QR-1011 restores defective ABCA4 splicing caused by multiple severe ABCA4 variants underlying Stargardt disease.

Stargardt disease type 1 (STGD1), the most common form of hereditary macular dystrophy, can be caused by biallelic combinations of over 2200 variants in the ABCA4 gene. This leads to reduced or absent ABCA4 protein activity, resulting in toxic metabolite accumulation in the retina and damage of the retinal pigment epithelium and photoreceptors. Approximately 21% of all ABCA4 variants that contribute to disease influence ABCA4 pre-mRNA splicing. This emphasizes the need for therapies to restore disrupted ABCA4 splicing and halt STGD1 progression. Previously, QR-1011, an antisense oligonucleotide (AON), successfully corrected splicing abnormalities and restored normal ABCA4 protein translation in human retinal organoids carrying the prevalent disease-causing variant c.5461-10T>C in ABCA4. Here, we investigated whether QR-1011 could also correct splicing in four less common non-canonical splice site (NCSS) variants flanking ABCA4 exon 39: c.5461-8T>G, c.5461-6T>C, c.5584+5G>A and c.5584+6T>C. We administered QR-1011 and three other AONs to midigene-transfected cells and demonstrate that QR-1011 had the most pronounced effect on splicing compared to the others. Moreover, QR-1011 significantly increased full-length ABCA4 transcript levels for c.5461-8T>G and c.5584+6T>C. Splicing restoration could not be achieved in the other two variants, suggesting their more severe effect on splicing. Overall, QR-1011, initially developed for a single ABCA4 variant, exhibited potent splice correction capabilities for two additional severe NCSS variants nearby. This suggests the possibility of a broader therapeutic impact of QR-1011 extending beyond its original target and highlights the potential for treating a larger population of STGD1 patients affected by multiple severe ABCA4 variants with a single AON.

Appropriate assessment of ethnic differences in adolescent use of psychotropic medication: multilevel analysis of discriminatory accuracy.

OBJECTIVE: In the present study, we used a multilevel approach to investigate the role of maternal country of birth (MCOB) in predicting adolescent use of psychotropic medication in Sweden. DESIGN: Using the Swedish Medical Birth Register we identified all 428,314 adolescents born between 1987 and 1990 and who were residing in Sweden in the year they turned 18. We applied multilevel logistic regression analysis with adolescents (level 1) nested within MCOBs (level 2). Measures of association (odds ratio) and measures of variance (intra-class correlation (ICC)) were calculated, as well as the discriminatory accuracy by calculating the area under the Receiver Operator Characteristic (AU-ROC) curve. RESULTS: In comparison with adolescents with Swedish-born mothers, adolescents with mothers born in upper-middle, lower-middle and low-income countries were less likely to use psychotropic medication. However, the variance between MCOBs was small (ICC = 2.5 in the final model) relative to the variation within MCOBs. This was confirmed by an AU-ROC value of 0.598. CONCLUSIONS: Even though we found associations between MCOB and adolescent use of psychotropic medication, the small ICC and AU-ROC indicate that MCOB appears to be an inaccurate context for discriminating adolescent use of psychotropic medication in Sweden.

Mother's country of birth and prescription of psychotropic medication in Swedish adolescents: a life course approach.

OBJECTIVES: Besides medical needs, psychotropic medication use in adolescence might be conditioned by the cultural context of the family. This knowledge is relevant for both detecting inequities in healthcare, and identifying information bias in epidemiological studies using psychotropic medication as a proxy for impaired psychological health. Therefore, we investigated whether, independent of needs, the socioeconomic characteristics of the mother's country of birth are associated with psychotropic medication use in Swedish-born adolescents. DESIGN: Prospective cohort study. SETTING: The Swedish population. PARTICIPANTS: By linking the Swedish Medical Birth Registry to other national registers, we identified all 324 510 singletons born between 1988 and 1990 and who were alive and residing in Sweden until the age of 18 years (2006-2008). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was participants' use of psychotropic medication in the year they turned 18. In the analyses, applying a life-course approach, we included both the mother's and the children's characteristics throughout pregnancy, delivery, infancy, childhood and adolescence when calculating a risk score (RS) to adjust for needs. We classified the mother's country of birth according to the gross national income (GNI) per capita of each country. RESULTS: Overall, the lower the income of the mother's birth country, the lower the probability of psychotropic medication use among children. When adjusting for needs, the association became even stronger. CONCLUSIONS: Besides medical needs, use of psychotropic medication by descendants of immigrants seems conditioned by the socioeconomic characteristics of the mothers' countries of birth. The threat of information bias must be considered if psychotropic medication is used a proxy for impaired psychological health in descendants of immigrants.