USE OF ENCAPSULATED CELL THERAPY FOR TREATMENT OF OPHTHALMIC DISORDERS
Described herein are methods and devices for the long term treatment of ophthalmic disorders. Also disclosed are encapsulated cell therapy (ECT) devices that secrete a biologically active molecule and methods for using the same for the treatment of various kinds of ophthalmic disorders, including retinitis pigmentosa, geographic atrophy (dry age-related macular degeneration), glaucoma and/or macular telangiectasia.
1 . A method of treating an ophthalmic disorder in a patient suffering therefrom comprising: implanting into an eye of the patient a biocompatible capsule comprising
a) a core comprising a cellular source of a biologically active molecule and
b) a semi-permeable membrane surrounding the core, wherein the membrane permits the diffusion of the biologically active molecule therethrough;
wherein the ophthalmic disorder is characterized by aberrant angiogenesis, inflammation, retinal degeneration, or any combination thereof, and wherein said biocompatible device produces therapeutically effective amounts of the biologically active molecule for at least 12 months post implantation.
2 . The method of claim 1 , wherein the biocompatible device produces therapeutically effective amounts of the biologically active molecules for at least 2 years post implant.
3 . The method of claim 1 , wherein the cellular source of the biologically active molecules is between 0.5-1×106 ARPE-19 cells that are genetically engineered to secrete the biologically active molecule.
4 . The method of claim 3 , wherein the ophthalmic disorder is glaucoma.
5 . The method of claim 3 , wherein the ophthalmic disorder is retinitis pigmentosa (RP).
6 . The method of claim 3 , wherein the ophthalmic disorder is geographic atrophy or age related macular degeneration (AMD).
7 . The method of claim 3 , wherein the ophthalmic disorder is macular telangiectasia.
8 . The method of claim 4 , wherein said treating improves optic nerve regeneration, preserves or improves visual field sensitivity, contrast sensitivity, Garway-Heath total deviation, preserves or improves the ganglion cell complex and/or the thickness of the outer retinal layer, preserves or improves the retinal fiber layer, or any combinations thereof.
9 . The method of claim 8 , wherein the preservation or improvement of visual field sensitivity or contrast sensitivity corresponds with the preservation or improvement of the anatomical structure of the retina.
10 . The method of claim 5 , wherein said treating improves visual acuity, increases macular volume, increases retinal thickness, or any combinations thereof.
11 . The method of claim 6 , wherein said treating stabilizes vision loss in a subject, decreases loss of best corrected visual acuity, decreases geographic atrophy, or any combinations thereof.
12 . The method of claim 6 , wherein said treating increases best corrected visual acuity.
13 . The method of claim 1 , wherein said capsule is configured as a hollow fiber.
14 . The method of claim 1 , wherein said device is implanted in the vitreous, in the aqueous humor, in the periocular space, in the anterior chamber, in the posterior chamber, or in the Subtenon' s space.
15 . The method of claim 1 , wherein the core further comprises a matrix disposed within the semipermeable membrane.
16 . The method of claim 15 , 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 are distributed thereon.
17 . The method of claim 16 , wherein the monofilaments comprise a biocompatible material selected from the group consisting of acrylic, polyester polyethylene, polypropylene, polyacrylonitrile, polyethylene terephthalate, nylon, polyamides, polyurethanes, polybutester, silk cotton, chitin, carbon, and biocompatible metals.
18 . The method of claim 17 , wherein the monofilaments comprise polyethylene terephthalate (PET) fibers that comprise between 40-85% of the internal volume of the device.
19 . The method of claim 1 , wherein the biologically active molecule is a cytokine.
20 . The method of claim 19 , wherein said cytokine is selected from the group consisting of CNTF, BDNF, TGF-˜, GDNF, NGF, bFGF, aFGF, IL-I˜, IL-10, IFN-˜, IFN-a, and VEGF inhibitors.
21 . The method of claim 20 , wherein the cytokine is CNTF.
22 . The method of claim 21 , wherein the therapeutically effective amount of CNTF is between 50 pg/eye/day and 500 ng/eye/day.
23 . The method of claim 22 , wherein the therapeutically effective amount of CNTF is 0.1 ng/eye/day and 50 ng/eye/day.
