De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent variants in the U4 RNA, transcribed from the gene, and in at least two other genes were discovered to cause neurodevelopmental disorder.

Optimized Prime Editing of Human Induced Pluripotent Stem Cells to Efficiently Generate Isogenic Models of Mendelian Diseases.

Prime editing (PE) is a CRISPR-based tool for genome engineering that can be applied to generate human induced pluripotent stem cell (hiPSC)-based disease models. PE technology safely introduces point mutations, small insertions, and deletions (indels) into the genome. It uses a Cas9-nickase (nCas9) fused to a reverse transcriptase (RT) as an editor and a PE guide RNA (pegRNA), which introduces the desired edit with great precision without creating double-strand breaks (DSBs).

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.

Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available.

Lebrikizumab is associated with improvements in patient-reported symptoms and quality-of-life measures across Eczema Area and Severity Index response categories: pooled results from phase-3 randomized ADvocate1 and ADvocate2 studies in patients with moderate-to-severe atopic dermatitis.

Background: Lebrikizumab monotherapy significantly improved signs and symptoms in patients with moderate-to-severe atopic dermatitis (AD) in phase 3 Advocate1 and ADvocate2 studies.

Objective: To evaluate improvements in patient-reported symptoms and quality-of-life (QoL) measures by Eczema Area and Severity Index (EASI) response categories using pooled Advocate1 and ADvocate2 data (post hoc analysis).

Methods: In the 52-week (W) (16-W induction + 36-W maintenance) double-blind, placebo-controlled ADvocate1 and ADvocate2 studies, patients were randomized (2:1) to receive subcutaneous lebrikizumab 250 mg or placebo every 2 weeks.

The efficacy of longer-term lebrikizumab treatment in patients with moderate-to-severe atopic dermatitis who did not meet protocol-defined response criteria at week 16 in two randomized controlled clinical trials.

Background: Lebrikizumab demonstrated statistically significant improvements in patients with moderate-to-severe atopic dermatitis at week 16 with a durable response up to week 52.

Objective: To investigate the efficacy of lebrikizumab-treated patients at 52 weeks who did not achieve the ADvocate1 and ADvocate2 protocol-defined response criteria (≥75% improvement in the Eczema Area and Severity Index [EASI 75] or Investigator Global Assessment [IGA] 0/1 with ≥2-point improvement without rescue medication) after 16 weeks.

Methods: This analysis includes observed data for patients who received lebrikizumab every 2 weeks during the induction period, did not achieve the protocol-defined response, and subsequently received open-label lebrikizumab treatment.