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| July 2007 | Inside IOVS | Volume 48/7 |
Rapid Decrease in Hyaluronan during Myopia Development
During the development of lens-induced myopia in mammals, selective remodeling of the sclera occurs, increasing the "creep rate" and causing the eye to elongate. Moring et al. (p. 2947) have found that levels of hyaluronan (HA) in the sclera drop within a day after the start of minus-lens wear. HA levels return to normal within a day after the lens is removed. Interacting with aggrecan and water, HA may reduce the ability of the layers of the sclera to slip across each other. Loss of HA may contribute to the increased scleral creep rate and the axial myopia.
Choroidal Regulation of Ocular Growth
Many clinical and experimental studies over the past 30 years suggest the presence of a locally controlled (i.e., within the eye) and vision-dependent mechanism which regulates postnatal ocular growth in order to minimize refractive error. Summers Rada and Palmer (p. 2957) report that the choroid produces suprachoroidal fluid which can regulate the rate of scleral glycosaminoglycan synthesis in a bi-directional manner, depending on the ocular growth state. Changes in choroidal permeability may represent a mechanism for controlling the delivery of bioactive factors to the sclera to regulate the rate of glycosaminoglycan synthesis, ocular elongation, and the refractive state of the eye.
Corneal Endothelial Cell Proliferation following Lentiviral Vector Transduction
Human corneal endothelial cells (CECs) act as the main "barrier and pump" to allow for corneal transparency. Corneal edema arises from loss of endothelial cells as they do not proliferate in vivo. Prior studies have shown the proliferative capacity of human CECs in vitro. Suh et al. (p. 3056) examine the viability of cryopreserving primary cultured human CECs and their ability to be genetically modified by the lentiviral vector, equine infectious anemia virus (EIAV). Their work shows that after cryopreservation, human CECs retain their phenotypic properties and are able to be genetically transduced with EIAV. These genetically modified cells can be selected to nearly pure populations with FACS sorting. The ability to store, genetically modify, and FACS sort these cells to pure populations has great potential for future therapeutic application of these cells for corneal endothelial disorders.
Some Eye Muscle Fibers Don’t Turn the Eye
Do all extraocular muscle fibers rotate the eye? Lim et al. (p. 3089) traced rectus muscle cell bundles in monkeys and humans from deep in the orbit anteriorly toward the eyeball. While nearly all fibers in the global layers of each muscle connected to the eyeball via classical large tendons, nearly all fibers in the orbital layers inserted on the connective tissues of the pulleys via small, short tendons. Fibers did not cross layer boundaries to insert on other fibers. This supports division of labor in extraocular muscles: orbital fibers rotate the eye, and global fibers shift the pulleys to influence direction of muscle action.
Increasing Soluble TNF Receptors and TNF-a in Uveitis
TNF-a has an important role in the etiology of ocular inflammation. Soluble tumor necrosis factor receptors (sTNF-Rs) have biological activities against TNF-a. Sugita et al. (p. 3246) provide evidence that sTNF-Rs are present in the ocular fluids of uveitis patients. Intraocular levels of sTNF-Rs are significantly increased in uveitis patients, particularly in those with active uveitis. And, significantly higher amounts of TNF-a were present in the ocular fluids of patients with active uveitis than in those with inactive uveitis. Intraocular sTNF-Rs may play a regulatory role in ocular inflammation such as is seen in uveitis.
Adaptive Optics Imaging of Cones in Retinal Degenerations
Retinal degenerations are characterized by progressive death of photoreceptors, which cannot be easily visualized in living eyes. Adaptive optics permit high resolution images of macular cones. Duncan et al. (p. 3283) studied cones near the fovea with adaptive optics scanning laser ophthalmoscopy (AOSLO) in patients with retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). Cone spacing was significantly increased and correlated significantly with measures of cone function in patients with RP and CRD. This in vivo imaging of cone structure in patients with mutations in rhodopsin and RPGR-ORF15 demonstrates that AOSLO imaging may advance understanding of cone loss in retinal degeneration patients.
Experimental Chimeras Demonstrate the Intrinsic Role of Pax6 in Eye Development
One "master control" gene for eye development, Pax6, is vital for early inductive events and is thought to play a critical role in neuronal development in the retina. Li et al. (p. 3292) used an experimental mouse chimera model to determine the potential of Pax6-null cells when early inductive events proceed normally. However, even in this normal developmental environment, the Pax6 mutant retinal progenitor cells die around the time of birth. In addition, Pax6 is required for the development of lens and corneal epithelium and retinal pigment epithelium. Therefore, the Pax6 gene is an intrinsic factor that is critically required for many cell types during eye development.
Absence of Caspase-8 Makes RPE Cells Resistant to Apoptosis
In most cells, when TNF receptors are engaged, caspase-8 is cleaved, causing extrinsic apoptotic pathway activation. However, retinal pigment epithelial (RPE) cells are resistant to TNF-mediated apoptosis, even when NF-kB, a transcription factor that up-regulates anti-apoptotic proteins, is blocked. Yang et al. (p. 3341) found that human RPE cell caspase-8 mRNA and protein levels are very low compared to levels in other non-neoplastic ocular cells and in cancer cells. Adenoviral-mediated RPE cell caspase-8 transduction induced RPE apoptosis. The authors conclude that low caspase-8 levels may protect RPE cells from apoptosis normally and in diseases such as age-related macular degeneration (AMD), and may promote pathological cell survival in proliferative vitreoretinopathy (PVR).
Photoreceptor Protection with bFGF-Impregnated Nanoparticles
Basic fibroblast growth factor (bFGF) has well documented protective neurotrophic activity in rats with photoreceptor degeneration. Sakai et al. (p. 3381) produced nanoparticles (NPs) for bFGF delivery and evaluated these effects in Royal College of Surgeons (RCS) rats. The authors show that intravitreally injected bFGF-NPs prevent photoreceptor degeneration by inhibiting apoptosis in the RCS rat retina due to targeting and sustained release of bFGF. Photoreceptor protection with nanotechnology could be a useful strategy to produce a prolonged protective effect in photoreceptor degeneration.
A Complementary Approach Expands the Potential for Ocular Gene Therapy
Single-stranded AAV (ssAAV) vectors depend upon host cells for second-strand synthesis, which is required for transgene expression. The efficiency of this rate-limiting step varies considerably among cell types. Yokoi et al. (p. 3324) show that self-complementary AAV (scAAV) vectors, which do not require second-strand synthesis, induce more rapid and higher level transgene expression in the retina than ssAAV vectors. This eliminates the latent period that prevents the use of AAV vectors in some disease models and allows for higher expression with lower vector doses, particularly in photoreceptors. After intravitreous injection of scAAV vectors, many more cells deep within the retina show robust transgene expression, which may expand the applications for intravitreous injections and reduce the need for subretinal injections, a major benefit for clinical use.
Aberrant Signaling by Surviving Neurons in Retinal Degenerations
Marc et al. (p. 3364) show that classical retinal degenerations such as retinitis pigmentosa are also progressive neurodegenerations in which photoreceptor stress and death trigger dysfunctional alterations in surviving retinal neurons. The authors exploit molecular imaging to document losses of key signaling pathways in survivor bipolar cells and visualize the concurrent emergence of aberrant endogenous signaling. Importantly, focal survival of even highly altered cones can prevent some aspects of remodeling. Neural reprogramming will likely impact the outcome of every proposed therapeutic intervention for retinitis pigmentosa, including prosthetic retinal implants, stem cell transplants, growth factor treatments, and gene therapy.
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