Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and dose-limiting toxicities of a single intravitreal (IVT) injection of PF-04523655, a 19-nucleotide, O-methyl stabilized, double-stranded small interfering ribonucleic acid targeting the RTP801 gene in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, phase 1, clinical multicentre trial, enrolled 27 patients with neovascular AMD unresponsive to prior treatment and best corrected visual acuity (BCVA) ≤ 20/200 in the study eye in stratum 1: (dose-escalating, open-label: 50 to 3000 µg of PF-04523655) and 27 patients who had potential to benefit from therapy and BCVA of ≤ 20/100 and ≥ 20/800 in stratum 2 (parallel, masked study of 1000, 1500, 2250, and 3000 µg of PF-04523655). The primary outcome was safety and tolerability assessment as well as pharmacokinetic profiling following a single IVT injection of PF-04523655. RESULTS: Doses of PF-04523655 ≥ 400 µg were generally detectable in the plasma at 1, 4, and 24 h post-injection. And all doses were below the lowest level of quantification by day 14. A single IVT injection of 50 to 3000 µg of PF-045237655 was generally safe and well tolerated over 24 months. There were no dose-limiting toxicities. CONCLUSION: A single IVT injection of PF-0523655 ≤ 3000 µg seems safe and well tolerated in eyes with neovascular AMD.

Material properties of the cornea and sclera: a modelling approach to test experimental analysis.

Material properties of cornea and sclera are important for maintaining the shape of the eye and the requisite surface curvatures for optics. They also need to withstand the forces of external and internal musculature and fluctuations in intraocular pressure (IOP). These properties are difficult to measure and variable results have been reported. A previously published experimental procedure, from which the material properties of the eyeball coats were obtained, has been modelled in this paper using Finite Element Analysis, in order to test the accuracy of the experiment. Material parameters were calculated from the model and the resulting relationships between stress and strain for the cornea and sclera compared to their experimentally obtained counterparts. The comparison between model and experiment was close for the sclera but more varied for the cornea. The pressure vessel model can be applied for measuring the material properties of the sclera but is less accurate for the cornea.

The stress on the anterior lens surface during human in vivo accommodation.

PURPOSE: To determine the qualitative change in stress on the lens capsule during in vivo human accommodation. METHODS: Nine subjects (mean age: 30 years; range: 25-38 years) were studied, each of whom had undergone a phakic refractive intraocular lens (PRL) surgical procedure. The change, during accommodation, of stress on the surface of the anterior lens capsule (ALS) was determined by employing high-resolution anterior segment optical coherence tomography (OCT). This was done by comparing the ratio of the intensity of the image from the anterior surface of the natural lens (ALS) to the images of the anterior corneal surface (ACS), posterior corneal surface (PCS) and the posterior surface of the phakic refractive intraocular lens (PPRLS) before and during accommodation. RESULTS: The intensities of the OCT images of the ACS and PPRLS did not significantly change during accommodation when compared with their respective baselines, while the intensity ratios: ALS/ACS, ALS/PCS and ALS/PPRLS all significantly increased during accommodation (p<0.01). CONCLUSIONS: The stress on the anterior lens capsule is increased during in vivo human accommodation. This observation is consistent with a mechanism of accommodation in which zonular tension increases with accommodation, which is opposite to the predictions of the Helmholtz theory.

Topographical changes of biconvex objects during equatorial traction: an analogy for accommodation of the human lens.

AIM: To assess and compare the changes in shape of encapsulated biconvex structures undergoing equatorial traction with those changes reported in the human lens during accommodation. METHODS: Equatorial traction was applied to several different biconvex structures: air, water, and gel filled mylar and rubber balloons and spherical vesicles. In the vesicles, traction was applied externally, using optical tweezers, or from within, by the assembly of encapsulated microtubules. The shape changes were recorded photographically and the change in central radius of curvature of water filled mylar balloons was quantified. RESULTS: Whenever an outward equatorial force was applied to the long axis of long oval biconvex objects, where the minor to major axis ratio was

Sensitivity study of human crystalline lens accommodation.

