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| March 2002 | Inside IOVS | Volume 43/3 |
| Basic Advances in Assessing and Treating Ocular Diseases |
Cadherins and Retinoblastoma
Adherens junctions between cells in the normal neuroretina consist of N-cadherin molecules that are linked to the cytoskeleton by the catenins. Immunohistochemically, the N-cadherin/catenin complexes display a regular honeycomb pattern. As reported in Van Aken et al. (p. 595), in retinoblastoma, this immunohistochemical pattern is disturbed, and the link of the N-cadherin/catenin complex with the cytoskeleton is weakened as evidenced by N-cadherin antibody capping. Since N-cadherin is needed for retinoblastoma invasion, as evidenced by inhibition of invasion through neutralizing antibodies, it may offer a novel target for therapy aiming at the restoration of the anti-invasive function of adherens junctions.
Immunosuppression and Limbal Transplantation
Limbal transplantation is a method of replacing damaged corneal epithelial stem cells. Mills et al. (p. 647) describe a new rat model of limbal transplantation to show that isografts do not reject, and the donor epithelial cells survive in recipients long-term. Most allografts however are rejected within 11 days, and donor cells do not survive on the recipient ocular surface long-term even in grafts that appear not to reject. Immunosuppression has a modest effect on clinical graft survival but does not improve donor cell survival. This suggests that limbal allografts require substantial immunosuppression for long-term survival.
Strabismus Immunotoxin Therapy
Christiansen et al. (p. 679) report that ricin-mAb35, a new, muscle-specific immunotoxin, causes long-term, dose-related muscle loss in extraocular muscle. Significant muscle loss was noted 105 days following injection. Myofiber number and muscle cross-sectional area then returned to normal at one year, although pronounced heterogeneity of myofiber size remained. Potent toxins, such as ricin, linked to skeletal muscle-specific monoclonal antibodies, may prove to be valuable in the treatment of strabismus and non-ocular muscle dystonias.
Apoptosis and Tenon’s Fibroblasts
Fibroblast apoptosis heralds the terminal stages of a wound healing response. Single short applications of mitomycin-C as used in glaucoma filtration surgery induce human Tenon’s fibroblast apoptosis in vitro. Crowston et al. (p. 692) demonstrate that mitomycin-C alters apoptosis gene expression in cultured human Tenon’s fibroblasts and primes fibroblasts to the effects of antibodies that ligate the death receptor Fas (CD95). Determining signals that regulate fibroblast apoptosis may help to refine therapeutic strategies for switching off the subconjunctival healing response and optimizing postoperative intraocular pressure control.
Latanoprost and MMP Transcription
Treatment with the glaucoma medication latanoprost increases matrix metalloproteinase (MMP) protein in ciliary muscle cells. To determine if this response reflects alteration of MMP gene transcription, Weinreb and Lindsey (p. 716) exposed human ciliary smooth muscle cell to latanoprost acid for 4 to 24 hours and then measured MMP-1, MMP-2, MMP-3, and MMP-9 mRNA from the cells using real time polymerase chain reaction. In general, MMP-1 gene transcription was increased in a dose and time-dependent manner by latanoprost. Transcription of the genes for MMP-3 and MMP-9 also were increased, however, transcription of the MMP-2 gene was decreased by latanoprost treatment. These results suggest that alteration of MMP gene transcription is involved in the response of ciliary muscle cells to latanoprost.
Laser Doppler Flowmetry
Laser Doppler flowmetry (LDF) allows the assessment of capillary blood flow in many tissues, including the choroid. Varying optical scattering properties within the tissue are an incommodious source of unduly erratic measurements with this technology. Gugleta et al. (p. 723) characterized the optical scattering properties within the tissue by calculating the quotient between the intensity of the returning light and the signal amplification used during the recordings. Correcting for this parameter markedly improved the reliability of the measurements, without affecting the sensitivity to blood flow changes.
IL-6 and Corneal Infection
Interleukin-6 is a well known early warning cytokine associated with virus-induced corneal inflammation but its precise function in this response is unknown. Fenton et al. (p. 737), using mice with a disrupted IL-6 gene, demonstrated that IL-6 induces resident corneal cells to produce chemoattractants, which in turn recruit neutrophils to the virus infected site. Thus, IL-6, or its receptor, constitutes a potential target for downregulating a too exuberant ocular inflammatory response.
NF-kB and Uveitis
Many inflammatory mediators, such as TNF-α, IL-1β, IL-6, and inducible nitric oxide synthase (iNOS), require NF-κB activation for their expression. Ohta et al. (p. 744) have demonstrated an activation of NF-κB in the iris-ciliary body (ICB) in endotoxin-induced uveitis. Treatment with PDTC, an antioxidant NF-κB inhibitor, decreased the gene expression of this proinflammatory cytokine in the ICB as detected by decreased protein levels in the aqueous humor. This led to an attenuation of ocular inflammation as characterized by decreased protein extravasation and cellular infiltration into the anterior chamber. These results demonstrated clearly that in vivo suppression of NF-κB can attenuate inflammation in the ICB.
Corneal Gene Therapy
Gene delivery into corneal endothelial cells offers potential treatment for genetic and degenerative diseases of cornea as well as graft rejection. For these purposes, most of endothelial cells need to be transduced and the expression of transduced gene needs to be stable and, preferably, inducible for certain purposes. In this report, Tsai et al. (p. 751) injected recombinant adeno-associated virus vector encoding lacZ gene into anterior chamber and then induced inflammation by an intravitreal injection of lipopolysaccharide. A tight correlation was found between inflammation and transgene expression. Moreover, the lacZ gene remained inducible in these cells for at least 60 days.
Posterior Segment Drug Delivery
Topical drug delivery targeting the posterior segment of the eye remains a significant hurdle because of perceived problems with ocular retention and permeability. However, Koevary et al. (p. 797) show that insulin, with a molecular weight of nearly 6000, accumulates in the retina and optic nerve following topical administration. These authors are ultimately interested in determining whether such treatment can influence the course of diabetic retinopathy. However, their study has broader implications because it suggests that other topically applied drugs of equally large size could be used to therapeutically target retinal structures not only in diabetes, but other conditions as well.
PEDF and Ischemic Retinopathy
Much research has been performed on stimulators of retinal neovascularization (NV), in particular, vascular endothelial growth factor (VEGF). Relatively little attention has been focused on potential inhibitors of retinal NV. Pigment epithelium-derived factor (PEDF) is a protein initially isolated from cultured retinal pigment epithelial (RPE) cells. PEDF has been studied extensively for its neurotrophic and neuroprotective properties and was recently found to have anti-angiogenic effects as well. Duh et al. (p. 821) demonstrate that intravitreal injection of PEDF protein dramatically suppresses neovascularization in a mouse model of ischemic retinopathy. In addition, PEDF suppresses VEGF stimulation of cultured retinal capillary endothelial cells. PEDF therefore could be used as a therapeutic modality for the treatment of ischemic retinopathies.
Drug Targeting for CNV
Age-related macular degeneration is resistant to current pharmaceutical therapies. One possibility to facilitate drug efficacy might be drug targeting using water-soluble polymers, which tend to accumulate and retain in a tissue with newly formed vasculature and immature lymph system such as choroidal neovascular membrane (CNVM). Drug combined with such polymers alters its pharmacokinetics according to that of large molecule. Yasukawa et al. (p. 842) designed a novel drug targeting system for a bioactive protein. The combination of interferon beta (IFNb) with dextran binding metal-chelating residues enabled IFNb to prolong circulating time in the blood, accumulate in experimental CNVM in rabbits, and inhibit the progression of CNVM.
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