No effective treatment for leber hereditary optic neuropathy (LHON) caused by ND1 mutation is available.This study evaluated the safety and efficacy of a single unilateral intravitreal injection rAAV2-ND1 in various doses for the treatment of LHON. Twelve patients with LHON (ND1 mutation) in two groups with six participants each.The low-dose group received injection of rAAV2-ND1 in a dose of 1.5 × 108 vg/eye while the high-dose group received 1.5 × 109 vg/eye.The safety endpoint was the incidence of adverse events (AEs).The primary efficacy endpoint was changes of best corrected visual acuity (BCVA).The secondary efficacy endpoints were improvement in visual field (VF), visual field index (VFI), and mean deviation (MD) and change in retinal nerve fiber layer (RNFL) thickness. In total,11 mild eye-related AEs occurred in the participants in both groups, and short-term drug treatment returned to normal.The difference was statistically significant in BCVA of the injected eyes in the low-dose group between 12 months after treatment and at baseline.The differences in BCVA of the uninjected eyes in the high-dose group between baseline and 3 months or 6 months after treatment were statistically significant.At 12 months after treatment, the rate of improvement in BCVA for the injected eyes in the low-dose groups was 66.7

This study aimed to assess the safety and efficacy of a rAAV2 carrying normal ND4 (rAAV2-ND4) (NR082) in individuals with visual loss due to LHON carrying the m.11778G>A mutation. Additionally, it aimed to determine a safe dose of NR082 for intravitreal injection. This was a single-arm, open-label, dose-finding clinical trial. A total of 12 participants with the m.11778G>A mitochondrial DNA mutation and vision loss exceeding 6 months in both eyes were enrolled in this trial. The participants received NR082 by unilateral intravitreal injections. 6 participants received 1.5 × 109 vg, 0.05 mL (Group I), and 6 participants received 4.5 × 109 vg, 0.05 mL (Group II) and were followed for 52 weeks and underwent safety assessments, with visual structure and function examinations. No serious ocular or systemic adverse events or dose-limiting toxicity were reported. Adverse events possibly related to treatment included uveitis, subconjunctival haemorrhage, vitreous opacity and keratic precipitates. In Group I, the mean baseline best-corrected visual acuity (BCVA) in injected eyes improved from 1.86 ± 0.36 LogMAR at baseline to 1.59 ± 0.10 LogMAR in week 52 post intravitreal rAAV2-ND4. In Group II, baseline BCVA was 2.15 ± 0.23 LogMAR, improving to 1.92 ± 0.32 LogMAR in week 52. Two eyes in Group I and four eyes in Group II showed significant improvement (at least 0.3 LogMAR BCVA improvement) after 52 weeks. This Phase 1/2 trial demonstrated no serious safety concerns among the 12 participants. And dose of 4.5 × 109 vg, 0.05 mL was to be used in future Phase 3 study.

Background:There was limited research comparing retinal nerve fibre layer (RNFL) involvement among different mitochondrial DNA (mtDNA) mutations associated with varying visual prognoses. This study aimed to observe and compare the thickness changes of RNFL among Leber's hereditary optic neuropathy (LHON) patients with G11778A, T14484C and G3460A mtDNA mutations. Methods:A retrospective cross-sectional analysis was conducted on LHON patients with G11778A (189 eyes of 121 patients), T14484C (20 eyes of 10 patients), or G3460A (28 eyes of 15 patients) mutations, enrolled between July 2017 and December 2020. We also recruited age-matched healthy individuals as the healthy control group. Patients were grouped based on their mutation type and disease duration (<6, 6-12, and >12 months). RNFL thickness measurements were obtained for all quadrants and compared among the three mutation groups. Results:During the subacute phase, the temporal quadrant RNFL thickness in LHON patients with G11778A, T14484C, or G3460A mutations was significantly reduced compared to healthy controls. In the dynamic phase, the RNFL thickness in all quadrants of G11778A or G3460A LHON patients was significantly thinned, except for the nasal quadrant in LHON patients with G3460A mtDNA mutation (P=0.29). As the disease progressed, RNFL thickness in all quadrants and average RNFL thickness were significantly thinner in all three mutation groups relative to controls, except for the nasal quadrant in T14484C mutation patients (P=0.10). Furthermore, during both the subacute and dynamic phases, RNFL thickness in all quadrants was thinner in G11778A and G3460A mutation patients compared to T14484C mutation patients. Conclusions:The papillomacular bundle was the initial and preferential site of involvement in LHON patients across all mutation types. The pattern of RNFL involvement was similar among the three mutations: temporal quadrant thinning occurred first, followed by the inferior and superior quadrants, and finally the nasal quadrant. Patients with G11778A and G3460A mutations exhibited earlier and more pronounced RNFL atrophy compared to those with T14484C mutations.

