Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy.

BACKGROUND: Retinitis pigmentosa (RP) is a genetically heterogeneous group of degenerative disorders causing progressive vision loss due to photoreceptor death. RP affects other retinal cells, including the retinal pigment epithelium (RPE). MicroRNAs (miRs) are implicated in RP pathogenesis, and downregulating miR-181a/b has shown therapeutic benefit in RP mouse models by improving mitochondrial function. This study investigates the expression profile of miR-181a/b in RPE cells and the neural retina during RP disease progression. We also evaluate how miR-181a/b downregulation, by knocking out miR-181a/b-1 cluster in RPE cells, confers therapeutic efficacy in an RP mouse model and explore the mechanisms underlying this process. RESULTS: Our findings reveal distinct expression profiles, with downregulated miR-181a/b in RPE cells suggesting a protective response and upregulated miR-181a/b in the neural retina indicating a role in disease progression. We found that miR-181a/b-2, encoded in a separate genomic cluster, compensates for miR-181a/b-1 ablation in RPE cells at late time points. The transient downregulation of miR-181a/b in RPE cells at post-natal week 6 (PW6) led to improved RPE morphology, retarded photoreceptor degeneration and decreased RPE aerobic glycolysis. CONCLUSIONS: Our study elucidates the underlying mechanisms associated with the therapeutic modulation of miR-181a/b, providing insights into the metabolic processes linked to its RPE-specific downregulation. Our data further highlights the impact of compensatory regulation between miR clusters with implications for the development of miR-based therapeutics.

CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models independent of the underlying rod-specific gene mutations. Therapeutic editing of the prolyl hydroxylase domain-containing protein gene (PHD2, also known as Egln1) in rod photoreceptors led to the sustained survival of both diseased rods and cones in both preclinical autosomal-recessive and dominant RP models. Adeno-associated virus-mediated CRISPR-based therapeutic reprogramming of the aerobic glycolysis node may serve as a gene-agnostic treatment for patients with various forms of RP.

The Protective Effects of Pyridoxine on Linezolid-Induced Hematological Toxicity, Hepatotoxicity, and Oxidative Stress in Rats.

OBJECTIVE: Linezolid is often used to treat antibacterial-resistant infections. Linezolid can cause side effects. To date, the effectiveness of the simultaneous administration of pyridoxine and linezolid is unclear. Here we investigate the protective effect of pyridoxine on linezolid-induced hematological toxicity, hepatotoxicity, and oxidative stress in rats. MATERIAL AND METHODS: The 40 male pediatric Spraque-Dawley rats were separated into 4 groups: control, linezolid, pyridoxine, and linezolid-pyridoxine. A complete blood count, liver function test, and measurements of antioxidant enzyme activities for superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation were performed in blood before treatment and 2 weeks after administration of the treatment. RESULTS: White blood cell and hemoglobin counts for the linezolid group decreased, and the alanine aminotransferase level in the linezolid group increased compared to their respective baseline values. Post-treatment white blood cell decreased in the linezolid and linezolid- pyridoxine groups compared to those in the control group (P < .001). Alanine aminotransferase levels increased in the linezolid and linezolid-pyridoxine groups compared to those in the control group (P < .001 and P < .05, respectively). The activity of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde levels increased in the linezolid group compared to the control group (P < .001, P < .05, P < .001, and P < .001, respectively). Linezolid plus pyridoxine treatment caused a significant decrease in malondialdehyde levels and superoxide dismutase, catalase, and glutathione peroxidase enzyme activities compared to the linezolid group (P < .001, P < .01, P < .001, and P < .01, respectively). CONCLUSION: Pyridoxine may be an effective adjuvant agent for the prevention of linezolid toxicity in rat models.

Phenotypic Variability of Retinal Disease Among a Cohort of Patients With Variants in the CLN Genes.

Purpose: To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature. Methods: Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes. Results: Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele. Conclusions: Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling.

Hemodynamic response to intravitreal triamcinolone in eyes with macular edema: intravitreal triamcinolone and ocular blood flow.

PURPOSE: To assess ocular hemodynamic response to intravitreal triamcinolone in patients with macular edema due to diabetes or retinal vein occlusion. METHODS: Forty-three patients that were injected by intravitreal triamcinolone acetonide (0.1 cc 4 mg) for unilateral macular edema due to diabetes mellitus (n = 17) and occlusion of retinal vein (n = 26) underwent ocular hemodynamic evaluation by color Doppler imaging (CDI) before and one, two and three months after injection. Non-injected fellow eyes as well as 16 healthy volunteers were also evaluated. RESULTS: In patients with diabetic macular edema, there was no hemodynamic difference between eyes to be injected and non-injected at baseline (P > 0.23). Compared to controls, a significant difference existed in the ophthalmic artery resistant index (P = 0.001) and end-diastolic velocity (P < 0.001) in diabetics. At one month, compared to fellow eyes, change in end diastolic velocity from baseline in treated eyes was significantly decreased in posterior ciliary arteries (0.68 +/- 0.34 cm/s [mean +/- SEM] vs. -1.04 +/- 0.81 cm/s, P = 0.012). Throughout the study period, no significant alteration from baseline in the resistant index of any artery was noted in treated diabetic eyes (P > 0.05). In eyes with retinal vein occlusion, baseline CDI evaluation demonstrated reduced posterior ciliary arteries systolic flow velocity compared to fellow and control eyes (13.24 +/- 1.04 cm/s, 16.37 +/- 0.76 cm/s and 14.33 +/- 1.41 cm/s, respectively, P = 0.007). Increased peak systolic velocity in the posterior ciliary arteries at one week (P = 0.02), one month (P = 0.005) and two months (P = 0.04), and increase in central retinal artery resistant index at one month was noted (P = 0.05). CONCLUSION: Intravitreal triamcinolone temporarily changed central retinal artery blood flow and posterior ciliary arteries' peak systolic blood velocity in eyes with retinal vein occlusion whilst no response of blood flow to triamcinolone injection but only transiently altered end diastolic blood velocity in posterior ciliary arteries was observed in diabetic eyes.