Late-stage Retinitis Pigmentosa Research Articles

A Novel Surgical Approach for Big Sheet Allogenic Retinal Pigment Epithelium-Bruch Membrane Complex Transplantation Into the Subretinal Space.

Allogenic transplantation of retinal pigmented epithelium monolayer sheet has experienced bottlenecks due to imperfect surgical techniques. In this study, we developed a novel approach for allogenic transplantation of big sheets of retinal pigment epithelium (RPE)-Bruch membrane complex. RPE-Bruch membrane complex sheets of 5 × 6 mm2 to 10 × 10 mm2 were taken from donated eyes. Through a novel approach, the sheets of RPE-Bruch membrane complex were transplanted into the subretinal space of eight eyes (8 patients) with late-stage retinitis pigmentosa. The patients were followed up for 5 ± 2 months. All RPE-Bruch membrane complexes were successfully inserted into the subretinal space during the surgery. Follow-up examinations also showed that the grafts attached well to the transplantation site. No rejection or retinal detachment was found. Through our technique, big sheets of allogenic RPE-Bruch membrane complexes could be implanted into the subretinal space smoothly. This novel approach may be useful for big sheet of allogenic RPE-derived or stem cells-derived RPE transplantation in the treatment of RP and other retinal dystrophic diseases.

One-Year Anatomical and Functional Outcomes of the Argus II Implantation in Korean Patients with Late-Stage Retinitis Pigmentosa: A Prospective Case Series Study

Purpose: To report the anatomical and functional outcomes of Argus II retinal prosthesis implantation in Korean patients. Methods: We included 5 consecutive patients with end-stage retinitis pigmentosa (RP) who underwent Argus II retinal prosthesis implantation and were followed for at least 12 months. The transcorneal electrical evoked response was utilized for patient selection. We used intraoperative optical coherence tomography (OCT) for optimal placement of the array and provided specialized vision rehabilitation training. A morphological evaluation using SD-OCT and a functional evaluation using computer-based visual function tests, a letter-reading ability test, and the Functional Low-Vision Observer Rated Assessment (FLORA) were conducted. Results: Postoperatively, the array was completely apposed to the retinal surface in all eyes, except for one eye which had a preexisting macular concavity. Fibrosis-like tissues of ≥50-μm thickness developed at the interface in 2 eyes. All of the patients showed improvement in computer-based visual function tests and could read ETDRS letters at a distance of 50 cm. Three patients could read Korean words. FLORA was improved in all patients, mainly in tasks of visual mobility, daily activities, and social interactions. Conclusions: Along with good anatomical outcomes and specialized rehabilitation practices, recipients of the Argus II implant showed profound improvements in functional vision and mobility.

Pupillographic campimetry: an objective method to measure the visual field.

Pupillographic campimetry allows measuring the visual field objectively by analyzing the pupil response to perimetric stimuli. One of the drawbacks of this technique, similar to static perimetry, is the need of reliable fixation of the subject. By using stimulus sizes comparable to static perimetry and applying gaze tracking, we enable a retinotopic visual field examination regardless of fixation problems and with an increased stability and improved spatial resolution. Here, we present the results of applying the method in eight normal sighted subjects as well as in three patients suffering from diseases usually diagnosed by perimetry. The results in normal sighted subjects show a reduction in the amplitude of the pupil response with increasing eccentricity as expected. We also demonstrate that gaze-controlled campimetry is able to detect organic visual field defects objectively in a patient group and classify the visual field defects without an organic background. Moreover, we show that our method is able to evaluate the visual field sensitivity loss beyond classical perimetry in patients with late-stage retinitis pigmentosa. Thus, gaze-controlled pupil campimetry can be used in addition to classical perimetry, allowing for an objective monitoring of disease progression, rendering it as a biomarker for novel treatments.

