Citations

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

ABSTRACT Aims Sarcoid myopathy (SaM) is characterised by granulomatous myositis (GM) and can overlap with inclusion body myositis (IBM), a late‐onset chronic idiopathic inflammatory myopathy with a still enigmatic pathogenesis. As GM can occur in different clinical contexts, we aimed to examine the histomorphologic features and gene expression profiles in cases of definite SaM that may inform diagnostic and therapeutic considerations. Methods We performed a multidimensional characterisation of muscle biopsy specimens from patients with ‘pure SaM’ (n=17), SaM with concomitant IBM (SaM‐IBM) (n=2), including histopathologic and ultrastructural analysis in addition to quantitative real‐time polymerase chain reaction. Additionally, bulk RNA sequencing was performed on 38 muscle biopsy specimens from patients with SaM (including SaM‐IBM) (n=30) and NGI (n=8). Results Histopathological analysis revealed a pattern of endomysial and perimysial granulomatous inflammation frequently extending to the fascia, endomysial fibrosis, muscle fibre atrophy, variation in muscle fibre size and capillary thickening. Findings from immunohistochemical studies established Chitinase 1 as a pure giant cell marker in SaM. On a subcellular level, ‘pure SaM’ was characterised by focal accumulation of large swollen mitochondria with rare cristae but an absence of irregular cristae. Transcriptomic analysis of patients with SaM confirmed markedly elevated expression of both type 1 and type 2 human leukocyte antigen molecules. Macrophage activity markers were highly elevated. Consistent with histologic findings, CHIT1 was specifically overexpressed in SaM samples but not in ‘pure IBM’ muscle biopsy specimens. Conclusions SaM is characterised by a stereotypical appearance at the histopathologic level and disease‐specific immune dysregulation that involves macrophage function and maturation. SaM‐IBM represents a noteworthy overlap syndrome that shares multiple dysregulated immune pathways with ‘pure SaM’.

Abstract Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich’s ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occurring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters alongside the repeat length to improve diagnostic precision of repeat analysis.

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Blood iron levels are related to many health conditions, affecting hundreds of millions of individuals worldwide. To aid in the prevention and treatment of iron-related disorders, previous research has developed a low-cost, accurate, point-of-care method for measuring iron from a single finger-prick blood sample. This study builds upon that work by introducing an improved imaging method that accurately reads sensor images irrespective of variations in environmental illumination and camera quality. Smartphone cameras were used as analytical tools, demonstrating an average coefficient of variation of 5.13% across different phone models, and absorbance results were found to be improved by 8.80% compared to the method in a previous study. The proposed method successfully enhances iron detection accuracy under diverse lighting conditions, paving the way for smartphone-based sensing of other colorimetric reactions involving various analytes.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.