To investigate the peripapillary retinal nerve fibre layer (RNFL) thickness changes and analyse factors associated with visual recovery of G11778A Leber hereditary optic neuropathy (LHON) patients. Patients diagnosed with G11778A LHON between July 2017 and December 2020 in Tongji hospital were included in this follow-up study. Patients were grouped according to disease duration. Variations in the RNFL thickness in each quadrant at different disease stages were characterised using optical coherence tomography. According to the absence or presence of significant visual acuity improvements, LHON patients of disease duration ≥ 6 months were divided into two groups. A bivariate logistic regression model was constructed to analyse the potential factors associated with spontaneous visual recovery. This study included 56 G11778A LHON patients (112 eyes) and 25 healthy controls (50 eyes), with a mean follow-up of 5.25 ± 1.42 months. All quadrants and mean RNFL thicknesses of LHON patients first increased and then decreased, except for the temporal RNFL. As the disease progressed, RNFL thinning slowed; however, gradual RNFL thinning occurred. Logistic regression revealed that baseline best corrected visual acuity was related to spontaneous visual recovery of LHON patients with disease duration ≥ 6 months. The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.

Background. LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and meta-analysis are aimed at summarizing epidemiology, disease onset and progression, visual recovery, risk factors, and treatment options of Leber’s hereditary optic neuropathy (LHON) with mitochondrial DNA mutation G11778A from current evidence. Methods. The PubMed database was examined from its inception date to November 2021. Data from included studies were pooled with either a fixed-effects model or a random-effects model, depending on the results of heterogeneity tests. Sensitivity analysis was conducted to test the robustness of results. Results. A total of 41 articles were included in the systematic review for qualitative analysis, and 34 articles were included for quantitative meta-analysis. The pooled estimate of proportion of G11778A mutation among the three primary mutations of mitochondrial DNA (G11778A, G3460A, and T14484C) for LHON was 73% (95% CI: 67% and 79%), and the LHON patients with G11778A mutation included the pooled male ratio estimate of 77% (76% and 79%), the pooled age estimate of 35.3 years (33.2 years and 37.3 years), the pooled onset age estimate of 22.1 years (19.7 years and 24.6 years), the pooled visual acuity estimate of 1.4 LogMAR (1.2 LogMAR and 1.6 LogMAR), and the pooled estimate of spontaneous visual recovery rate (in either 1 eye) of 20% (15% and 27%). Conclusions. The G11778A mutation is a prevalent mitochondrial DNA mutation accounting for over half of LHON cases with three primary mutations. Spontaneous visual recovery is rare, and no effective treatment is currently available.

Review question / Objective: P: diabetic retinopathy; I:—; C:—; O: prevalecne rate; S:cross-sectional study. Objective:To analyze the epidemiological characteristics of diabetic retinopathy and to provide scientific basis for its prevention and control． Condition being studied: Diabetic retinopathy is one of the common microvascular complications in patients with diabetes mellitus, which ultimately seriously affects the vision of patients. It is the leading cause of blindness among young and middle-aged workers worldwide. It is one of the main causes of binocular blindness in elderly patients in western countries.Because of the high incidence, wide range, complex pathogenesis, serious consequences and poor treatment effect of DM and its DR,many countries have actively carried out epidemiological research on the population of DM patients in order to understand the incidence, distribution and related risk factors of DR, and to provide scientific basis for the formulation of targeted public prevention and control measures.

