Daily Endocrinology Research Analysis
Analyzed 75 papers and selected 3 impactful papers.
Summary
Three studies stand out today in endocrinology and metabolic medicine: a first-in-human in vivo base-editing therapy achieving durable PCSK9 and LDL-C reductions; a genomic diagnostics advance detecting low-level mosaic variants in congenital hyperinsulinism from blood; and a noninvasive urinary lncRNA (MALAT1) biomarker that improves biopsy-level discrimination of diabetic vs non-diabetic kidney disease.
Research Themes
- Gene editing therapeutics for lipid disorders
- Genomic diagnostics and mosaicism in endocrine disease
- Noninvasive RNA biomarkers for diabetic kidney disease
Selected Articles
1. In Vivo Base Editing of
In a phase 1, single-ascending-dose study of 35 adults, a one-time in vivo base-editing therapy (VERVE-102) produced dose-dependent, durable reductions in circulating PCSK9 (up to 88%) and LDL cholesterol (up to 62%; −78 mg/dL at the highest dose), without dose-limiting toxicities. Safety signals included mild–moderate infusion reactions and transient ALT elevations; one aspiration pneumonitis occurred.
Impact: This is the first human study demonstrating durable LDL lowering via in vivo base editing of PCSK9, marking a potential paradigm shift toward one-time genetic therapies for atherosclerotic risk reduction.
Clinical Implications: If confirmed in later-phase trials, a single-infusion gene-editing therapy could provide long-term LDL reduction for patients with familial hypercholesterolemia or high ASCVD risk who are intolerant or nonadherent to conventional therapies.
Key Findings
- Dose-dependent mean PCSK9 reductions from 51% (0.3 mg/kg) to 88% (1.0 mg/kg).
- Corresponding LDL-C reductions from 9% to 62% (−78 mg/dL at highest dose).
- No dose-limiting toxic effects; mild–moderate infusion reactions and transient ALT elevations observed; one aspiration pneumonitis.
Methodological Strengths
- Prospective, dose-escalation design with predefined safety and pharmacodynamic endpoints.
- Durability assessment with ≥1-year follow-up in a subset; registered trial (NCT06164730).
Limitations
- Open-label, single-arm phase 1 design without a control group.
- Long-term safety, off-target editing, and cardiovascular outcomes remain to be established.
Future Directions: Conduct randomized or controlled phase 2/3 trials to evaluate long-term safety, off-target effects, and cardiovascular outcomes, and to define patient populations and dosing that optimize benefit-risk.
BACKGROUND: Persons carrying loss-of-function variants of proprotein convertase subtilisin-kexin type 9 ( METHODS: In this phase 1, open-label, single-ascending-dose study, we administered one intravenous infusion of VERVE-102 at one of six doses (ranging from 0.3 to 1.0 mg of total RNA per kilogram of body weight [mg per kilogram]) to adults with heterozygous familial hypercholesterolemia or premature coronary artery disease. VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting RESULTS: A total of 35 participants across the six dose cohorts received VERVE-102 and had at least 28 days of follow-up. No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease. Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose. Corresponding reductions in the LDL cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose. Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants. CONCLUSIONS: One dose of VERVE-102 led to dose-dependent, substantial, and sustained reductions in PCSK9 and LDL cholesterol levels. (Funded by Verve Therapeutics; ClinicalTrials.gov number, NCT06164730.).
2. Low-level mosaic variants causing the pancreatic disease congenital hyperinsulinism can be detected from blood DNA.
In a large CHI cohort (n=1252), targeted NGS with Mutect2 detected 40 low-VAF mosaic pathogenic variants across dominant CHI genes, with 26/35 validated by ddPCR (median VAF 3.6%). No candidates were found in neonatal diabetes (n=312). Findings support adding mosaic-variant screening to routine CHI genetics with orthogonal confirmation.
Impact: It provides a validated workflow to uncover missed genetic diagnoses in CHI by detecting ultra-low VAF mosaics from blood, with immediate implications for counseling and management.
Clinical Implications: Clinical laboratories evaluating CHI should include sensitive mosaic-variant calling in tNGS pipelines and confirm positives with ddPCR to improve diagnostic yield and guide therapy.
Key Findings
- Detected 40 low-VAF pathogenic variants in 39 CHI individuals; 26/35 validated by ddPCR.
- Median validated VAF was 3.6% (range 1.0–7.8%).
- No candidate low-VAF variants were identified in the neonatal diabetes cohort; variants with VAF <1% had higher false-positive rates.
Methodological Strengths
- Large, disease-specific cohorts with predefined VAF threshold and state-of-the-art variant caller (Mutect2).
- Orthogonal validation using TaqMan-based ddPCR to confirm low-frequency calls.
Limitations
- Retrospective sequencing analysis; generalizability depends on assay performance across laboratories.
- Limited to known pathogenic variants and selected genes; tissue-level mosaic distribution not assessed.
Future Directions: Prospective implementation studies to define clinical workflow, VAF cutoffs minimizing false positives, expansion to broader gene panels, and correlation with phenotype and tissue mosaicism.
