Purpose: To develop an animal model of atrophic age-related macular degeneration (aAMD) in aged mice that more closely mimics the natural progression of the disease. Methods: 12- and 18-month-old CBl57/6JRj mice were immunized with murine serum albumin (MSA) conjugated with carboxyethyl pyrrole (CEP). The immunization, given into the hock, was followed by 3 booster injections into the neck over a 3-month period. Immunized mice and age-matched controls were trained for a visual discrimination and an optokinetic response task to determine the objective visual threshold (OVT) at arrival and at 3 months; funduscopy and ocular coherence tomography were performed. After sacrifice, the eyes were enucleated for histological, immunofluorescent and electron microscopy analyses. Results: Retinal imaging confirmed that all mice had normal retinas upon arrival. Three months after mice were immunized the normal retinal age-related alterations were significantly more pronounced in CEP-immunized than in control mice as evidenced by drusenoid alterations, increased retinal thickness, immune activation, signs of retinal degeneration, decreased OVT. Electron microscopy indicated degeneration of the retinal pigment epithelium (RPE). Conclusions: The retinal and behavioral changes in the aged CEP-immunized mice will be useful for the investigation of novel treatments of aAMD. Translational relevance: The enhanced Aged-CEP-Mouse model enables the generation of results highly transferable to human patients and promotes the development of efficient, safe AMD therapies.
Abstract In a consanguineous Pakistani family with two affected individuals, a homozygous variant Gly399Val in the eighth transmembrane domain of the taurine transporter SLC6A6 was identified resulting in a hypomorph transporting capacity of ~15% compared with normal. Three-dimensional modeling of this variant has indicated that it likely causes displacement of the Tyr138 (TM3) side chain, important for transport of taurine. The affected individuals presented with rapidly progressive childhood retinal degeneration, cardiomyopathy and almost undetectable plasma taurine levels. Oral taurine supplementation of 100 mg/kg/day resulted in maintenance of normal blood taurine levels. Following approval by the ethics committee, a long-term supplementation treatment was introduced. Remarkably, after 24-months, the cardiomyopathy was corrected in both affected siblings, and in the 6-years-old, the retinal degeneration was arrested, and the vision was clinically improved. Similar therapeutic approaches could be employed in Mendelian phenotypes caused by the dysfunction of the hundreds of other molecular transporters.
More than 200 Pakistani consanguineous families with multiple individuals having recessive visual impairments were evaluated by exome sequencing and genotyping. One of the families, F315, from the Kohat region of Pakistan contained 2 affected individuals with a homozygous deleterious variant Gly399Val (NM_003043.5:c.1196G>T) in the taurine transporter SLC6A6 (MIM:186854) which segregated with the phenotype of progressive retinal degeneration. Gly399 is highly conserved in vertebrates and molecular modeling suggests that the increased bulk of the valine substitution displaces Tyr138 which participates in substrate coordination and transport and is consistent with the hypomorphic variant exhibiting only ~15% of the transport capacity of the native protein as determined by taurine uptake analyses in HEK‐293 cells transiently or stably expressing SLC6A6 or the Gly399Val variant. The reduced function was attributed to a catalytic effect rather than plasma membrane levels and analysis of patient‐derived fibroblasts of affected individuals mirrored these findings. Affected individuals exhibited cone‐rod retinopathy and cardiomyopathy and remarkably taurine supplementation for 24 months resulted in resolution of the cardiomyopathy and clinical stabilization of the retinopathy. Support or Funding Information ProVisu foundation and ERC grant 219968 to S.E.A., and NIH grant DA027845 to L.K.H.
To evaluate the outcomes and safety of a minimally invasive technique for sutured IOL scleral fixation in case of compromised capsular and iris support.In this retrospective study, we explain our mini-invasive technique and assess the outcomes in terms of visual acuity, pre- or postoperative complications, and IOL position (Sensar AR40e, AMO) in a case series of three patients.The expected best corrected visual acuity could be achieved after one month. Surgeries were uneventful with a stable eye. No postoperative complications occurred except for one patient who had a conjunctival disinsertion. Neither postoperative hypotony nor raised IOP was found. Additionally, no patient experienced corneal edema at one week control, IOL dislocation, vitreous hemorrhage, or new pupil's irregularity.In conclusion, each scleral technique has its own advantages and its inherent postoperative complications. To date, there is no evidence of superiority of any single technique. By improving our scleral sutured lens techniques, we could improve peroperative ocular stability, potentially decrease postoperative complication rate, and offer a rapid recovery with a stable visual acuity within a month.
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Background: Techniques for the preparation of grafts for Descemet membrane endothelial keratoplasty (DMEK) can be classified into those that involve the manual dissection of the Descemet membrane (DM) and those that use an injection of a liquid or a gas to achieve a separation of the DM from the posterior corneal stroma. The purpose of this study was to evaluate the efficiency of the liquid bubble technique. Methods: The success rate of the technique was calculated retrospectively using the operating reports. Video files for each graft preparation were retrieved and the time, number of injections, and number of injections sites required for the hydrodissection were measured. The number of cases in which a manual dissection of the Descemet membrane was necessary was recorded. Information on donor age and graft preservation time were retrieved from the eye bank file. Results: In 58 cases, the success rate was 98.3%. In the 28 procedures where a video was available, the median time for hydrodissection was 4.4 min. The median number of injection sites was 2, with a median number of injections of 3.5. Manual dissection as a rescue technique was performed in 25% of cases, with one case resulting in graft tears. The mean graft diameter was 7.6 mm. The mean donor age was 66 years, and the mean graft storage time was 22 days. Conclusions: The liquid bubble technique can be a fast and valuable choice for DMEK graft preparation, especially in centers where the tissue is prepared in the operating theater.