Background & objectives: Tear proteomic changes can be a candidate etiopathogenesis of lacrimal duct obstruction diseases (LDODs). Studies on proteomics have focused primarily on nasolacrimal duct obstruction, and some specific inflammatory cytokines such as interferon (IFN)-α2a, interleukin (IL)-8 and IL-10, have not been investigated. In addition, differences in inflammatory cytokines in tears according to the LDOD subtype have not been reported. This study aimed to quantitatively compare inflammatory cytokines in tears from patients with LDOD and investigate tear-cytokine differences among different LDOD subtypes. Methods: Tear samples were collected from both eyes of 30 patients with unilateral LDOD: five patients with prelacrimal obstruction, five with acute dacryocystitis and 20 with chronic dacryocystitis. The contralateral eyes were used as controls. IFN-α2a, IFN-β, IFN-γ, IL-17A, IL-6, IL-8, tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF)-A, induced protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1) were quantified in all samples. Results: The expression of eight cytokines (except for IP-10 and MCP-1) were significantly increased in the affected eyes compared with those in the control eyes. The levels of nine inflammatory cytokines (except for IP-10) in the affected eyes of patients with chronic dacryocystitis were higher than those in the affected eyes of patients with prelacrimal obstruction. In addition, patients with chronic dacryocystitis presented significantly higher IFN-γ level than those with prelacrimal obstruction or acute dacryocystitis. Interpretation & conclusions: Specific pro-inflammatory cytokines were increased in tears of patients with LDOD compared with those in the controls. The specific cytokine profiles observed in the tears of individuals with different LDOD subtypes may be associated with the unique aetiopathogenesis of these conditions.

BACKGROUND:Bisphenols and triclosan (TCS) are common endocrine disrupters (EDCs) that may induce oxidative stress. However, there is limited information as to whether these EDCs interact with genetic variants to modify the levels of oxidative stress on a genome-wide scale. METHODS:We first performed a genome-wide scan among a Chinese population and also measured three urinary EDCs, including bisphenol A (BPA), bisphenol F (BPF) and TCS, and three urinary oxidative stress markers [4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α) and 8-hydroxy-deoxyguanosine (8-OHdG)]. Subsequently, we examined interactions between three urinary EDCs and nearly 4.6 million genetic variants for three urinary oxidative stress markers by the general linear model. RESULTS:Urinary BPA, BPF and TCS were positively associated with HNE-MA, 8-isoPGF2α and 8-OHdG. Significant rs6855040 (4p15.32/between SNORA75B and QDPR)-BPA, rs1112943 (4q35.1/SNX25)-TCS interactions were associated with the 8-isoPGF2α levels (all P < 5 × 10-8). In addition, rs4656116 (1p22.3/CACL1), rs16958760 (17p11.2/between USP43 and DHRS7C) and rs11651078 (17p11.2/LOC339260) showed significant gene-TCS interactions with 8-OHdG (all P < 5 × 10-8). The gene-level analysis found significant interaction between SNX25 and TCS for 8-isoPGF2α levels (P < 2.12 × 10-6). CONCLUSION:Our results identify several gene-EDCs interactions for oxidative stress, highlighting that EDCs may modify the effect of genetic variants on oxidative stress.