24 . An implantable cell culture device, the device comprising:
a) a core comprising a cellular source of a biologically active molecule;
b) a semi-permeable membrane surrounding the core, wherein the membrane permits the diffusion of the biologically active molecule therethrough;
wherein the device secretes between 0.1 and 20 ng/day of the biologically active molecule upon implantation; and
wherein secretion of the biologically active molecule at therapeutically effective levels is maintained for at least two years post-implantation.
25 . The device of claim 24 , wherein the cellular source of the biologically active molecules is between 0.5-1×106 ARPE-19 cells that are genetically engineered to secrete the biologically active molecule.
26 . The device of claim 25 , wherein said biologically active molecule is CNTF.
27 . The device of claim 26 , wherein the device secretes between 0.1 and 20 ng/day of CNTF upon implantation and between 0.1-0.4 ng/day of CNTF at explant following implantation for at least two years.
28 . The device of claim 26 , wherein the device secretes between 0.1 and 20 ng/day of CNTF upon implantation and between 0.6-2.8 ng/day of CNTF following implantation for at least two years.
29 . The device of claim 26 , wherein the core further comprises a matrix disposed within the semi-permeable membrane.
30 . The device of claim 29 , 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 stands, and wherein the cells are distributed thereon.
31 . The device of claim 30 , wherein the monofilaments comprise 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.
32 . The device of claim 31 , wherein the monofilaments comprise polyethylene terephthalate (PET) fibers that comprises between 40-85% of internal volume of the device.
33 . The device of claim 24 , wherein the device further comprises a tether anchor.
34 . The device of claim 33 , wherein the tether anchor comprises an anchor loop.
35 . The device of claim 34 , wherein the anchor loop is adapted for anchoring the device to an ocular structure.
36 . The device of claim 24 , 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.
37 . The device of claim 24 , wherein the semi-permeable membrane comprises a permselective, immunoprotective membrane.
38 . The device of claim 24 , wherein the semi-permeable membrane comprises an ultrafiltration membrane or a microfiltration membrane.
39 . The device of claim 37 , wherein the semi-permeable membrane has a median pore size of 100 nm.
40 . The device of claim 24 , wherein the semi-permeable membrane comprises a non-porous membrane material.
41 . The device of claim 40 , wherein the non-porous membrane material is a hydrogel or a polyurethane.
42 . The device of claim 24 , wherein the nominal molecular weight cut off (MWCO) of the semi-permeable membrane is 500 kD.
43 . The device of claim 24 , wherein the semi-permeable membrane is between 90-120 μm thick.
44 . The device of claim 24 , wherein the capsule is configured as a hollow fiber or a flat sheet.
45 . The device of claim 24 , wherein the length of the device is between 4 mm-11 mm.
46 . The device of claim 24 , wherein the device has an internal diameter of between 0.9 mm-1.2 mm.
47 . The device of claim 24 , wherein the ends of the device are sealed using methyl methacrylate.
48 . The device of claim 24 , wherein at least one additional biologically active molecule is codelivered from the device.
49 . The device of claim 24 , wherein the at least one additional biologically active molecule is from a non-cellular source.
50 . The device of claim 24 , wherein the at least one additional biologically active molecule is from a cellular source.
51 . The device of claim 50 , wherein the at least one additional biologically active molecule is produced by one or more genetically engineered ARPE-19 cells in the core.
52 . The device of claim 24 , further comprising two or more additional characteristics selected from the group consisting of:
a) the core comprises between 0.5-1.0×106 ARPE-19 cells;
b) length of the device is between 4 mm-11 mm;
c) the internal diameter of the device is between 0.9 mm-1.2 mm;
d) the ends of the device are sealed using methyl methacrylate;
e) the semi-permeable membrane has a median pore size of about 100 nm;
f) the nominal molecular weight cut off (MWCO) of the semi-permeable membrane is 500 KD;
g) the semi-permeable membrane is between 90-120 μm thick;
h) core comprises an internal scaffold, wherein the scaffold comprises polyethylene terephthalate (PET) fibers that comprises between 40-85% of internal volume of the device; and
i) combinations thereof.
53 . The device of claim 52 , wherein the device comprises 3, 4, 5, 6, 7, or all of additional characteristics a)-i).
54 . The device of claim 38 , wherein the semi-permeable membrane has a median pore size of 100 nm.
55 . A method for making the ophthalmic biocompatible device of claim 25 , comprising:
a) genetically engineering at least one ARPE-19 cell to secrete a cytokine, and
b) encapsulating said genetically engineered ARPE-19 cell within a semipermeable membrane, wherein said membrane allows the diffusion of the cytokine therethrough.