Molecular Diagnosis & Therapy最新文献

Background: Accurate interpretation of genetic variants still represents a major challenge. According to current recommendations from the American College of Medical Genetics and Genomics (ACMG), variant interpretation relies on a comprehensive analysis including, among others, computational data for prediction of variant pathogenicity. However, the predictive accuracy of in silico tools is often limited, and results are frequently inconsistent. In the current study, we evaluated the predictive performance of a previously described innovative classifier (MutScore) for missense variants in our cohort of probands with inherited cardiac diseases (InCDs).

Methods: We retrospectively reviewed missense variants detected in our cohort of probands with InCDs. Variants were analyzed with four in silico tools commonly used in our diagnostic pipelines (CADD, Polyphen-2, Alpha-missense and Revel) and with MutScore, a new meta-predictor combining data on variant location with the output of 16 existing predictors. For each variant, we recorded the original classification (established according to scientific evidence available at the time of molecular diagnosis) and the updated classification performed at the present time, according to ACMG standards.

Results: We detected 252 missense variants in our cohort of 517 patients affected by InCDs. MutScore was the most proficient tool in classifying variants (0.89 maximum area under the curve [95% confidence interval (CI) 0.85-0.94]). Compared to Revel, the second-best predictor, MutScore showed superior sensitivity (73% vs 57%) at the maximum tolerated false-positive rate of 10%, higher specificity (0.83 vs 0.36) and a markedly lower false-positive rate (0.17 vs 0.64), supporting a more nuanced and accurate assessment, especially for benign or likely benign variants. MutScore also appeared to perform better for variants located in genes associated with channelopathies than for variants in cardiomyopathy-related genes. Notably, when comparing the original and updated classification, 27% (69/252) of missense variants underwent a change in classification over the 9-year follow-up period. Among these, reclassification had a significant impact on clinical management in one third of cases (i.e., variants of uncertain significance upgraded to pathogenic or likely pathogenic variants or vice versa), with a 4.8% increase in molecular diagnosis of InCDs over the 9-year period.

Conclusion: Our study supports the excellent performance of MutScore in a real-life dataset of missense variants associated with the rare subset of InCDs. MutScore represents a promising application of artificial intelligence with major potential in cardiogenetics to improve diagnostic precision in clinical practice. In addition, our results highlight the importance of periodic reanalysis of variants, incorporating newly available scientific evidence, as attested by

Revakinagene taroretcel (revakinagene taroretcel-lwey; ENCELTO™) is an encapsulated cell-based gene therapy containing 200,000-440,000 allogeneic retinal pigment epithelial (RPE) cells expressing recombinant human ciliary neurotrophic factor (rhCNTF). Available as a single-dose intravitreal implant, it has been developed by Neurotech Pharmaceuticals, Inc. for the treatment of chronic retinal diseases. In March 2025, revakinagene taroretcel received its first approval for the treatment of adults with idiopathic macular telangiectasia (MacTel) type 2 in the USA. It is the first US FDA-approved treatment for this disease. Revakinagene taroretcel has been granted Orphan Drug Designation for retinitis pigmentosa and Fast Track Designation for retinitis pigmentosa and dry age-related macular degeneration in the USA. This article summarises the milestones in the development of revakinagene taroretcel leading to this first approval for the treatment of adults with idiopathic MacTel type 2 in the USA.

Surgery remains the gold standard in the management of head and neck squamous cell carcinoma (HNSCC). However, the anatomical complexity of these cancers, combined with the difficulty in discriminating between healthy and cancerous tissue and the detection of microlesions, complicates tumor resection, resulting in positive surgical margins, which are associated with a poor patient prognosis. Fluorescence-guided surgery (FGS) has emerged as a promising technique in the management of HNSCC, improving tumor resection and margin assessment. FGS strategies can be roughly divided into three approaches; namely, natural tissue autofluorescence, passive delivery of fluorescent contrast agents, and active targeting. This review provides a comprehensive overview of the advances made in FGS of head and neck cancers, particularly aiming to improve surgical margin assessment. Recently, the field has shown promising results by addressing contrast agents targeted to the overexpressed epidermal growth factor receptor (EGFR), both in preclinical and clinical settings. The identification of new targets such as αVβ6 integrin, uPAR, PARP1, and so on, as well as the development of contrast agents, are key steps in the further development of FGS of head and neck cancers, making it an essential tool in precision oncology. Among these, as was demonstrated in preclinical studies, the αVβ6 integrin is emerging as a promising target due to its high and specific expression in tumor and tumor margins.

