Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT).

UNLABELLED: Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 µm, mean ± 95% CI) than non-responders (3.5 ± 1.2 µm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01014052.

Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial.

BACKGROUND: Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. METHODS: In our open-label, prospective, phase 1b trial, we enrolled patients (aged ≥6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill University's Montreal Children's Hospital. Patients received 7 days of oral QLT091001 (10-40 mg/m(2) per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2·2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052. FINDINGS: Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6-38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28-683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2-30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients). INTERPRETATION: Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations. FUNDING: QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision.

Phenotypic variability due to a novel Glu292Lys variation in exon 8 of the BEST1 gene causing best macular dystrophy.

OBJECTIVE: To study the phenotypic characteristics of patients with a novel p.E292K mutation in BEST1. METHODS: Affected individuals underwent ophthalmic examination and testing that included photography, autofluorescence, optical coherence tomography, and electrophysiological testing. Their DNA was analyzed for BEST1 mutations. RESULTS: Five patients aged 5 to 59 years who expressed the p.E292K mutation in BEST1 were identified in 3 families. Electro-oculographic light-rise was subnormal in all probands and carriers. Carriers had normal findings from fundus examination, multifocal electroretinography, and visual acuity, and were emmetropic or myopic. Only probands had hyperopia and fundus findings typical of Best macular dystrophy. Optical coherence tomography of vitelliform lesions demonstrated retinal pigment epithelium elevation without subretinal fluid; atrophic lesions exhibited disruption of the hyperreflective outer retina-retinal pigment epithelium complex. Intense hyperautofluorescence correlated with the vitelliform lesion. CONCLUSIONS: Patients with the Glu292Lys variation in BEST1 exhibit intrafamilial and interfamilial phenotypic variability. A disproportionate fraction (26%) of Best disease-causing mutations occurs in exon 8, suggesting that the portion of protein encoded by this exon (amino acids 290-316) may be especially important to bestrophin's function. Relatively good visual acuity with vitelliform lesions can be explained by preservation of the outer retina, demonstrated by optical coherence tomography. Clinical Relevance A novel mutation in this region of BEST1 carries implications for disease pathogenesis.

Effects of long-term administration of 9-cis-retinyl acetate on visual function in mice.

PURPOSE: Long-term effects of treatment with 9-cis-retinyl acetate (9-cis-R-Ac), an artificial retinoid prodrug, were tested on changes in rod and cone visual functions in mice. METHODS: The acetyl ester of the functional geometric chromophore 9-cis-retinal was delivered by oral gavage to C57BL/6 female mice. In initial experiments, 10-month-old mice were used for the single treatment with 9-cis-R-Ac or the control vehicle. In long-term experiments, 4-month-old mice were treated with 9-cis-R-Ac monthly for 6 and 10 months. Photoreceptor status was evaluated by various electroretinographic (ERG) techniques, retinoid analyses, and retinal morphology. Opsin, the predicted target of oxidized 9-cis-R-Ac, was purified and its chromophore was characterized. RESULTS: Age-related changes observed in vehicle-treated mice at 10 months of age, compared with those in 4-month-old mice, included a progressive decline in ERG responses, such as a decreased rate of dark adaptation and a lowered rhodopsin/opsin ratio. Administration of 9-cis-R-Ac increased the rhodopsin regeneration ratio, and improved ERG responses and dark adaptation. Compared with vehicle-treated control animals, 10- and 14-month-old mice treated monthly with 9-cis-R-Ac for 6 or 10 months exhibited improved dark adaptation. In 14-month-old mice treated monthly, changes in the expression of retina-specific genes in the eye were detected by mRNA expression profiling, but no significant effects in gene expression were detected in the liver and kidney. CONCLUSIONS: Deteriorating photoreceptor function documented in mice at 10 and 14 versus 4 months of age was improved significantly by long-term, monthly administration of 9-cis-R-Ac. These findings suggest a potential therapeutic approach to prevent age-related retinal dysfunction.

Impact of retinal disease-associated RPE65 mutations on retinoid isomerization.

