Polymeric gene delivery system

• US 20010020011A1
• Filed: 03/23/2001
• Published: 09/06/2001
• Est. Priority Date: 03/15/1994
• Status: Active Grant

• Current Assignee: Edith Mathiowitz, Kim Boekelheide, Yong Shik Jong
• Original Assignee: Edith Mathiowitz, Kim Boekelheide, Yong Shik Jong
• Inventors: Mathiowitz, Edith, Boekelheide, Kim, Jong, Yong Shik
• Granted Patent: US 6,620,617 B2
• Time in Patent Office: Days
• US Class Current: 514/44
• 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: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

A means for obtaining efficient introduction of exogenous genes into a patient, with long term expression of the gene, is disclosed. The gene, under control of an appropriate promoter for expression in a particular cell type, is encapsulated or dispersed with a biocompatible, preferably biodegradable polymeric matrix, where the gene is able to diffuse out of the matrix over an extended period of time, for example, a period of three to twelve months or longer. The matrix is preferably in the form of a microparticle such as a microsphere (where the gene is dispersed throughout a solid polymeric matrix) or microcapsule (gene is stored in the core of a polymeric shell), a film, an implant, or a coating on a device such as a stent. The size and composition of the polymeric device is selected to result in favorable release kinetics in tissue. The size is also selected according to the method of delivery which is to be used, typically injection or administration of a suspension by aerosol into the nasal and/or pulmonary areas. The matrix composition can be selected to not only have favorable degradation rates, but to be formed of a material which is bioadhesive, to further increase the effectiveness of transfer when administered to a mucosal surface.

Claims

1. A delivery system for a gene into a cell comprising

a biocompatible polymeric device and

a gene under the control of a promoter which is capable of being expressed in a mammalian cell,

wherein the gene is entrapped in the polymer and released when the polymer is implanted into tissue.

2. The system of

claim 1

wherein the polymeric device is selected from the group consisting of microparticles, microspheres, microcapsules, stents, coatings, implants, slabs, films, and gels.

3. The system of

claim 1

wherein the polymeric device is formed of a biodegradable polymer.

4. The system of

claim 3

wherein the polymer is selected from the group consisting of synthetic polymers, polysaccharides, proteins, and combinations thereof.

5. The system of

claim 1

further comprising a component selected from the group consisting of compounds inhibiting inflammation due to the polymer device and compounds increasing inflammation due to the polymeric device.

6. The system of

claim 1

wherein the gene includes a promoter and a transcription termination signal.

7. The system of

claim 1

further comprising compounds selected from the group consisting of antiinflammatories, inhibitors of capsule formation, and inhibitors of cytokines.

8. The system of

claim 1

wherein the polymer is bioadhesive.

9. The system of

claim 1

comprising between 0.01 and 90% by weight gene.

10. A method for delivery of a gene into a cell in vivo comprising

entrapping a gene under the control of a promoter which is capable of being expressed in a mammalian cell in a biocompatible polymeric device which releases the gene following implantation of the polymer.

11. The method of

claim 10

wherein the polymeric device is selected from the group consisting of microparticles, microspheres, microcapsules, stents, coatings, implants, slabs, films, and gels.

12. The method of

claim 10

wherein the polymeric device is formed of a biodegradable polymer.

13. The method of

claim 12

wherein the polymer is selected from the group consisting of synthetic polymers, polysaccharides, proteins, and combinations thereof.

14. The method of

claim 10

further comprising a component selected from the group consisting of compounds inhibiting inflammation due to the polymer device and compounds increasing inflammation due to the polymeric device.

15. The method of

claim 10

wherein the gene includes a promoter, a transcription termination signal, and the promoter is tissue specific.

16. The method of

claim 10

further comprising antiinflammatories, inhibitors of capsule formation, and inhibitors of cytokines.

17. The method of

claim 10

for targeting release of the gene into inflammatory cells comprising selecting a biodegradable polymer as the polymer forming the device.

18. The method of

claim 10

for targeting release of the gene into inflammatory cells comprising selecting a polymer which elicits an inflammatory reaction as the polymer forming the device.

19. The method of

claim 10

for targeting release of the gene into tissue specific cells comprising selecting a non-biodegradable polymer as the polymer forming the device.

20. The method of

claim 10

for targeting release of the gene into tissue specific cells comprising selecting a biocompatible polymer as the polymer forming the device.

21. The method of

claim 10

further comprising selecting a bioadhesive polymer as the polymer forming the implant.

22. The method of

claim 10

further comprising loading between 0.01 and 90% by weight gene into the polymer.