Local and systemic responses following intravitreous injection of AAV2-encoded modified Volvox channelrhodopsin-1 in a genetically blind rat model

We previously designed a modified channelrhodopsin-1 (mVChR1) protein chimera with a broader action than that of Chlamydomonas channelrhodopsin-2 and reported that its transduction into retinal ganglion cells can restore visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats, with photostimuli ranging from 486 to 640 nm. In the current study, we sought to investigate the safety and influence of mVChR1 transgene expression. Adeno-associated virus type 2 encoding mVChR1 was administered by intravitreous injection into dystrophic RCS rats. Reverse-transcription PCR was used to monitor virus and transgene dissemination and the results demonstrated that their expression was restricted specifically within the eye tissues, and not in non-target organs. Moreover, examination of the blood, plasma and serum revealed that no excess immunoreactivity was present, as determined using standard clinical hematological parameters. Serum antibodies targeting the recombinant adeno-associated virus (rAAV) capsid increased after the injection; however, no increase in mVChR1 antibody was detected during the observation period. In addition, retinal histological examination showed no signs of inflammation in rAAV-injected rats. In conclusion, our results demonstrate that mVChR1 can be exogenously expressed without harmful immunological reactions in vivo. These findings will aid in studies of AAV gene transfer to restore vision in late-stage retinitis pigmentosa.

Daylight vision repair by cell transplantation.

Human daylight vision depends on cone photoreceptors and their degeneration results in visual impairment and blindness as observed in several eye diseases including age-related macular degeneration, cone-rod dystrophies, or late stage retinitis pigmentosa, with no cure available. Preclinical cell replacement approaches in mouse retina have been focusing on rod dystrophies, due to the availability of sufficient donor material from the rod-dominated mouse retina, leaving the development of treatment options for cone degenerations not well studied. Thus, an abundant and traceable source for donor cone-like photoreceptors was generated by crossing neural retina leucine zipper-deficient (Nrl(-/-) ) mice with an ubiquitous green fluorescent protein (GFP) reporter line resulting in double transgenic tg(Nrl(-/-); aGFP) mice. In Nrl(-/-) retinas, all rods are converted into cone-like photoreceptors that express CD73 allowing their enrichment by CD73-based magnetic activated cell sorting prior transplantation into the subretinal space of adult wild-type, cone-only (Nrl(-/-)), or cone photoreceptor function loss 1 (Cpfl1) mice. Donor cells correctly integrated into host retinas, acquired mature photoreceptor morphology, expressed cone-specific markers, and survived for up to 6 months, with significantly increased integration rates in the cone-only Nrl(-/-) retina. Individual retinal ganglion cell recordings demonstrated the restoration of photopic responses in cone degeneration mice following transplantation suggesting, for the first time, the feasibility of daylight vision repair by cell replacement in the adult mammalian retina.

Randomized Trial of Ciliary Neurotrophic Factor Delivered by Encapsulated Cell Intraocular Implants for Retinitis Pigmentosa

To evaluate the safety and effect on visual function of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa (RP). Ciliary neurotrophic factor for late-stage retinitis pigmentosa study 3 (CNTF3; n = 65) and ciliary neurotrophic factor for early-stage retinitis pigmentosa study 4 (CNTF4; n = 68) were multicenter, sham-controlled dose-ranging studies. Patients were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoints were change in best-corrected visual acuity (BCVA) at 12 months for CNTF3 and change in visual field sensitivity at 12 months for CNTF4. Patients had the choice of retaining or removing the implant at 12 months for CNTF3 and 24 months for CNTF4. There were no serious adverse events related to either the encapsulated cell implant or the surgical procedure. In CNTF3, there was no change in acuity in either ciliary neurotrophic factor- or sham-treated eyes at 1 year. In CNTF4, eyes treated with the high-dose implant showed a significant decrease in sensitivity while no change was seen in sham- and low dose-treated eyes at 12 months. The decrease in sensitivity was reversible upon implant removal. In both studies, ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness. Long-term intraocular delivery of ciliary neurotrophic factor is achieved by the encapsulated cell implant. Neither study showed therapeutic benefit in the primary outcome variable.

Topical isopropyl unoprostone for retinitis pigmentosa: microperimetric results of the phase 2 clinical study.

