis inhibitors, MIS, Herceptin, interferons, TGF-beta factors, steroid or orphan receptors, chimeric transcription factors, antibodies and antisense.

8. The method of claim 7 wherein the biological modifier is MIS and the cells are engineered to secrete biologically active MIS to produce serum levels effective to stop tissue proliferation or regress excessive tissue.

9. The method of claim 8 wherein the cell-matrix structure is implanted into a patient with a disorder selected from the group consisting of vulvar epidermoid carcinomas, cervical carcinomas, endometrial adenocarcinomas, ovarian adenocarcinomas, ocular melanomas, prostate, lymphoid, breast, cutaneous, and germ cell tumors.

10. The method of claim 1 wherein the inflammatory disorder is restenosis and the cells are not endothelial cells, or an endocrine disorder.

11. The method of claim 1 wherein the cells are genetically engineered to express the biological modifier from recombinant DNA encoding the biological modifier.

12. The method of claim 1 wherein the cells are selected based on natural production of the biological modifier and the cell-matrix structure is implanted at a site where the biological modifier can stop proliferation or cause tissue regression.

13. A cell-matrix structure for implantation into a patient having attached thereto an effective amount of cells stably expressing a gene encoding at least one biological modifier to stop or regress excessive tissue proliferation in a patient in need thereof, wherein the cells are either genetically engineered to produce the biological modifier or of a different cell type than the tissue that has proliferated excessively.

14. The cell-matrix structure of claim 13 wherein the cells produce a biological modifier effective to treat a disorder selected from the group consisting of malignant and benign neoplasias, vascular, inflammatory conditions causing excessive proliferation of cells, keloid formation, endometriosis, congenital or endocrine abnormalities, and infections causing excessive proliferation of cells.

15. The cell-matrix structure of claim 13 wherein the matrix is selected from the group consisting of fibrous scaffolds, polymeric hydrogels, and micromachine or micromolded substrates.

16. The cell-matrix structure of claim 13 wherein the cells are selected from the group consisting of tissue specific cells, progenitor cells, and stem cells.

17. The cell-matrix structure of claim 13 wherein the cells are genetically engineered to produce the biological modifier.

18. The cell-matrix structure of claim 13 wherein the biological modifier is a protein.

19. The cell-matrix structure of claim 13 wherein the biological modifier is selected from the group consisting of angiogenesis inhibitors, MIS, angiogenesis inhibitors, MIS, Herceptin, interferons, TGF-beta factors, steroid or orphan receptors, chimeric transcription factors, antibodies and antisense.

20. The cell-matrix structure of claim 19 wherein the biological modifier is MIS and the cells are engineered to secrete biologically active MIS to produce serum levels effective to stop tissue proliferation or regress excessive tissue.

21. The cell-matrix structure of claim 20 wherein the cell-matrix structure is implanted into a patient with a disorder selected from the group consisting of vulvar epidermoid carcinomas, cervical carcinomas, endometrial adenocarcinomas, ovarian adenocarcinomas, ocular melanomas, prostate, lymphoid, breast, cutaneous, and germ cell tumors.

22. The cell-matrix structure of claim 13 wherein the cells are genetically engineered to express the biological modifier from recombinant DNA encoding the biological modifier.

23. The cell-matrix structure of claim 13 wherein the cells are selected based on natural production of the biological modifier and the cells are implanted at a site where the biological modifier can stop proliferation or cause tissue regression.