Gene therapy for proliferative vitreoretinopathy

#This invention relates to gene therapy for treating ocular disorders involving intraocular cellular proliferation, such as, for example, proliferative vitreoretinopathy or PVR. More particularly, this invention relates to the treatment of ocular disorders associated with intraocular cellular proliferation, such as proliferative vitreoretinopathy, by transducing replicating ocular cells with a polynucleotide encoding an agent which is capable of providing for the inhibition, prevention, or destruction of the growth of the replicating ocular cells. The agent may be a negative selective marker, such as, for example, a viral thymidine kinase. Such transduction then may be followed by the administration of an interaction agent, such as, for example, ganciclovir or acyclovir, thereby killing the replicating ocular cells.

#One of the most common causes of retinal detachment is proliferative vitreoretinopathy, an intraocular, non-malignant cellular proliferation. This process results ultimately in a separation of the retina from the retinal pigment epithelium, or RPE, because of tractional forces applied directly to the inner and outer retinal surfaces. This is the major cause for failure of retinal re-attachment surgery. (Ophthalmology, Vol. 90, pgs. 121-123 (1983)).

#Proliferative vitreoretinopathy is characterized by the formation of contractile cellular membranes on both sides of the retina. (Clarkson, et al., Am. J. Ophthalmol., Vol. 84, pgs. 1-17 (1977); Constable, Trans. Ophthalmol. Soc. U.K., Vol. 95, pgs. 382-386 (1975); Constable, et al., Retina Congress, Pruett, et al., eds., pgs. 245-257, Appleton-Century-Crofts, New York (1972); Daicker, et al., Graefe's Arch. Klin. Exp. Ophthalmol., Vol. 210, pgs. 109-120 (1979); Fastenberg, et al., Am. J. Ophthalmol., Vol. 93, pgs. 565-572 (1982); Glaser, et al., Ophthalmology, Vol 94, pgs. 327-332 (1987); Green, et al., Trans. Ophthalmol. Soc. U.K., Vol. 99, pgs. 63-77 (1979); Kampik, et al., Arch. Ophthalmol., Vol. 99, pgs. 1445-1454 (1981); Machemer, et al., Am. J. Ophthalmol., Vol. 85, pgs. 181-191 (1978)). While the pathobiology of proliferative vitreoretinopathy is not clear, it appears that RPE cells are key to the development of these membranes. (Green, et al., 1979; Kampik, et al., 1981; Machemer, et al., 1978; Laqua, et al., Am. J. Ophthalmol., Vol. 80, pgs. 602-618 (1975); Hiscott, et al., Br. J. Ophthalmol., Vol. 68, pgs. 708-715 (1984)). A large body of evidence supports the concept that previously quiescent RPE cells, when displaced into the vitreous cavity and exposed to the appropriate combination of cytokines, will divide and differentiate. This differentiation results in cells having myofibroblastic characteristics including adhesiveness and contractility. As these membranes form tight adhesions with the retinal surfaces, tractional forces are generated and detachment ensues.

#The invention now will be described with respect to the drawings, wherein:

#FIG. 1 is a graph depicting the transduction efficiency of the G1BgSvNa retroviral vector in the presence of varying concentrations of vitreous from the eyes of rabbits;

#FIG. 2A is a graph of the number of cells in cultures having various proportions of HSV-tk positive and HSV-tk negative rabbit dermal fibroblasts three days after exposure to ganciclovir;

#In accordance with an aspect of the present invention, there is provided a method of treating an ocular disorder involving intraocular cellular proliferation. The method comprises transfecting replicating ocular cells in a host in vivo with a polynucleotide encoding an agent which is capable of providing for the inhibition, prevention, or destruction of the growth of the replicating ocular cells upon expression of the polynucleotide encoding the agent.

#The term “polynucleotide” as used herein means a polymeric form of nucleotide of any length, and includes ribonucleotides and deoxyribonucleotides. Such term also includes single- and double-stranded DNA, as well as single- and double-stranded RNA. The term also includes modified polynucleotides such as methylated or capped polynucleotides.

#The polynucleotide encoding the agent which is capable of providing for the inhibition, prevention, or destruction of the growth of the replicating ocular cells may be contained within an appropriate expression vehicle which is transduced into the replicating ocular cells. Such expression vectors include, but are not limited to, eukaryotic vectors, prokaryotic vectors (such as, for example, bacterial vectors), and viral vectors.