Pathogenic mutations in the RPE65 gene are associated with a spectrum of congenital blinding diseases in humans. We evaluated changes in the promoter region, coding regions, and exon/intron junctions of the RPE65 gene by direct sequencing of DNA from 36 patients affected with Leber's congenital amaurosis (LCA), 62 with autosomal recessive retinitis pigmentosa (arRP), and 21 with autosomal dominant/recessive cone-rod dystrophies (CORD). Fifteen different variants were found, of which 6 were novel. Interesting was Gly244Val, a novel mutation close to the catalytic center. To assess the role of this mutation in RPE65 inactivation, we performed detailed biochemical studies of the mutant along with a structural analysis of the 244 amino acid position with respect to amino acids known to be important for RPE65-dependent retinoid isomerization. Bicistronic plasmid expression of the RPE65 Gly244Val mutant and enhanced green fluorescent protein (EGFP) allowed us to document both its instability in cultured cells by cell sorting and immunoblotting methodology and its loss of RPE65-dependent isomerase activity by enzymatic assays. Further insights into the structural requirements for retinoid isomerization by RPE65 were obtained by using the carotenoid oxygenase (ACO) from Synechocystis (PDB accession code 2BIW ) as a structural template to construct a RPE65 homology model and locating all known inactivating mutations including Gly244Val within this model.

Combination treatment with reduced-fluence photodynamic therapy and intravitreal injection of triamcinolone for subfoveal choroidal neovascularization in macular degeneration.

PURPOSE: To evaluate combination treatment with reduced-fluence photodynamic therapy (PDT) and intravitreal triamcinolone acetonide (IVT) injection for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). METHODS: This is a retrospective consecutive case series of 23 previously untreated eyes of 22 patients with subfoveal CNV secondary to AMD. Six eyes were treated with 50 J/cm; 8, with 40 J/cm; and 9, with 25 J/cm. PDT was immediately followed by a 4-mg IVT injection. Patients were observed for 6 months at 6-week intervals. RESULTS: : The 50 J/cm subset lost a mean of 2.2 lines of Snellen visual acuity at the 6-month follow-up compared with a 1-line lost in the 40 J/cm subset and a 0.9-line gain in the 25 J/cm subset. In the 50 J/cm subset, 60% lost < or =3 lines of Snellen visual acuity, 33% gained > or =0 line, and 33% gained > or =3 lines. In the 40 J/cm subset, 75% lost < or =3 lines of Snellen visual acuity, 50% gained > or =0 line, and 25% gained > or =3 lines. In the 25 J/cm subset, 89% lost < or =3 lines of Snellen visual acuity, 56% gained > or =0 line, and 33% gained > or =3 lines. Fifty percent of the 50 J/cm subset, 50% of the 40 J/cm subset, and 33% of the 25 J/cm subset required retreatment by 6 months. CONCLUSION: Although the sample in this study was small, there was a dose-response trend toward better visual outcomes and fewer treatments in the group treated with IVT injection and reduced-fluence PDT. This study along with other previously reported work suggests that studies using PDT in combination treatment for CNV should consider adding a reduced-fluence PDT arm.

Novel RDH12 mutations associated with Leber congenital amaurosis and cone-rod dystrophy: biochemical and clinical evaluations.

The purpose of this study was to determine the role of the retinol dehydrogenase 12 (RDH12) gene in patients affected with Leber congenital amaurosis (LCA), autosomal recessive retinitis pigmentosa (arRP) and autosomal dominant/recessive cone-rod dystrophies (CORD). Changes in the promoter region, coding regions and exon/intron junctions of the RDH12 gene were evaluated using direct DNA sequencing of patients affected with LCA (n=36 cases), RP (n=62) and CORD (n=21). The allele frequency of changes observed was assessed in a multiethnic control population (n=159 individuals). Detailed biochemical and structural modeling analysis of the observed mutations were performed to assess their biological role in the inactivation of Rdh12. A comprehensive clinical assessment of retinal structure and function in LCA patients carrying mutations in the RDH12 gene was completed. Of the six changes identified, three were novel including a homozygous C201R change in a patient affected with LCA, a heterozygous A177V change in patients affected with CORD and a heterozygous G46G change in a patient affected with LCA. A novel compound heterozygote T49M/A269fsX270 mutation was also found in a patient with LCA, and both homozygous and heterozygous R161Q changes were seen in 26 patients affected with LCA, CORD or RP. These R161Q, G46G and the A177V sequence changes were shown to be polymorphic. We found that Rdh12 mutant proteins associated with LCA were inactive or displayed only residual activity when expressed in COS-7 and Sf9 cells, whereas those mutants that were considered polymorphisms were fully active. Thus, impairment of retinal structure and function for patients carrying these mutations correlated with the biochemical properties of the mutants.

