Use of PEDF in an Encapsulated Cell-Based Delivery System

• US 20110111008A1
• Filed: 10/06/2010
• Published: 05/12/2011
• Est. Priority Date: 10/08/2009
• Status: Abandoned Application

• Current Assignee: Neurotech USA, Inc. (Woodbrook Group Holdings, Inc.)
• Original Assignee: Neurotech USA, Inc. (Woodbrook Group Holdings, Inc.)
• Inventors: Ling, Vincent, Stabila, Paul, Kauper, Konrad, Tao, Weng
• Application Number:
  US12/899,026
• Publication Number:
  US 20110111008A1
• Time in Patent Office: Days
• US Class Current: 424/428
• CPC Class Codes: A61F 2220/0008 Fixation appliances for connecting prostheses to the body
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C12N 2510/02 Cells for production
• CPC Class Codes: C12N 5/0621 Eye cells, e.g. cornea, iris pigmented cells photoreceptors C12N5/062
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a device for delivery of pigment epithelium derived factor (PEDF) to the eye utilizing encapsulated PEDF-secreting cells and related methods for the treatment and prevention of ophthalmic diseases and disorders.

Claims

1. An implantable cell culture device, the device comprising:

a) a core comprising one or more ARPE-19 cells that are genetically engineered to secrete PEDF; and

b) a semipermeable membrane surrounding the core, wherein the membrane permits the diffusion of PEDF therethrough.

2. The device of claim 1, wherein the cells secrete a PEDF variant.

3. The device of claim 2, wherein the PEDF variant comprises the amino acid sequence of SEQ ID NO:

1.

4. The device of claim 2, wherein the PEDF variant is a biologically active fragment of PEDF.

5. The device of claim 1, wherein the core further comprises a matrix disposed within the semipermeable membrane.

6. The device of claim 5, wherein the matrix comprises a hydrogel or extracellular matrix components.

7. The device of claim 6, wherein the hydrogel comprises alginate cross-linked with a multivalent ion.

8. The device of claim 5, wherein the matrix comprises a plurality of monofilaments, wherein said monofilaments are

a) twisted into a yarn or woven into a mesh or

b) twisted into a yarn that is in non-woven strands,

and wherein the cells or tissue are distributed thereon.

9. The device of claim 8, wherein the filamentous cell-supporting matrix comprises a biocompatible material selected from the group consisting of acrylic, polyester, polyethylene, polypropylene polyacetonitrile, polyethylene terephthalate, nylon, polyamides, polyurethanes, polybutester, silk, cotton, chitin, carbon, and biocompatible metals.

10. The device of claim 1, wherein the device further comprises a tether anchor.

11. The device of claim 10, wherein the tether anchor comprises an anchor loop.

12. The device of claim 11, wherein the anchor loop is adapted for anchoring the device to an ocular structure.

13. The device of claim 12, wherein the device is implanted into the eye.

14. The device of claim 13, wherein the device is implanted in the vitreous, the aqueous humor, the Subtenon'"'"'s space, the periocular space, the posterior chamber, or the anterior chamber of the eye.

15. The device of claim 1, wherein the jacket comprises a permselective, immunoisolatory membrane.

16. The device of claim 1, wherein the jacket comprises an ultrafiltration membrane or a microfiltration membrane.

17. The device of claim 1, wherein the jacket comprises a non-porous membrane material.

18. The device of claim 17, wherein the non-porous membrane material is a hydrogel or a polyurethane.

19. The device of claim 1, wherein the device is configured as a hollow fiber or a flat sheet.

20. The device of claim 1, wherein at least one additional biologically active molecule is co-delivered from the device.

21. The device of claim 20, wherein the at least one additional biologically active molecule is from a non-cellular source.

22. The device of claim 20, wherein the at least one additional biologically active molecule is from a cellular source.

23. The device of claim 22, wherein the at least on additional biologically active molecule is produced by one or more genetically engineered ARPE-19 cell in the core.