PURPOSE:To investigate retinal nerve fiber layer (RNFL) thickness changes at different stages of Leber's hereditary optic neuropathy (LHON) in patients bearing the ND4 G11778A mutation. METHODS:Ninety-eight clinically diagnosed, G11778A-positive LHON patients underwent 538 optical coherence tomography (OCT) examinations from September 2015 to September 2017. Patients were grouped based on disease duration at examination. Fifty healthy volunteers underwent 100 examinations as controls. Differences in RNFL thickness were compared across groups. RESULTS:During the onset of LHON patients with G11778A mutation, the thickness of nerve fiber layer in temporal quadrant decreased slowly within 1-3 months (p > .05), then entered in the rapid thinning period, which generally lasted until about 12 months of the course of disease (p < .05), and no obvious change occurred in the stable stage (p > .05); The optic nerve fiber layer in other quadrants was usually stayed in a significant thickening period within 1-3 months (p < .05), then entered in the rapid thinning period, which generally lasted until about 24 months of the course of disease (p < .05), and no obvious change occurred in the stable stage (p > .05) . CONCLUSION:In LHON patients with G11778A mutation, the thickness of optic nerve fiber layer in the temporal side will experience slow thinning stage, rapid thinning stage and stable stage; The thickness of optic nerve fiber layer in other directions varies with the course of disease. Generally, it will experience five periods: significant thickening period, swelling period, recovery period, rapid thinning period and stable period.

Objective:To observe the changes of vision and visual evoked potentials (VEP) in patients with Leber hereditary optic neuropathy (LHON) before and after gene therapy.Methods:A retrospective cohort study. From December 2017 to October 2018, 35 cases of 70 eyes of m11778G.A/MT-ND4 mutant LHON patients who were diagnosed in the Tongji Hospital of Huazhong University of Science and Technology and received gene therapy were included in the study. There were 30 males (87.71%) and 5 females (12.29%), with the mean age of 23.31±6.72 years. The gene therapy method was intravitreal injection of rAAV2-ND4 (recombinant adeno-associated virus carrying NADH-ubiquinone oxidoreductase subunit 4 gene) into one eye. The eye with poor visual acuity was chosen as the injection eye. If both eyes had the same visual acuity, the right eye was designated as the injection eye. Seventy eyes were divided into the injected eye group and the non-injected eye group, in which were both 35 eyes. The best corrected visual acuity (BCVA) and pattern VEP (PVEP) examinations were performed in the injected eye group and the non-injected eye group before treatment (baseline), 1, 3, and 6 months after injection. Compare the changes of BCVA and PVEP between the injected eye group and the non-injected eye group at baseline, 1 month, 3 months, and 6 months after injection. Independent sample t test, paired sample t test or two independent sample nonparametric test were performed to compare the two groups. Results:Compared with baseline, 1, 3, and 6 months after treatment, the BCVA of the injected eye group ( t=3.530, 4.962, 5.281; P=0.001, 0.000, 0.000) and the non-injected eye group ( t=3.288, 2.620, 2.252; P=0.002, 0.013, 0.031) increased, and the difference was statistically significant; there was no statistically significant difference between VEP IT ( tinjected eye group=-0.158, 1.046, -1.134; Pinjected eye group = 0.875, 0.303, 0.190; tnon-injected eye group=0.773, -0.607, -0.944; Pnon-injected eye group = 0.445, 0.548, 0.352) and VEP A ( Zinjected eye group=-0.504, -0.934, -1.065; Pinjected eye group = 0.614, 0.351, 0.287; Znon-injected eye group=-0.521, -0.115, -0.491; Pnon-injected eye group = 0.602, 0.909, 0.623). Conclusion:After gene therapy, the visual acuity of the injected and non-injected eyes of LHON patients improved; PVEP did not change significantly, and remained stable compared with baseline.

Background: The number of pediatric outpatient visits in the general hospitals of China shows an increasing trend year by year. To analyze the current situation of clinical trials of drugs with indications for children in China in order to provide references for research and development of drugs for children and in formulating relevant policies. Methods: Drug clinical trials with indications for children registered before January 9, 2020 were retrieved based on the drug clinical trial registration and information publicity platform. The data were extracted and statistically analyzed by excel 2010 and SPSS 22.0, respectively. Results: There were 256 clinical trials of drugs with indications for children, which accounted for 2.61% of the total registered trials. The overall average annual growth rate of the number of trials from 2007 to 2019 was 43.30% (P=0.0000). The host company and the lead organization were mainly located in the eastern and northern parts of China. There were 67 trials (26.17%) with children as subjects; 102 trials (39.84%) with research drugs only for children; the drug type was mainly the chemical drug, and indications mainly included infections, nervous and mental diseases and respiratory diseases. Conclusion: The prospects associated with pediatric drug development are positive, but it still needs new incentives or technical guidance to further promote.