Surgical evacuation of submacular exudates secondary to a vasoproliferative tumor of the retina.

PURPOSE: To report a case demonstrating excellent visual recovery following surgical removal of subfoveal exudation secondary to a vasoproliferative tumor of the retina (VPTR). DESIGN: Observational case report. METHODS: Review of medical records. RESULTS: A 39-year-old man presented with decreased vision secondary to subfoveal exudation from a VPTR. The tumor was successfully treated with cryoretinopexy, but the hard exudates that had formed in under the fovea remained. There was no change in vision for 18 months following the cryoretinopexy. A decision was made to surgically remove the exudates using similar techniques to those presented in the literature for diabetic exudation. Over the next several weeks the patients vision recovered to the 20/25 level and has remained this way for 5 years. CONCLUSIONS: Patients with subfoveal exudates secondary to VPTR may benefit from subretinal surgery to remove the exudates.

Effects of cytotoxic T lymphocyte antigen 4 (CTLA4) signaling and locally applied steroid on retinal dysfunction by recoverin, cancer-associated retinopathy antigen.

PURPOSE: To assess the cytotoxic T lymphocyte antigen 4 (CTLA4) pathway in the recoverin peptide (R64; AYAQHVFRSF) mouse model of cancer-associated retinopathy (CAR) and to assess the protective effects of subconjunctival triamcinalone injections in this model. METHODS: To study the role of the CTLA4 pathway on the R64-induced mouse model of CAR, BALB/c mice were immunized with R64. The mice were further intraperitoneally treated with anti-CTLA4 antibody to get stronger immunoreaction. The development of CAR was evaluated by electroretinogram (ERG) examinations 21 days after treatment. A cytotoxicity assay was employed to detect induction of R64-specific cytotoxic T lymphocytes (CTLs). Immunoblotting to assess the development of anti-recoverin antibody and a T cell proliferation assay to determine the activity of lymphocytes against R64 were examined in two experimental groups, anti-CTLA4 antibody treated and untreated mice.To study the protective effect of subconjunctival triamcinalone in this model, mice immunized with R64 peptide and anti-CTLA4 antibody were either treated with 50 mg/kg/body weight of triamcinalone or phosphate buffered saline (PBS). These mice were assayed using ERG and histological examination 35 days after the first R64 immunization. RESULTS: When mice were challenged with R64 peptide and anti-CTLA4 antibody, R64 peptide-specific CTLs were induced and decreased b-wave amplitudes were observed in ERG. Conversely, no CAR symptoms were detected in mice not treated with anti-CTLA4 antibody. Anti-CTLA4 antibody treatment did not give any significant differences in T cell proliferation and humoral reaction against recoverin. Subconjunctival triamcinalone treated mice show a trend toward improved survival of outer nuclear layer cell bodies, but did not show significant improvement of ERG amplitudes compared to the untreated mice. CONCLUSIONS: Inhibition of the CTLA4 pathway is essential for the development of recoverin-induced murine CAR, suggesting that strengthening negative T cell signaling through CTLA4 may lessen the retinal degenerations in CAR-affected subjects. The positive effects of attenuation of the CTLA4 pathway must be weighed against a potential negative effect on survival since this pathway may also provide natural immunotherapy against the underlying malignancy. Subconjunctival injections of triamcinalone may have beneficial effects on the integrity of the outer nuclear layer (ONL) of the retina in the CAR model, although there was no significant effect on the ERG recordings.

Autosomal recessive retinitis pigmentosa and E150K mutation in the opsin gene.