24. The device of claim 1, wherein the semipermeable membrane has a molecular weight cutoff of from 1 to 1500 kilodaltons.

25. The device of claim 1, wherein the device is a hollow fiber having an outer diameter between 200 and 350 μ

m and a length of between 0.4 mm and 6 mm.

26. The device of claim 25, wherein the hollow fiber is a polyether sulfone hollow fiber.

27. The device of claim 1, wherein the device has a core volume of between 1 and 3 μ

l.

28. The device of claim 1, wherein the device has a core volume of between 0.05 and 0.1 μ

l.

29. The device of claim 1, wherein the capsule contains from 10⁴ to 10⁷ cells.

30. The device of claim 1, wherein the semipermeable membrane is formed from a material selected from the group consisting of polyacrylates (including acrylic copolymers), polyvinylidenes, polyvinyl chloride copolymers, polyurethanes, polystyrenes, polyamides, cellulose acetates, cellulose nitrates, polysulfones (including polyether sulfones), polyphosphazenes, polyacrylonitriles, poly(acrylonitrile/covinyl chloride), and derivatives, copolymers and mixtures thereof.

31. A method for treating an ophthalmic disease or disorder characterized by retinal degeneration, neovascularization fluid accumulation in the eye, or any combination thereof, in a subject in need of such treatment, comprising implanting the implantable cell culture device of claim 1 into the eye of the subject and allowing PEDF to diffuse from the device into the eye, thereby treating the disease or disorder.

32. The method of claim 31, wherein the subject is a human.

33. The method of claim 31, wherein the ophthalmic disease or disorder is age-related macular degeneration, retinitis pigmentosa, diabetic macular edema, or diabetic retinopathy.

34. The method of claim 31, wherein the device is implanted intraocularly or periocularly.

35. The method of claim 31, wherein between 0.1 pg and 1000 μ

g per eye per patient per day of PEDF diffuse into the eye.

36. A method for inhibiting neural or retinal degradation or degeneration in a host comprising implanting the cell culture device of claim 1 into the eye of a host, wherein the device secretes a therapeutically effective amount of PEDF into the eye, thereby allowing PEDF to function as a neurotrophic or neuroprotective agent.

37. The method of claim 36, wherein the device is implanted intraocularly or periocularly.

38. A method of delivering PEDF to a recipient host, comprising implanting the implantable cell culture device of claim 1 into a target region of the recipient host, wherein the encapsulated one or more ARPE-19 cells secrete PEDF at the target region.

39. The method of claim 38, wherein the target region is selected from the group consisting of the central nervous system, including the brain, ventricle, spinal cord, and the aqueous and vitreous humors of the eye.

40. The method of claim 38, wherein between 0.1 pg and 1000 μ

g per patient per day of PEDF diffuses into the target region.

41. A method for inhibiting vasopermeability associated with angiogenesis, retinal disease, or a combination thereof in a host comprising implanting the cell culture device of claim 1 into the eye of a host, wherein the device secretes a therapeutically effective amount of PEDF into the eye, thereby allowing PEDF to inhibit vasopermeability.

42. A method for making the implantable cell culture device of claim 1, comprising

a) genetically engineering at least one ARPE-19 cell to secrete a PEDF polypeptide encoded by the nucleic acid sequence of SEQ ID NO:

2 or SEQ ID NO;

4, and

b) encapsulating said genetically modified ARPE-19 cells within a semipermeable membrane, wherein said membrane allows the diffusion of PEDF therethrough.

43. A method for making the implantable cell culture device of claim 1 comprising

a) genetically engineering at least one ARPE-19 cell to secrete a PEDF polypeptide comprising the amino acid sequence of SEQ ID NO:

1, and

b) encapsulating said genetically modified ARPE-19 cells within a semipermeable membrane, wherein said membrane allows the diffusion of PEDF therethrough.