IntroductionThe purpose of this study was to determine whether topical 0.15% isopropyl unoprostone (IU), a BK-channel activator, could improve or maintain the central retinal sensitivity in patients with middle- to late-stage retinitis pigmentosa (RP). IU was approved for glaucoma and ocular hypertension in 1994. The drug re-profiling strategy is one of the effective ways to develop safe drugs for patients with RP.MethodsA randomized, double-blind, and placebo-controlled phase II safety/efficacy trial was conducted. One hundred and nine patients with middle- to late-stage RP having a visual acuity of ≥0.5 were studied at six ophthalmological centers in Japan. The treatments of IU/day were divided into three groups: placebo group; two-drop group; and four-drop group for 24 weeks. The primary outcome measure was changes in the retinal sensitivity from baseline in the central 2° determined by MP-1 microperimetry (MP-1, Nidek, Japan). The secondary outcomes were changes in best-correct visual acuity, contrast sensitivity, retinal sensitivity of the central 10° by MP-1, mean deviation (MD) by a Humphrey field analyzer (HFA; Carl Zeiss Meditec, Dublin, CA, USA) 10-2, and the Visual Functioning Questionnaire 25 (VFQ-25) questionnaire scores.ResultsThere was a tendency for a dose-dependent responsiveness in retinal sensitivity in the central 2°, MD, and total VFQ-25 score after 24 weeks of IU instillation by a simple linear regression analysis. A stratified analysis showed a significant dose-dependent responsiveness of the 2° central retinal sensitivity in more advanced patients (P = 0.028). The number of patients having a ≥4 dB decrease in the primary outcome measure was significantly fewer in the four-drop group than in the placebo group (P = 0.02). No adverse reactions were observed.ConclusionsA higher dose of IU can delay progression of the central retinal sensitivity decrease through an improvement of retinal sensitivity.

The state of visual prosthetics--Hype or promise?

The miracle of restoring sight to the blind, told in legends and myths throughout human cultures and history, is moving from dream to possibility in our times. Several dozen groups around the world now claim that electronic or neurochemical prostheses may soon restore some measure of functional vision. This editorial examines such claims by reviewing the proposed approaches and assessing their promise. We base our opinions on our involvement with some of these efforts and on presentations and discussions during the most recent biennial Eye and the Chip: World Congress on Artificial Vision organized by the Detroit Institute of Ophthalmology in June 2006; for a recent overview of many current activities in this area, see Dagnelie [1]. The retina extensively preprocesses and reduces image information, and the cortical map and magnification add further complexity; therefore, functional replacement of neural elements should be done at the earliest available stage of visual processing to limit surrogate processing that provides but a poor substitute for the native system. Thus, for example, a retinal prosthesis should be used if the nerve fibers and optic nerve are intact, such that the prosthesis stimulates the most distal remaining cell population available. Despite such considerations, the first attempts at vision restoration almost 40 years ago were directed at the visual cortex [2]. Early cortical implants used electrodes placed between the meninges, avoiding the complications of glial cell encapsulation plaguing most penetrating electrodes. A mapping procedure is used to determine the location of each electrode's phosphene in the visual field, and real-time image processing and stimulation software then extracts and projects contours onto the best-matching electrodes. These phosphenes do not convey real-form vision, yet they do allow the wearer crude localization of outlines in the scene. Newer penetrating probes such as the 100-electrode array developed at the University of Utah--currently being considered for use by the European CortiVis consortium--and the hatpin electrodes--developed at the National Institute of Neurological Disorders and Stroke and since adopted by the group at the Illinois Institute of Technology --may provide smaller phosphenes, and thus better resolution, at much lower and safer charge injection levels. In the early 1990s, intraoperative stimulation in patients with late-stage retinitis pigmentosa (RP) showed that phosphenes could be elicited from blind retinal areas long after photoreceptor degeneration [3]. Researchers are working on various implants in which a matrix of electrodes stimulates the surviving retinal cells with imagery collected by an external camera and reduced to match the resolution of the electrode array. Two research groups have progressed to the stage of prototype implants in patients with late-stage RP. A consortium formed by Second Sight Medical Products LLC and by the Doheny Retina Institute has performed six implants of 4 x 4 electrode arrays based on cochlear implant electronics; these patients can detect phosphenes at individual electrodes, discriminate crude shapes upon multiple electrode stimulation, and recognize simple stimuli presented via a head-mounted camera. A consortium formed by IIP Technologies GmbH and German universities has performed several 50-electrode implants and is reporting that patients have similar discrimination abilities with computer-generated stimuli. Other retinal prosthesis groups are exploring integrated concepts in which the eye's optics become part of a prosthetic imaging device, which in turn generates the signals to drive the secondary neurons. The simplest implementation of such a device, an array of small photodiodes under the retina, appears to have a neurotrophic beneficial effect in RP patients with some remaining vision; 30 patients have received this Optobionics ASR implant in Food and Drug Administration trials [4]. …