Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE.

PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). DESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. PARTICIPANTS: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography. METHODS: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. MAIN OUTCOME MEASURES: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. RESULTS: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. CONCLUSIONS: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references

The functions of class 3 semaphorins in axon guidance and cardiac development

In order to establish the architecture of the nervous system, neurons must connect with their targets. A search for cues that help guide growth cones resulted in the purification and cloning of a chemorepellent, semaphorin 3A. This gene is now known to be a member of a gene family with at least twenty members in every vertebrate species. This thesis describes the identification characterization of another semaphorin, semaphorin 3C. Semaphorin 3A and 3C have distinct biological activities; semaphorin 3A collapses the growth cones of dorsal root ganglion (DRG) neurons and sympathetic chain ganglion (SCG) neurons while semaphorin 3C only collapses SCG neurons. Semaphorin 3A and its relatives semaphorin 3C, 3D and 3E bind to overlapping but distinct axon tracts. We infer that there are distinct receptors with different affinities for 3A, C, D and E. These four semaphorins, all bind recombinant neuropilin with similar affinities. We propose that neuropilin is a common component of a semaphorin receptor complex, and that additional differentially expressed receptor components interact with the semaphorin domains to confer binding specificity. Although semaphorin 3A and semaphorin 3C can function as chemorepellents in vitro, little is known about their functions in vivo. Misexpression of semaphorin 3A disrupts many sensory axon pathways including the dorsal funiculus, the olfactory nerve, the trigerminal nerve, the glosspharyngeal nerve and the vagus nerve. Overexpression of semaphorin 3A in the dorsal midbrain also leads to pathfinding defects of the trochlear nerve. Misexpression of semaphorin 3C does not result in any obvious pathfinding errors. These studies confirm a repellent role for semaphorin 3A in vivo but do not support any such role for semaphorin 3C. To further investigate the function of semaphorin 3C in vivo, we have disrupted the semaphorin 3C locus in mice. Semaphorin 3C knock out mice die postnatally from congenital cardiac defects. Our results raise the possibility that semaphorin 3C may function as an important specification, guidance, or differentiation cue for the cardiac neural crest. We have mapped the genomic location of semaphorin 3A, 3B, 3C, and 3E to mouse chromosome 5 corresponding to human chromosome 7q. Defects in human semaphorin 3C might underlie some forms of congenital cardiac disease

Results Of The 2-Year Ocriplasmin For Treatment For Symptomatic Vitreomacular Adhesion Including Macular Hole (Oasis) Randomized Trial

Purpose The Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial was designed to evaluate the long-term efficacy and safety profile of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA)/vitreomacular traction, including full-thickness macular hole (FTMH). Design Phase 3b, randomized, sham-controlled, double-masked, multicenter clinical trial. Participants Sample size was 220 subjects (146 ocriplasmin, 74 sham) randomized in a 2:1 ratio to receive intravitreal ocriplasmin 0.125 mg or sham injection. Methods The trial involved 12 visits over 24-months. Inclusion criteria included presence of VMA and best-corrected visual acuity (BCVA) of 20/32 or worse in the study eye. Exclusion criteria included FTMH \u3e400 μm, presence of epiretinal membrane (ERM), and aphakia in the study eye. Main Outcome Measures The primary efficacy end point was the proportion of subjects with pharmacologic VMA resolution at day 28. Secondary efficacy end points were assessed at month 24 and included proportion of subjects with BCVA gain from baseline, nonsurgical FTMH closure, vitrectomy, and Visual Function Questionnaire 25 (VFQ-25) outcomes. Results The OASIS trial met its primary end point with pharmacologic VMA resolution at day 28 being significantly higher in the ocriplasmin group (41.7%) compared with the sham group (6.2%). The treatment effect was maintained until study end. In the ocriplasmin group, pharmacologic VMA resolution at day 28 was higher in subgroups with the following baseline characteristics compared with the complementary subgroups without them: presence of focal VMA, presence of FTMH, absence of ERM, and phakic lens status. In the ocriplasmin group, 50.5% of subjects had a ≥2-line improvement in BCVA from baseline compared with 39.1% of subjects in the sham group. The nonsurgical FTMH closure rate was 30.0% for the ocriplasmin group compared with 15.4% for the sham group. All other secondary end points also favored ocriplasmin over sham. Regarding safety, most adverse events were mild to moderate, had a short onset time, and were transient, with no new safety signals identified. Conclusions The OASIS trial demonstrates the long-term efficacy and safety of ocriplasmin, providing improved resolution of symptomatic VMA compared with previous phase 3 trials with no additional safety signals identified

Generation of Cre Transgenic Mice with Postnatal RPE-Specific Ocular Expression

The authors characterize a new transgenic mouse line, BEST1-cre, that provides RPE-specific ocular cre expression. These mice begin expressing cre at postnatal day 10 and maintain expression into adulthood without causing retinal dysfunction. Cre expression is present in up to 90% of RPE nuclei. Therefore, these mice provide a useful tool for studying the postnatal function of genes within the RPE