PURPOSE: To compare the types and dosages of anti-VEGFs to ascertain whether specific dosages or types of injection were associated with retreatment in clinical practice in the US. DESIGN: Multicenter, retrospective, consecutive series. SUBJECTS: Patients with ROP treated with anti-VEGF injections from 2007 to 2021. METHODS: Sixteen sites from the US participated. Data collected included demographics, birth characteristics, examination findings, type and dose of anti-VEGF treatment, retreatment rates, and time to retreatment. Comparisons of retreatment rates between bevacizumab and ranibizumab intravitreal injections were made. MAIN OUTCOME MEASURES: Relative rate of retreatment between varying types of anti-VEGF therapy, including bevacizumab and ranibizumab, and the various dosages used for each. RESULTS: Data from 873 eyes of 661 patients (61% males and 39% females) were collected. After exclusion of 40 eyes treated with laser prior to anti-VEGF injection and 266 eyes retreated with laser at or beyond 8 weeks after the initial anti-VEGF treatment, 567 eyes of 307 patients (63% males and 37% females) remained and were included in the primary analysis. There was no difference between the no-retreatment and retreatment groups in terms of birthweight, gestational age, age at first injection, ROP stages, or number of involved clock hours. The retreatment group had a larger percentage of A-ROP (34 vs 18%, P < .001), and greater percentage of Zone 1 ROP (49 vs 34%, P = .001) than the no retreatment group. Ranibizumab use was associated with a higher rate of retreatment than bevacizumab use (58% vs 37%, P < .001), while the rate of retreatment was not associated with a specific dose of ranibizumab (R2 = .67, P = .32). Meanwhile, lower doses of bevacizumab were associated with higher rates of retreatment compared to the higher doses (R2 = .84, P = .01). There was a dose specific trend with higher doses trending towards lower retreatments for bevacizumab. CONCLUSIONS: In a multicenter study of ROP patients initially treated with anti-VEGF therapy, ranibizumab and lower dose bevacizumab use were associated with an increased rate of retreatment when compared to higher dose bevacizumab.

BACKGROUND AND OBJECTIVES: Archetypal analysis (AA), a form of unsupervised machine learning, can identify quantifiable visual field (VF) patterns seen in optic neuritis (ON), known as archetypes (ATs). We hypothesized that AT weight changes over time would reflect the course of recovery and the effects of therapy in ON. We explored whether baseline AT weights would be associated with VF status at the clinical trial outcome and if ATs would indicate residual VF defects in eyes with mean deviation (MD) ≥ -2.00 at six months. METHODS: We used a published 16-AT model derived from 3892 Optic Neuritis Treatment Trial VFs (456 eyes) for all analyses. We measured AT weight changes over the six-month study period and used asymptotic regression to analyze the rate of change. We compared AT weights at six months between treatment groups. We evaluated associations between baseline AT weight thresholds and VF outcome or treatment effect. We calculated residual AT weights in eyes with MD ≥ -2.00 dB at six months. RESULTS: Over six months, AT1 (a normal VF pattern) demonstrated the greatest median weight change, increasing from 0.00% (IQR 0.00-0.00%) at baseline to 60.0% (IQR 38.3-70.8%) at six months (p < 0.001). At outcome, the intravenous methylprednisolone (IVMP) group had the highest median AT1 weight (IVMP: 63.3%, IQR 51.3-72.8%; placebo: 56.2%, IQR 35.1-71.6%; prednisone 58.3%, IQR 35.1-71.6%; p = 0.019). Eyes with AT1 weight ≥ 19% at baseline had superior median MD values (-0.91 vs. -2.07 dB, p < 0.001) and AT1 weights (70.8% vs. 57.8% p < 0.001) at six months. Only eyes with AT1 weight < 19% at baseline showed a treatment benefit for IVMP, with a higher six-month median AT1 weight compared to placebo (p = 0.015) and prednisone (p = 0.016), and a higher median MD compared to placebo (p = 0.027). At six months, 182 (80.2%) VFs with MD ≥ -2.00 had at least one abnormal AT. DISCUSSION: Changes in quantifiable, archetypal patterns of VF loss reflect recovery in ON. Machine learning analysis of the VFs in optic neuritis reveals associations with response to therapy and VF outcome, and uncovers residual deficits, not readily seen with standard evaluations.

PURPOSE: Clinical registries are increasingly important in research and clinical advancement. This review explores and compares current uveitis registries and recommends future directions on how uveitis registries can complement one another for synergistic effect and benefit. METHODS: From a systematic search, 861 citations were screened for longitudinal, non-interventional, and multicenter uveitis-specific registries. Additional registries were identified via consultations with uveitis experts. Characteristics of all registries were analyzed and compared. RESULTS: Four registries were identified: Treatment Exit Options for Non-infectious Uveitis, AutoInflammatory Disease Alliance International Registry, Ocular Autoimmune Systemic Inflammatory Infectious Study, and Fight Uveitis Blindness!. Despite certain differences, these registries have the overarching goal of collecting large quantities of real-world, high-quality patient data to improve the understanding of uveitis. CONCLUSION: The four uveitis registries share similar goals and collect clinical data from overlapping geographical regions. There is vast potential for collaboration, including data sharing to further augment datasets for analysis.