Background Limited studies have identified the changes in peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with chronic Leber’s hereditary optic neuropathy (LHON) at different stages of the disease. We aimed to characterise the pRNFL thickness changes in patients with LHON having m.11778G>A (MT-ND4) mutation. Methods This retrospective cross-sectional study included 221 eyes from patients with LHON (n=145)—classified into seven groups according to disease duration—and 52 eyes from healthy controls (n=26). All subjects underwent pRNFL examinations. pRNFL thickness of the superior, nasal and inferior, and temporal quadrants, and the 360° average were measured. Results Within 3 months of onset, the temporal pRNFL thickness decreased significantly, whereas the remaining quadrants and the average pRNFL thickness initially increased. The temporal quadrant (p<0.01) and average pRNFL thickness (p=0.02) significantly decreased at 3–6 months. Excluding that in the nasal quadrant (p=0.93), pRNFL thickness significantly decreased in all other quadrants at 6–9 months. At 9–12 months, the average and individual quadrant pRNFL thicknesses continued to decrease. Compared with 12–24 months, the pRNFL thickness was thinner at 24–60 months and >60 months. Conclusions The papillomacular bundle was affected first and preferentially in LHON. pRNFL thickness initially increased and then decreased, corresponding to the retinal ganglion cell swelling and apoptosis. pRNFL thinning first occurred in the temporal quadrant, followed by the inferior and superior quadrants, and finally, the nasal quadrant. pRNFL continued to thin slowly in some quadrants even after 60 months.

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial mutation with simultaneous or consecutive binocular painless loss of vision and central visual field (VF) defects.1 In 2008, we initiated recombinant adeno-associated virus-mediated gene therapy research for LHON. Between 2011 and 2012, we evaluated the efficacy, durability, and long-term safety in 9 patients with the LHON mt11778G→A mutation (ClinicalTrials.gov identifier, NCT01267422). Except for patient 1, all patients received a single intravitreal injection of gene therapy agent.

PURPOSETo analyse the factors associated with rapid and significant improvement in visual acuity in patients with Leber's hereditary optic neuropathy (LHON) after gene therapy and explain the theory of this improvement.METHODSWe recruited 149 patients with LHON, who underwent gene therapy, and divided them into two groups according to the absence or presence of rapid and significant visual acuity improvements within 3 days of treatment. A bivariate logistic regression model was used to analyse relevant factors including age, the period between onset and treatment, baseline values of best corrected visual acuity (BCVA), visual field index (VFI) and pretreatment average retinal nerve fibre-layer thickness (GRNFL). The corresponding parameters for the injected and non-injected eyes were analysed separately.RESULTSThe period between onset and treatment, and pretreatment baseline BCVA was significantly associated with rapid and significant improvement in visual acuity for both, the injected and non-injected eyes. Moreover, pretreatment baseline VFI and GRNFL were not significantly associated with rapid and significant improvement in visual acuity. Age was significantly associated with rapid and significant improvement in visual acuity of the injected eyes.CONCLUSIONThe period between onset and treatment, and pretreatment baseline BCVA may be important predictors of rapid and significant improvement in visual acuity in patients with LHON after gene therapy.