Neuroblastoma (NB) is a pediatric extracranial solid tumor that accounts for approximately 15% of all pediatric cancer deaths. More than 50% of patients with newly diagnosed NB are classified into a high-risk group with an approximately 50% long-term survival rate. Although most high-risk patients with NB achieve remission, more than half may have minimal residual disease (MRD) that eventually causes relapse. Looking towards an optimal outcome, the accurate evaluation of MRD in patients with NB (NB-MRD) is essential to monitor the treatment response and disease burden. Over the past decades, the quantification of NB-associated messenger RNA (NB-mRNA) by reverse transcriptase-polymerase chain reaction has become widely used to detect NB-MRD, owing to the lack of recurrent genomic aberrations in NB cells. To achieve a more accurate and sensitive detection, the current NB-MRD assays quantify a set of NB-mRNAs to detect NB cells in bone marrow, peripheral blood, and peripheral blood stem cell samples. Among a growing number of NB-MRD assays, several assays quantitating different but overlapping sets of NB-mRNAs are reported to have a significant prognostic value. However, the clinical significance of NB-MRD remains to be established. In this review, we summarize the recent progress in NB-MRD and evaluate its clinical value.

Acute lymphoblastic leukemia (ALL) is a complex hematologic disorder primarily affecting children, characterized by genetic mutations that disrupt normal lymphoid cell differentiation and promote abnormal proliferation. A particularly high-risk subtype, Philadelphia chromosome-like ALL (Ph-like ALL), mirrors the genetic profile of Philadelphia chromosome-positive (Ph-positive) ALL but lacks the BCR::ABL1 fusion gene. While Ph-like ALL has been extensively studied in high-income countries (HICs), it remains under-researched in low- and middle-income countries (LMICs), where resource limitations hinder accurate diagnosis and targeted therapy. This review addresses this gap by providing a comprehensive overview of the incidence, genetic landscape, and detection strategies for Ph-like ALL, with a special focus on LMICs. It underscores the prevalence of Ph-like ALL and its association with poor clinical outcomes, emphasizing the critical need for cost-effective diagnostic methodologies tailored to resource-constrained settings. Despite advancements in diagnostic technologies, such as whole gene expression profiling and next-generation sequencing, their high cost and extended turnaround times limit their feasibility in LMICs. Innovative methods, such as the PGIMER In-House Rapid and Cost-Effective (PHi-RACE) classifier, which employs real-time quantitative polymerase chain reaction (PCR), offer promising solutions by delivering high sensitivity and specificity at a significantly reduced cost. This approach is further complemented using fluorescence in situ hybridization (FISH) to characterize kinase alterations, enabling the identification of targeted therapies. This method addresses the urgent need for accessible diagnostic tools in LMICs, enabling early detection and personalized treatment planning. As the landscape of Ph-like ALL detection evolves, integrating low-cost, rapid-turnaround approaches holds significant promise for improving patient outcomes globally. This review aims to highlight the challenges and opportunities in diagnosing and treating Ph-like ALL in LMICs, fostering efforts towards more accessible and effective diagnostic strategies to enhance patient care and prognosis.

Obecabtagene autoleucel (AUCATZYL^®) is a CD19-directed genetically modified autologous T cell immunotherapy which is being developed by Autolus for the treatment of hematological cancers and systemic lupus erythematosus. In comparison with other chimeric antigen receptor T (CAR T) therapies, obecabtagene autoleucel has a fast off-rate binder for CD19. Obecabtagene autoleucel received approval following positive results from the FELIX phase I/II trial in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), and it is the first CAR T therapy that does not have mandatory Risk Evaluation Mitigation Strategy monitoring requirements. This article summarizes the milestones in the development of obecabtagene autoleucel leading to this first approval for the treatment of adults with relapsed or refractory B-cell precursor ALL.

Clinical endpoints caused by hyperlipoproteinemia include atherosclerotic cardiovascular disease and acute pancreatitis. Emerging lipid-lowering therapies targeting proprotein convertase subtilisin/kexin 9 (PCSK9), lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3 represent promising advances in the management of patients with hyperlipoproteinemia. These therapies offer novel approaches for lowering pathogenic lipid and lipoprotein species, particularly in patients with serious perturbations who are not adequately controlled with conventional treatments or who are unable to tolerate them. Molecular targets for these novel therapeutic agents were identified and validated through genetic epidemiology studies. Proprotein convertase subtilisin/kexin 9 inhibitors (e.g., monoclonal antibodies and small interfering RNA) have revolutionized hypercholesterolemia management by significantly reducing both low-density lipoprotein cholesterol levels and major cardiovascular events. Genome editing of PCSK9 promises to provide a potential cure for patients with familial hypercholesterolemia. Several investigational lipoprotein(a)-targeting therapies aim to reduce the risk of atherosclerotic cardiovascular disease and aortic valve disease, although definitive clinical endpoint studies remain to be completed. Inhibition of APOC3 messenger RNA expression by olezarsen and plozasiran significantly lowers plasma triglyceride levels and markedly reduces pancreatitis risk in patients with familial chylomicronemia syndrome. Finally, angiopoietin-like protein 3 inhibition by the monoclonal antibody evinacumab has transformed management of patients with homozygous familial hypercholesterolemia. Together, these novel agents expand the therapeutic cache, offering personalized lipid-lowering strategies for high-risk patients with hyperlipoproteinemia, improving clinical outcomes and addressing previously unmet medical needs.