Retinitis pigmentosa (RP) is a heterogeneous group of hereditary disorders of the retina caused by mutation in genes of the photoreceptor proteins with an autosomal dominant (adRP), autosomal recessive (arRP), or X-linked pattern of inheritance. Although there are over 100 identified mutations in the opsin gene associated with RP, only a few of them are inherited with the arRP pattern. E150K is the first reported missense mutation associated with arRP. This opsin mutation is located in the second cytoplasmic loop of this G protein-coupled receptor. E150K opsin expressed in HEK293 cells and reconstituted with 11-cis-retinal displayed an absorption spectrum similar to the wild type (WT) counterpart and activated G protein transducin slightly faster than WT receptor. However, the majority of E150K opsin showed a higher apparent molecular mass in SDS-PAGE and was resistant to endoglycosidase H deglycosidase. Instead of being transported to the plasma membrane, E150K opsin is partially colocalized with the cis/medial Golgi compartment markers such as GM130 and Vti1b but not with the trans-Golgi network. In contrast to the endoplasmic reticulum-retained adRP mutant, P23H opsin, Golgi-retained E150K opsin did not influence the proper transport of the WT opsin when coexpressed in HEK293 cells. This result is consistent with the recessive pattern of inheritance of this mutation. Thus, our study reveals a novel molecular mechanism for retinal degeneration that results from deficient export of opsin from the Golgi apparatus.

Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial.

Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo.

The retinoid cycle is a recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments. Photoreceptor-specific retinol dehydrogenase (prRDH) catalyzes reduction of all-trans-retinal to all-trans-retinol and is thought to be a key enzyme in the retinoid cycle. We disrupted mouse prRDH (human gene symbol RDH8) gene expression by targeted recombination and generated a homozygous prRDH knock-out (prRDH-/-) mouse. Histological analysis and electron microscopy of retinas from 6- to 8-week-old prRDH-/- mice revealed no structural differences of the photoreceptors or inner retina. For brief light exposure, absence of prRDH did not affect the rate of 11-cis-retinal regeneration or the decay of Meta II, the activated form of rhodopsin. Absence of prRDH, however, caused significant accumulation of all-trans-retinal following exposure to bright lights and delayed recovery of rod function as measured by electroretinograms and single cell recordings. Retention of all-trans-retinal resulted in slight overproduction of A2E, a condensation product of all-trans-retinal and phosphatidylethanolamine. We conclude that prRDH is an enzyme that catalyzes reduction of all-trans-retinal in the rod outer segment, most noticeably at higher light intensities and prolonged illumination, but is not an essential enzyme of the retinoid cycle.

Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study.

OBJECTIVE: To evaluate the safety, effect on visual function, and fluorescein angiographic appearance of subfoveal choroidal neovascularization (CNV) through 2 years after photodynamic therapy with verteporfin (Visudyne; Novartis AG, Basel, Switzerland) in patients with ocular histoplasmosis syndrome (OHS). DESIGN: Open-label, 3-center, uncontrolled clinical study. PARTICIPANTS: Ocular histoplasmosis syndrome patients with subfoveal CNV (N = 26) with a greatest linear dimension no larger than 5400 microm with classic or occult CNV extending under the geometric center of the fovea, and best-corrected visual acuity letter score of approximately 20/40 to 20/200. METHODS: The methods were similar to those described in the 1-year results with follow-up examinations every 3 months continuing through the second year. During the second year, additional therapy was recommended if fluorescein angiography showed leakage at a scheduled visit. MAIN OUTCOME MEASUREMENTS: Visual function measurements included the changes from baseline in visual acuity and contrast sensitivity scores. Lesion size and leakage from classic and occult CNV were assessed at month 12 and month 24. Safety assessments also were made. RESULTS: A 24-month examination was completed in 22 of the 26 enrolled participants (85%). At the 24-month examination, median improvement from baseline in visual acuity of the 22 patients evaluated was 6 letters; median contrast sensitivity improved by 3.5 letters. At the 24-month examination, 10 patients (45%) gained 7 or more letters of visual acuity from baseline, whereas 4 patients (18%) lost 8 or more letters, including 2 patients (9%) who lost at least 15 letters. There was absence of fluorescein angiographic leakage from classic CNV in 17 of the 20 evaluable lesions (85%), and leakage from occult CNV was absent in all eyes. No serious ocular adverse events were reported, and no serious systemic event was considered to be associated with treatment. CONCLUSIONS: Median visual acuity improved and fluorescein angiographic leakage decreased after verteporfin therapy in this small, uncontrolled clinical study of patients with subfoveal CNV resulting from OHS. Verteporfin therapy seemed to be relatively safe in these patients. The selected cases feature fluorescein angiographic examples of CNV that are important in determining when to apply verteporfin therapy.