IMPORTANCE:Factors affecting visual acuity prognosis after gene therapy in Leber's hereditary optic neuropathy (LHON) patients with mutation at site 11 778 are unknown. BACKGROUND:To analyse correlations between visual acuity prognosis and baseline characteristics of LHON after rAAV2-ND4 gene therapy. DESIGN:Retrospective study. PARTICIPANTS:Fifty-three LHON patients with a mutation at site 11 778. METHODS:Single-eye intravitreal injection of rAAV2-ND4. MAIN OUTCOME MEASURES:Sex, onset age, duration of disease, best-corrected visual acuity (BCVA), visual field index (VFI) and mean deviation (MD) were recorded for all patients at baseline. BCVA was recorded at 1- and 3-month follow-up visits after gene therapy. Correlations between BCVA prognosis and baseline characteristics were analysed by univariate analysis. Logistic regression analysis was performed on independent factors affecting BCVA prognosis. RESULTS:Univariate analysis showed significant differences in the VFI and MD of the injected eye between BCVA improvement and non-improvement groups after 3 months of treatment, with greater VFI and smaller absolute MD in the BCVA improvement group. Logistic regression showed that VFI and baseline BCVA were independent prognostic factors for visual acuity. The correlation between VFI and MD was statistically significant. CONCLUSIONS AND RELEVANCE:VFI and baseline BCVA were correlated with the visual acuity prognosis of LHON patients receiving gene therapy, with greater baseline VFI and better baseline BCVA predicting better visual acuity prognosis. MD was strongly correlated with VFI and might be correlated with gene therapy prognosis. This finding may form a basis for predicting the efficacy of gene therapy in these patients and guiding subsequent treatment.

Background: During the first few trials of gene therapy for Leber's hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber's hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment. Case presentation: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment. Conclusion: We suspect that in some patients with Leber's hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a "dormant" state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber's hereditary optic neuropathy.

Gene therapy in ophthalmology has developed rapidly, and there has been a breakthrough in the treatment of Leber's hereditary optic neuropathy. After receiving an intravitreal injection of rAAV2-ND4, patients followed up over a certain time period showed a definite increase in visual acuity. Visual acuity testing is critical for assessing the efficacy of rAAV2-ND4 intravitreal injection.

Proliferation of the adult hepatocyte population represents a central feature of tissue regeneration after liver injury and resection. This process could be driven by a diverse range of mitogens, such as hepatocyte growth factor (HGF) and fibroblast growth factor (FGF). Among FGF family, FGF2 is closely related to wound repair and cell proliferation. FGF2 does function in the process of angiogenesis in regenerating liver, while fewer reports are concerned with the impact and underlying mechanism of FGF2 on liver cell proliferation. To this end, an immortalized human normal hepatocyte L02 and mouse primary hepatocytes were exposed to FGF2 in this study. We demonstrate that FGF2 significantly enhances liver cell proliferation. Treatment with FGF2 obviously increases the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Activity inhibition or expression down-regulation prove that both ERK1/2 and JNK signaling are required for FGF2-mediated effect on liver cell proliferation. Interestingly, interfering of ERK1/2 signaling results in marked decrease of JNK activation under FGF2 treatment, and JNK signaling is also involved in regulation of FGF2-induced ERK1/2 activation, suggesting that cross-talk between ERK1/2 and JNK signaling is important for FGF2 mitogenic activity. Both ERK1/2 and JNK signal via CREB to function in proliferation impact of FGF2 on liver cells. Taken together, this study reveals that ERK and JNK pathways synergistically regulate FGF2-induced liver cell proliferation via phosphorylating CREB, which will contribute to the understanding of FGF2 impact on liver cell proliferation and liver regeneration.

INTRODUCTION:Leber's Optic Hereditary Neuropathy (LHON) is a common cause of teenaged blindness in both eyes for which there is currently no effective treatment. In 1871, the German ophthalmologist Theodor Leber was the first to describe the clinical characteristics of his namesake disease, and through unremitting efforts over the past 100 years, researchers have continued to increase their understanding of LHON. In recent years, using gene therapy, several groups have obtained breakthroughs in the treatment of the disease.CONCLUSION:In this article, we will review the challenging journey that researchers faced towards our current understanding of LHON, and describe the transition of gene therapy research for LHON from the bench to bedside.