BACKGROUND: A substantial proportion of individuals with a well-defined monogenic disorder remain without a genetic diagnosis. Low-level mosaic pathogenic variants are recognised as an underappreciated cause of monogenic disease but are technically challenging to detect, particularly in organ-specific conditions when affected tissue is inaccessible. METHODS: We systematically investigated low-level mosaic variants in individuals with congenital hyperinsulinism (CHI: n = 1252) or neonatal diabetes (NDM: n = 312), two opposing pancreatic disorders of insulin secretion. We screened for established pathogenic variants with variant allele fraction (VAF) < 8% in dominant CHI (ABCC8, GCK, GLUD1, HK1) or dominant NDM (ABCC8, KCNJ11, INS) genes in targeted next-generation sequencing (tNGS) data using Mutect2. FINDINGS: This called 40 variants across the four genes in 39 individuals with CHI. No candidate variants were found in the NDM cohort. Orthogonal validation of 35 variants using TaqMan-based droplet digital PCR (ddPCR) confirmed 26/35 variants. The median VAF for confirmed variants was 3.6% (1.0-7.8%), while false positives (9/35) predominantly had a VAF <1% with some overlap in VAF with true positives. INTERPRETATION: This study shows that disease-causing low-level mosaic variants in dominant CHI genes can be detected in blood using tNGS but require orthogonal validation. These results provide a framework to improve diagnostic yield in organ-specific conditions where mosaic variants may represent an important missed cause of disease. FUNDING: This work was supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with the Team CHIbra and Congenital Hyperinsulinism International [MDBR-23-020-CHI] and the Wellcome Trust [223187/Z/21/Z].
3. Integrated multicompartment urinary long non-coding RNAs profiling (cellular, cell-free, and extracellular vesicle) for better differential diagnosis of biopsy-proven diabetic and non-diabetic kidney disease beyond conventional markers.
Urinary MALAT1, especially from urinary cells, robustly distinguished DKD from NDKD in biopsy-proven cohorts (discovery: ΔCt<8.3, sensitivity 90%, specificity 89.6%; validation: sensitivity 90%, specificity 88.5%). Adding MALAT1 to current clinical markers significantly improved reclassification (NRI 0.53).
Impact: Demonstrates a clinically actionable, noninvasive biomarker with biopsy-level discrimination for DKD vs NDKD and validated performance, supporting earlier, safer triage in T2DM kidney disease.
Clinical Implications: Incorporating urinary cell-derived MALAT1 into diagnostic algorithms could reduce unnecessary biopsies, prioritize high-risk patients for histology, and refine DKD-targeted management.
Key Findings
- MALAT1 and PVT1 levels were elevated across urinary compartments in DKD; MALAT1 showed the most consistent diagnostic performance.
- Urinary cell-derived MALAT1 (ΔCt<8.3) distinguished DKD from NDKD with 90% sensitivity and 89.6% specificity in discovery; 90%/88.5% in validation.
- Adding MALAT1 to clinical/biochemical markers improved classification with an NRI of 0.53.
Methodological Strengths
- Biopsy-proven reference standard with multicompartment urinary profiling and tissue corroboration.
- Discovery–validation design with quantitative performance metrics (ROC, NRI).
Limitations
- Sample sizes are modest and validation cohort size details are limited.
- Cross-sectional design limits assessment of prognostic value and treatment response.
Future Directions: Multicenter prospective validation, assay standardization, head-to-head comparison with emerging biomarkers, and evaluation of impact on biopsy rates, outcomes, and cost-effectiveness.
INTRODUCTION: Renal involvement in type 2 diabetes (T2DM) can be due to diabetes (diabetic kidney disease, DKD) or other causes (non-DKD, NDKD) or both (mixed kidney disease). Available clinical and laboratory parameters have limitations in predicting a diagnosis (gold standard renal biopsy). Long non-coding RNAs (lncRNAs) evaluated in preclinical models but unexplored in biopsy-proven kidney disease in T2DM. We aimed to determine whether there is differential expression of lncRNAs in DKD (compared with NDKD). RESEARCH DESIGN AND METHODS: lncRNAs preselected through database search for evaluation in humans.Discovery cohort: Preselected lncRNAs () evaluated in three components of urine (urinary cell, urinary exosome, and cell-free urine) from biopsy-proven DKD, NDKD, T2DM without kidney disease and healthy subjects (n=40/group). lncRNAs found consistently significant in all components were checked in kidney tissue. Receiver operating characteristic curves were performed to evaluate diagnostic performance.Validation cohort: Best performing lncRNA (in discovery cohort) evaluated in independent cohort. CLINICAL UTILITY: The utility of identified lncRNAs was further assessed for clinical decision-making. RESULTS: Discovery cohort: Level of MALAT1 and PVT1 differed in all urinary components of DKD and elevated in kidney biopsy tissue. MALAT1 showed the most consistent results. Urinary cell-derived MALAT1 showed the most consistent results (ΔCt <8.3, sensitivity 90%, specificity 89.6% OR 53.9, p<0.0001) to differentiate DKD from NDKDValidation cohort: Urinary cell-derived MALAT1 showed sensitivity (90%) and specificity (88.5%). CLINICAL UTILITY: Addition of MALAT1 to currently existing clinical/biochemical discriminators of DKD from NDKD helps improve clinical decision making, with a net reclassification improvement (NRI) of 0.53, 64% of DKD cases were correctly reclassified to a higher probability of disease (NRI+ = 0.280), and 62.5% of NDKD controls were correctly reclassified to a lower probability of disease (NRI- = 0.250). CONCLUSIONS: Urinary cell-derived MALAT1 improves the ability to differentiate DKD from NDKD over and above currently used clinical and biochemical parameters.