Gene therapy is emerging as a modality in 21st-century medicine. Adeno-associated viral (AAV) gene transfer is a leading technology to achieve efficient and durable expression of a therapeutic transgene. However, the structural complexity of the capsid has constrained efforts to engineer the particle toward improved clinical safety and efficacy. Here, we generate a curated library of barcoded AAVs with mutations across a variety of functionally relevant motifs. We then screen this library in vitro and in vivo in mice and nonhuman primates, enabling a broad, multiparametric assessment of every vector within the library. Among the results, we note a single residue that modulates liver transduction across all interrogated models while preserving transduction in heart and skeletal muscles. Moreover, we find that this mutation can be grafted into AAV9 and leads to profound liver detargeting while retaining muscle transduction-a finding potentially relevant to preventing hepatoxicities seen in clinical studies.

Chemotherapy is often used to treat retinoblastoma; however, this treatment method has severe systemic adverse effects and inadequate therapeutic effectiveness. Extracellular vesicles (EVs) are important biological information carriers that mediate local and systemic cell-to-cell communication under healthy and pathological settings. These endogenous vesicles have been identified as important drug delivery vehicles for a variety of therapeutic payloads, including doxorubicin (Dox), with significant benefits over traditional techniques. In this work, EVs were employed as natural drug delivery nanoparticles to load Dox for targeted delivery to retinoblastoma human cell lines (Y-79). Two sub-types of EVs were produced from distinct breast cancer cell lines (4T1 and SKBR3) that express a marker that selectively interacts with retinoblastoma cells and were loaded with Dox, utilizing the cells' endogenous loading machinery. In vitro, we observed that delivering Dox with both EVs increased cytotoxicity while dramatically lowering the dosage of the drug. Dox-loaded EVs, on the other hand, inhibited cancer cell growth by activating caspase-3/7. Direct interaction of EV membrane moieties with retinoblastoma cell surface receptors resulted in an effective drug delivery to cancer cells. Our findings emphasize the intriguing potential of EVs as optimum methods for delivering Dox to retinoblastoma.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G > A mutation in the MT-ND4 gene being the most common disease-causing mitochondrial DNA (mtDNA) variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G > A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary endpoint was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary endpoint). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (p < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (p < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G > A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

PURPOSE: To review the literature on the efficacy of surgical procedures to improve visual acuity (VA) in patients with infantile nystagmus syndrome (INS). METHODS: Literature searches were last conducted in January 2022 in the PubMed database for English-language studies with no date restrictions. The combined searches yielded 354 abstracts, of which 46 were reviewed in full text. Twenty-three of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: One included study was a randomized trial; the remaining 22 were case series. The 23 studies included children and adults with INS and a variable proportion with anomalous head position (AHP), strabismus, and sensory diagnoses. The surgical interventions evaluated included large recessions, tenotomy and reattachment (TAR), myectomy with or without pulley fixation, and anterior extirpation of the 4 horizontal rectus muscles, as well as various procedures to correct an AHP in which VA was reported as a secondary outcome. The data were mixed, with improvements in binocular best-corrected visual acuity (BCVA) ranging from no improvement to 0.3 logarithm of the minimum angle of resolution (logMAR), or 3 lines. (Most studies were in the range of 0.05-0.2 logMAR.) Statistically significant improvement in VA was noted in 12 of 16 studies (75%) that performed statistical analyses, with no clear advantage of any single procedure. Complications and reoperations were lowest in patients who underwent TAR and highest in those who underwent myectomy or anterior extirpation. CONCLUSIONS: The best available evidence suggests that eye muscle surgery in patients with INS results in a modest improvement in VA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting.

OBJECTIVE: To quantify changes in ductions following nasal transposition of the split lateral rectus muscle (NTSLR) for treating third nerve palsy. DESIGN: Retrospective cohort study. PARTICIPANTS: A single eye from each patient with third nerve palsy treated with NTSLR with ocular motility measurements. METHODS: Observation of changes in pre- and postoperative ductions. Outcome measures including patient demographic and surgical factors associated with the ability to adduct beyond the midline after NTSLR were evaluated using multivariable logistic regression. RESULTS: A total of 116 patients met the inclusion criteria for this study. The NTSLR significantly decreased abduction (median of 0 limitation [interquartile range (IQR), 0-0] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001), with a corresponding improvement in adduction (median, -5 [IQR, -5 to -4] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001). There was no change in median supraduction or infraduction after NRSLR (p > 0.05). The ability to adduct beyond the midline after NTSLR was demonstrated in 42% of patients. Although not statistically significant, a trend toward a postoperative ability to adduct beyond the midline was seen in patients who had concurrent superior oblique muscle tenotomy (odds ratio [OR] = 5.08; 95% CI, 0.91-40.9) or who were designated with partial rather than complete third nerve palsy (OR = 2.29; 95% CI, 0.82-6.70). CONCLUSIONS: NTSLR improves the horizontal midline positioning of eyes with third nerve palsy. Most eyes lose the ability to abduct, but some regain a modest ability to adduct while vertical ductions remain unchanged.