A nonlinear axisymmetric finite element method (FEM) analysis was employed to determine the critical geometric and material properties that affect human accommodation. In this model, commencing at zero, zonular traction on all lens profiles resulted in central lenticular surface steepening and peripheral surface flattening, with a simultaneous increase in central lens thickness and central optical power. An age-related decline in maximum zonular tension appears to be the most likely etiology for the decrease in accommodative amplitude with age.

The effect of changing intraocular pressure on the corneal and scleral curvatures in the fresh porcine eye.

AIM: To measure corneal and scleral radii of curvature in response to intraocular pressure (IOP). METHODS: Using digital photographic profile images of 16 fresh porcine eyes, the curvatures of the cornea and sclera were determined in response to five consecutive incremental 100 mul saline intravitreal injections. IOP was measured and ocular rigidity calculated. Elastic moduli of the cornea and sclera were estimated. RESULTS: Intraocular pressure and the radius of curvature of the sclera increased linearly with increasing volume. There was no statistical change in corneal curvature. The elasticity of the cornea and sclera was constant during the 15-50 mm Hg increase in IOP. The estimated range of the elastic moduli of the cornea and sclera were, respectively 0.07-0.29 MPa and 0.2 MPa to 0.5 MPa. The scleral rigidity ranged from 0.0017 to 0.0022. CONCLUSIONS: The elastic moduli of the cornea and sclera are independent of IOP. The modulus of elasticity of the sclera is higher than that of the cornea. Elevation of IOP changes the curvature of the sclera but not that of the cornea. Porcine scleral rigidity is similar to human scleral rigidity. Scleral curvature could be a novel method for measuring IOP.

Insights into the age-related decline in the amplitude of accommodation of the human lens using a non-linear finite-element model.

AIM: To understand the effect of the geometric and material properties of the lens on the age-related decline in accommodative amplitude. METHODS: Using a non-linear finite-element model, a parametric assessment was carried out to determine the effect of stiffness of the cortex, nucleus, capsule and zonules, and that of thickness of the capsule and lens, on the change in central optical power (COP) associated with zonular traction. Convergence was required for all solutions. RESULTS: Increasing either capsular stiffness or capsular thickness was associated with an increase in the change in COP for any specific amount of zonular traction. Weakening the attachment between the capsule and its underlying cortex increased the magnitude of the change in COP. When the hardness of the total lens stroma, cortex or nucleus was increased, there was a reduction in the amount of change in COP associated with a fixed amount of zonular traction. CONCLUSIONS: Increasing lens hardness reduces accommodative amplitude; however, as hardness of the lens does not occur until after the fourth decade of life, the age-related decline in accommodative amplitude must be due to another mechanism. One explanation is a progressive decline in the magnitude of the maximum force exerted by the zonules with ageing.

Computer image analysis of ultrasound biomicroscopy of primate accommodation.

PURPOSE: To assess and correct images of the eye for movements that can confound the evaluation of the presence, direction, and magnitude of intraocular movement of the crystalline lens equator during centrally induced ciliary muscle contraction (accommodation). METHOD: Ultrasound biomicroscopic (UBM) video images of a cynomologus monkey crystalline lens were obtained from an independent source. The images, prior to, during, and following electrical stimulation of the Edinger-Westphal (EW) nucleus were compared for evidence of movement of the crystalline lens equator. Extraocular eye movements were assessed by use of objective computer imaging analysis techniques. RESULTS: Extraocular eye movements were identified and reduced by using objective computer imaging analysis techniques to register and realign the corneal images. Highly significant corrections are required to effect corneal realignment. Analysis of paired and registered images from this data source indicates that any movements of the primate lens equator are not detectable when maximum accommodation was induced by EW stimulation. CONCLUSION: The displacement of the edge of the primate crystalline lens equator during electrically induced contraction of the ciliary muscle is a small displacement phenomenon, only analysable after confounding extraocular movements are removed from the compared images.

Mechanism of human accommodation as analyzed by nonlinear finite element analysis.

Results of nonlinear finite element analysis support the Schachar theory of accommodation and demonstrate that the long-held Helmholtz theory of accommodation is impossible.

Theoretical basis for the scleral expansion band procedure for surgical reversal of presbyopia [SRP].

