Safety evaluation of "retina implant alpha IMS"--a prospective clinical trial.

BACKGROUND: To restore vision in patients with retinitis pigmentosa, several types of electronic devices have been developed to stimulate neurons at different levels along the visual pathway. Subretinal stimulation of the retina with the Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) has been demonstrated to provide useful vision in daily life. Here we evaluated the safety of this device. METHODS: An interventional, prospective, multi-center, single-arm study was conducted in patients with retinitis pigmentosa with the Retina Implant Alpha IMS. The results from the first nine patients of a single center regarding safety of the device are reported. Any untoward medical occurrence related or unrelated to the tested device was documented and evaluated. RESULTS: Nine adult subjects were included in the study at the Tübingen site. Seventy-five adverse events occurred in total, and 53 affected the eye and its adnexa. Thirty-one ocular adverse events had a relationship to the implant that was classified as "certain" while 19 had a probable or possible relationship; three had no relationship to the implant. Thirty-nine ocular adverse events resolved without sequelae, two resolved with sequelae, 11 remained unresolved, and in one the status was unknown. The intensity of ocular adverse events was mild in the majority of cases (n = 45), while six were of moderate and two of severe intensity. There was no non-ocular adverse event with certain relationship to the device. One subject lost light perception (without light localization) in her study eye. CONCLUSIONS: In conclusion, this prospective study, "Safety and Efficacy of Subretinal Implants for Partial Restoration of Vision in Blind Patients," shows that the Retina Implant Alpha IMS is an option for restoring vision using a subretinal stimulation device with a clinically acceptable safety profile.

Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase.

The GUCA1A gene encodes the guanylate cyclase activating protein 1 (GCAP1) of mammalian rod and cone photoreceptor cells, which is involved in the Ca2+-dependent negative feedback regulation of membrane bound guanylate cyclases in the retina. Mutations in the GUCA1A gene have been associated with different forms of cone dystrophies leading to impaired cone vision and retinal degeneration. Here we report the identification of three novel and one previously detected GUCA1A mutations: c.265G>A (p.Glu89Lys), c.300T>A (p.Asp100Glu), c.476G>T (p.Gly159Val) and c.451C>T (p.Leu151Phe). The clinical data of the patients carrying these mutations were compared with the functional consequences of the mutant GCAP1 forms. For this purpose we purified the heterologously expressed GCAP1 forms and investigated whether the mutations affected the Ca2+-triggered conformational changes and the apparent interaction affinity with the membrane bound guanylate cyclase. Furthermore, we analyzed Ca2+-dependent regulatory modes of wildtype and mutant GCAP1 forms. Although all novel mutants were able to act as a Ca2+-sensor protein, they differed in their Ca2+-dependent activation profiles leading to a persistent stimulation of guanylate cyclase activities at physiological intracellular Ca2+ concentration.

ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies.

The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

Relationship between suspected reasons of intraocular inflammation and the results of diagnostic vitrectomy: an observational study.

BACKGROUND: Intraocular inflammation of the posterior segment may be associated with neoplastic, infectious, and inflammatory diseases. Biopsy of vitreous and additional ocular tissue might be required for a definitive diagnosis. We therefore aimed to investigate the safety and usefulness of diagnostic vitrectomy in intraocular inflammation. METHOD: We performed an observational retrospective study of patients who underwent vitreous biopsy due to atypical intraocular inflammation, experienced failed resolution to empirical therapy, or for whom there was suspicion of an underlying neoplastic process. RESULTS: Seventy consecutive patients were included due to idiopathic uveitis of the posterior segment unresponsive to systemic corticosteroids (n = 33, 47%), suspected vitreoretinal or choroidal lymphoma (n = 18, 26%), viral retinitis (n = 17, 24%), and suspected endogenous endophthalmitis (n = 2, 3%). Suspected viral retinitis was most often confirmed (13/17, 76%), followed by lymphoma (6/18, 33%). Remarkably, a proportion of suspected idiopathic uveitis was infectious (7/33, 21%). The most prevalent adverse event following diagnostic vitrectomy was cataract surgery in phakic patients (n = 16/41, 39% of phakic patients). Retinal detachments were observed chiefly in infectious or neoplastic disease (n = 5, 7%) after a median time of 105 days. CONCLUSION: Diagnostic vitrectomy was helpful in substantiating the clinical suspected diagnosis of posterior segment inflammation. Potential secondary adverse events should be kept in mind.

Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy.

BACKGROUND: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. MATERIAL AND METHODS: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. RESULTS: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. CONCLUSION: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.

Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration.

PURPOSE: Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone-rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders. METHODS: Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers. RESULTS: GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did. CONCLUSIONS: GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene.