Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2001-06-12
2003-02-11
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C435S001100
Reexamination Certificate
active
06517833
ABSTRACT:
BACKGROUND OF THE INVENTION
Macular degeneration is a disease of the retina which affects over thirteen million people in the United States and is characterized by loss of central vision due to the loss of photoreceptors in the central part of the retina, the macula lutea. D'Amico et al. (1994)
New England J. Med.
331:95-106 and Kliffen et al. (1997)
Microscopy Res
. &
Techniq.
36:106-122. The macula is the most important part of the eye for high resolution vision because there is a greater concentration of cone type photoreceptors which are responsible for color vision and visual acuity.
Photoreceptor cells, especially rod cells, renew their outer segments at a high rate. Thus, as new lamellae discs are formed and added to the photoreceptor cells, the older lamellae discs at the tip are discarded. Retinal pigment epithelial (RPE) cells function to provide support for the retinal photoreceptors and are responsible for the metabolic digestion of the discarded outer segments of the neural retina. Thus, RPE cells are responsible for the phagocytosis and digestion of the discarded discs at a turn over rate of approximately 30-100 discs each day. Underlying the RPE cells is the choriocapillaris which contains the vasculature to provide nutrients and remove metabolic by-products from the retina.
In macular degeneration, the RPE cells are dysfunctional, thereby leading to a build up of metabolic by-products, including discarded discs in the retina. The presence of metabolic debris and excess fluid in the retina damage photoreceptor cells, thereby compromising visual acuity. Cingle et al. (1996)
Curr. Eye. Res.
15:433-438 and Curcio et al. (1996)
Invest. Ophthal
. &
Vis. Sci.
37:1236-1249. In addition, the degeneration of the RPE layer is also reflected by ensuing atrophy of the choriocapillaris.
In the dry form of macular degeneration, loss of vision is gradual and is associated with retinal pigment changes, deposits in the subretinal space called drusen, atrophy of the blood vessels supplying the retina and ultimately geographic atrophy in the absence of neovascularization. Although this form of macular degeneration has a slower progression to blindness, it is far more common, accounting for approximately 90% of the cases of acute macular degeneration. In the wet form of the disease, vessels arise from the choriocapillaris and penetrate Bruch's membrane and the RPE cell layer to impinge upon the neural retina where they cause damage that leads to loss of central vision. Patients with the wet form of the disease are at high risk for subretinal neovascularization, geographic atrophy and retinal pigment epithelial detachment, all of which result in a rapid and severe loss of visional acuity.
Currently, there are few therapeutic alternatives for patients diagnosed with macular degeneration. Laser photocoagulation has been used for some cases of the wet form of the disease, but the clinical experience with this therapy has not been promising. If the retinal damage is close to the fovea, laser therapy is withheld to avoid potential loss of central photoreceptors. Lambert et al. (1992)
Am. J. Ophthalmol.
113:257-262. In addition, radiation and photodynamic therapy has been performed for cases where neovascularization is diffuse or too severe. Although follow-up data showed an advantage of laser photocoagulation, reoccurrence of neovascularization occurred in over half of the patients, thereby undermining the initial benefit of the treatment. Macular Photocoagulation Study Group (1993)
Arch. Ophthalmol.
111:1200-1209.
Opthalmic surgery can also be performed to remove neovascularization in the wet form of macular degeneration. Although this surgery has been reported to reduce the progression of the disease, restoration of visual acuity is limited.
The other competitive approach to treating macular degeneration is surgical implantation of human RPE cells. Although early clinical analysis has been promising, broader clinical application of human transplants to patients with macular degeneration will be extremely limited by the availability of human donors. Thus, a need exists for alternative sources of retinal cells and methods of retinal transplantation which can minimize the damage caused by retinal disorders such as macular degeneration.
SUMMARY OF THE INVENTION
The instant invention pertains to an isolated retinal cell or an isolated population of retinal cells suitable for transplantation into an allogeneic or xenogeneic subject, particularly a human subject. The retinal cells of the invention include neural retinal cells (e.g., rod or cone photoreceptor cells), retinal pigment epithelial (RPE) cells, iris epithelial cells and retinal stem cells (e.g., retinal progenitor cells). Thus, one aspect of the invention pertains to a transplantable composition for use in a subject comprising a retinal cell (e.g., a neural retina cell, RPE cell or iris epithelial cell) obtained from a pig, e.g., a fetal pig.
The porcine retinal cells of the invention include porcine neural retinal cells, retinal pigment epithelial (RPE) cells, iris epithelial cells and their precursors. Typically, these retinal cells are obtained from fetal pigs during selected stages of gestational development. For example, it has been determined that fetal retinal cells obtained from a fetal pig between about days 30 and 100, more preferably about days 40 and 90, and still more preferably about days 50 and 80, and yet more preferably about days 60 and 70, and most preferably about day 60-65 of gestation are suitable for transplantation into xenogeneic subjects, particularly human subjects.
Another aspect of the invention pertains to a porcine retinal cell or a population of retinal cells which are obtained from a pig predetermined to be free from at least two organisms which originate in pigs and which are capable of transmitting infection or disease to a xenogeneic recipient, e.g., a human, of the cells.
Categories of organisms from which the cells are free can include zoonotic, cross-placental, neurotropic, and/or ocular-infecting organisms. Within each of these categories, the organism can be a parasite, bacteria, mycoplasma, and/or a virus. In one embodiment, the retinal cells are free of one or more of the following organisms found in pigs: Toxoplasma, eperythrozoon, brucella, listeria, mycobacterium TB, leptospirillum, hemophilus suis, M. Hypopneumonia, porcine respiratory reproductive syndrome, rabies, pseudorabies, parvovirus, encephalomyocarditis virus, swine vesicular disease, teschen (Porcine polio virus), hemagglutinating encephalomyocarditis, suipoxvirus, swine influenza type A, adenovirus, transmissible gastroenteritis virus, bovine viral diarrhea, and vesicular stomatitis virus.
In another aspect of the invention, the retinal cell, in unmodified form, has at least one antigen on the cell surface which is capable of stimulating an immune response against the cell in a xenogeneic subject, for example, a human. The antigen on the surface of the retinal cell is altered to inhibit rejection of the cell when introduced into a xenogeneic subject. In one embodiment, the cell surface antigen which is altered is an MHC class I antigen. This MHC class I antigen can be contacted, prior to transplantation into a xenogeneic subject with at least one anti-MHC class I antibody, or a fragment or derivative thereof, which binds to the MHC class I antigen on the cell surface but does not activate complement or induce lysis of the cell. One example of an anti-MHC class I antibody is an anti-MHC class I F(ab′)
2
fragment, such as an anti-MHC class I F(ab′)
2
fragment of a monoclonal antibody PT85. The retinal cells can further be screened as described above such that the cells are isolated from a pig predetermined to be essentially free of organisms which are capable of being transmitted to a xenogeneic subject, e.g., a human subject.
Another aspect of the invention features a composition comprising a porcine retinal cell, e.g., a porcine neural retina cell, RPE cell or iris epithelial cell, and
CeConti, Jr., Esq. Giulio A.
Diacrin, Inc.
Lahive & Cockfield LLP
Williams, Esq. Megan E.
Witz Jean C.
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