Rhodopsin signaling and organization in heterozygote rhodopsin knockout mice.

Rhodopsin (Rho) resides within internal membrane structures called disc membranes that are found in the rod outer segments (ROS) of photoreceptors in the retina. Rho expression is essential for formation of ROS, which are absent in knockout Rho-/- mice. ROS of mice heterozygous for the Rho gene deletion (Rho+/-) may have a lower Rho density than wild type (WT) membranes, or the ROS structure may be reduced in size due to lower Rho expression. Here, we present evidence that the smaller volume of ROS from heterozygous mice is most likely responsible for observed electrophysiological response differences. In Rho+/- mice as compared with age-matched WT mice, the length of ROS was shorter by 30-40%, and the average diameter of ROS was reduced by approximately 20%, as demonstrated by transmission and scanning electron microscopy. Together, the reduction of the volume of ROS was approximately 60% in Rho+/- mice. Rho content in the eyes was reduced by approximately 43% and 11-cis-retinal content in the eye was reduced by approximately 38%, as determined by UV-visible spectroscopy and retinoid analysis, respectively. Transmission electron microscopy of negatively stained disc membranes from Rho+/- mice indicated a typical morphology apart from the reduced size of disc diameter. Power spectra calculated from disc membrane regions on such electron micrographs displayed a diffuse ring at approximately 4.5 nm(-1), indicating paracrystallinity of Rho. Atomic force microscopy of WT and Rho+/- disc membranes revealed, in both cases, Rho organized in paracrystalline and raftlike structures. From these data, we conclude that the differences in physiological responses measured in WT and Rho+/- mice are due to structural changes of the whole ROS and not due to a lower density of Rho.

A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface.

G protein-coupled receptors (GPCRs) are ubiquitous and essential in modulating virtually all physiological processes. These receptors share a similar structural design consisting of the seven-transmembrane alpha-helical segments. The active conformations of the receptors are stabilized by an agonist and couple to structurally highly conserved heterotrimeric G proteins. One of the most important unanswered questions is how GPCRs couple to their cognate G proteins. Phototransduction represents an excellent model system for understanding G protein signaling, owing to the high expression of rhodopsin in rod photoreceptors and the multidisciplinary experimental approaches used to study this GPCR. Here, we describe how a G protein (transducin) docks on to an oligomeric GPCR (rhodopsin), revealing structural details of this critical interface in the signal transduction process. This conceptual model takes into account recent structural information on the receptor and G protein, as well as oligomeric states of GPCRs.

The G protein-coupled receptor rhodopsin in the native membrane.

The higher-order structure of G protein-coupled receptors (GPCRs) in membranes may involve dimerization and formation of even larger oligomeric complexes. Here, we have investigated the organization of the prototypical GPCR rhodopsin in its native membrane by electron and atomic force microscopy (AFM). Disc membranes from mice were isolated and observed by AFM at room temperature. In all experimental conditions, rhodopsin forms structural dimers organized in paracrystalline arrays. A semi-empirical molecular model for the rhodopsin paracrystal is presented validating our previously reported results. Finally, we compare our model with other currently available models describing the supramolecular structure of GPCRs in the membrane.

Subluxation of transscleral sutured posterior chamber intraocular lens (TSIOL).

PURPOSE: To evaluate factors related to late-onset transscleral sutured posterior chamber intraocular lens (TSIOL) subluxation. METHODS: Retrospective observational case series. Analysis of subluxated TSIOLs in seven eyes from seven patients treated between May 1999 and May 2001. RESULTS: Mean age at the time of TSIOL surgery was 33 +/- 6 years. Mean time from TSIOL surgery to its subluxation was 78 +/- 19 months. Initial diagnoses requiring TSIOL surgeries were previous history of trauma and Marfan syndrome. Subluxation of TSIOLs was associated with blunt trauma in three eyes, whereas the other four eyes experienced spontaneous lens dislocation. CONCLUSION: Subluxation of TSIOL is not uncommon in younger patients with history of trauma or Marfan syndrome.