A new technique, the scleral expansion band procedure, has been developed for the surgical reversal of presbyopia. An understanding of demonstrable clinical effects of the scleral expansion band procedure, based on Schachar's theory, requires a revision of historically held views concerning the mechanism of accommodation.

A closed shell structured eyeball model with application to radial keratotomy.

A closed shell structured eyeball model was developed for predicting the displacements and curvatures in an eyeball due to radial keratotomy. Both the cornea and sclera are modeled as an ellipsoidal cap, and the two caps are connected at the limbus to form a closed shell. The analysis of the number of corneal collagen laminae required for the tissue to be theoretically transversely isotropic was presented. The cornea, as well as the limbus and sclera, is considered as macroscopically homogeneous and isotropic in this study. A procedure to obtain the principal curvature at a point on the exterior surface was established. In the basic formulation, large displacements are contemplated. However, the FORTRAN computer program that was prepared to implement the procedure considers small displacements, and the resulting equations are linear. Although the results from this shell structured eyeball model are fairly good quantitatively, they do show vividly the following qualitative corneal behavior after the operation is performed: The opening of an incision has a V-shape, the radial displacements through the corneal thickness are nearly the same, and the largest in-plane displacement is only one-tenth of the largest radial displacement.

In vivo increase of the human lens equatorial diameter during accommodation.

The movement of the human lens equator during accommodation was examined in vivo. High-resolution ultrasound images of the lens equator were obtained from young human subjects whose amplitude of accommodation was controlled with 1% tropicamide and 2% pilocarpine. To avoid errors that otherwise arise from eye rotation or other movement, the cornea and sclera were used as positional references in comparative studies of the video images obtained from the unaccommodated and accommodated states. During accommodation, the movement at the lens equator involved small displacement; i.e., < 100 microns, and the equator did not move anteriorly or posteriorly but peripherally toward the sclera. These results indicate that the lens equator is under increased zonular tension during accommodation, in contradiction to Helmholtz's widely accepted theory of accommodation.

The effect of gravity on the amplitude of accommodation.

We measured the amplitude of accommodation in the supine and prone positions of young subjects. We found that gravity does not influence accommodative amplitude. These findings support Schachar's zonular function and accommodative hypotheses that the lens is stable and under tension during accommodation.

Pathophysiology of accommodation and presbyopia. Understanding the clinical implications.

As a consequence of a new understanding of the mechanism of accommodation, a unique surgical procedure has been developed which can reverse presbyopia. The basic pathophysiology involved in the development of presbyopia may have implications in the etiology and treatment of ocular hypertension and primary open angle glaucoma.

Zonular function: a new hypothesis with clinical implications.

A new hypothesis about zonular function is presented that has implications in regard to the cause and treatment of ocular hypertension and open-angle glaucoma. This hypothesis is based on the concept that the lens is under constant tension. The anterior and posterior zonules serve a different function than do the equatorial zonules. The anterior and posterior zonules are passive in terms of structural support of the lens; the equatorial zonules are the active components during accommodation.

A physical model demonstrating Schachar's hypothesis of accommodation.

Schachar's hypothesis of accommodation states that there is increased zonular tension during accommodation and the observed in vivo changes in lenticular curvature that occur during accommodation are the result of zonular forces. To demonstrate that there can be steepening of the central curvature of the lens with increased zonular tension, profile photographs of an equatorially unstretched and stretched gelatin-filled balloon and profile photographs from the literature of an unstretched and equatorially stretched human lens were digitized. Their radii of curvature were determined. We found that equatorial stretching of both the gelatin-filled balloon and the human lens produced central curvature steepening that was consistent with Schachar's hypothesis of accommodation.

Experimental support for Schachar's hypothesis of accommodation.

To determine the physical effect of a change in the equatorial lenticular diameter on optical power, sclera-ciliary bodies of bovine eyes were stretched radially. The effective optical power and lenticular equatorial diameter were measured. We found that an increase in the equatorial diameter of the bovine lens produced an increase in its effective optical power. Our results directly contradict Helmholtz's hypothesis of accommodation and its modifications. These results support Schachar's hypothesis of accommodation, which states that there is increased zonular tension during accommodation.