Molecular Diagnosis & Therapy最新文献

Dengue fever, caused by the dengue virus and transmitted primarily by Aedes mosquitoes, poses significant public health challenges across tropical and subtropical regions. With rising temperatures, changing mosquito habitats, and increasing global dengue incidence including to countries previously dengue-naive, accurate and timely diagnosis is crucial for effective disease management and outbreak control. This review explores the current state of both laboratory and point-of-care (POC) tests for dengue fever diagnosis. We discuss the performance characteristics, specifically sensitivity and specificity, of commercially available diagnostic options, highlighting their strengths and limitations. Additionally, we discuss emerging biosensor technologies designed for POC dengue diagnosis, which hold promise but are largely still in development. This overview aims to highlight the evolving landscape of dengue diagnostics and the potential impact of novel technologies.

Neurodegenerative diseases (NDDs) remain among the most challenging disorders to treat, owing to their multifactorial pathology, limited drug delivery across the blood-brain barrier, and lack of effective disease-modifying therapies. Smart nanomedicines are emerging as powerful tools to overcome these challenges by enabling targeted delivery, controlled release, and enhanced bioavailability of therapeutics. In parallel, advances in molecular imaging, combined with machine learning (ML) and artificial intelligence (AI), are transforming the design, validation, and optimization of nanomedicines. This article integrates the rapidly evolving fields of nanomedicine and AI/ML-driven imaging to evaluate their synergistic potential toward NDD therapy. The capabilities of AI-aided imaging for mapping nanomedicine biodistribution, predicting therapeutic outcomes, guiding nanoparticle design, and ensuring quality control at preclinical and clinical stages in NDDs are discussed. This synergistic approach opens new avenues for precision medicine, enabling personalized and adaptive treatment strategies for Alzheimer's, Parkinson's, and other NDDs by linking smart nanocarriers with intelligent imaging analytics. Hence, this article presents a roadmap for translating AI-guided nanomedicine-integrated imaging platforms into clinically viable solutions, marking a paradigm shift in the diagnosis and treatment of NDDs.

Background: Sarcoma represents a diverse group of over 70 subtypes with overlapping morphological and immunophenotypic features, often leading to diagnostic uncertainty. Gene fusions are commonly associated with specific sarcoma subtypes and can aid in diagnosis and management. RNA-based next-generation sequencing (NGS) enables sensitive detection of gene fusions, particularly in cases with limited tissue or ambiguous histopathology.

Methods: We conducted a retrospective review of 124 patients with suspected sarcoma who underwent RNA-based NGS using the Illumina TruSight RNA Fusion Panel (TRFP) at a dedicated sarcoma centre between June 2020 and June 2023. The impact of fusion testing on diagnostic classification and treatment decisions was evaluated by expert pathologists and oncologists.

Results: Gene fusions were detected in 75 of 124 cases (60%). Fusion results confirmed the initial diagnosis in 58 cases (47%) and altered the diagnosis in 17 cases (14%). In 14 cases (11%), findings directly influenced clinical management, including treatment de-escalation (nine cases) and initiation of targeted or alternative therapies (five cases). A definitive diagnosis was achieved in 59% of cases with limited tissue (41 of 70), 48% with uncertain tumour differentiation (25 of 52), and 43% with inconclusive or failed prior molecular testing (ten of 23), underscoring the utility of RNA-based NGS in diagnostically complex scenarios.

Conclusions: RNA-based NGS fusion panels provide diagnostic and clinical utility in the evaluation of mesenchymal tumours. Their integration into routine diagnostic workflows improves diagnostic accuracy and informs personalised treatment decisions, especially in diagnostically complex or resource-limited settings.

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder marked by the progressive and selective loss of spiny projection neurons (SPNs), resulting in a characteristic triad of motor, cognitive, and psychiatric symptoms. Despite ongoing research, no disease-modifying treatments are available, and existing therapies are limited to symptomatic relief. Stem cell-based approaches represent a promising avenue to restore striatal circuitry by replacing lost neurons and/or delivering trophic support to preserve the remaining neural tissue.In this review, we present a critical analysis of past and current clinical trials exploring cell-based therapies for HD. Early studies using human fetal tissue were hindered by sample heterogeneity and inconsistent outcomes, ultimately limiting their clinical applicability. More recent trials have shifted focus toward mesenchymal stem cells (MSCs), which are valued for their neuroprotective secretome but are not suitable for neuronal replacement. To address these limitations, human pluripotent stem cells (hPSCs) have emerged as a renewable and scalable source for the development of advanced therapy medicinal products (ATMPs). In vitro differentiation protocols mimic key developmental signaling pathways to generate striatal-like neural progenitor cells (NPCs). We review the cellular composition of these hPSC-derived ATMPs and summarize findings from preclinical transplantation studies, including data on graft survival, neuronal maturation, synaptic integration, and functional recovery. In addition, we discuss other emerging strategies such as direct neuronal reprogramming. Finally, we examine the major challenges that remain-such as ensuring graft safety, consistency, and regulatory compliance-and highlight the importance of international collaboration to overcome these barriers and accelerate clinical translation.

Dorocubicel (Zemcelpro^®) is a cell therapy that includes UM171-expanded CD34⁺ haematopoietic stem cells derived from umbilical cord blood. It is being developed by Cordex Biologics for the treatment of haematological malignancies and non-malignant haematological disorders. In patients with haematological malignancies requiring an allogeneic haematopoietic stem cell transplantation (HSCT), transplantation with dorocubicel has been shown to result in neutrophil and platelet engraftment, as well as rapid T cell reconstitution. This article summarizes the key milestones in the development of dorocubicel leading to this first approval for the treatment of adult patients with haematological malignancies who require an allogeneic HSCT following myeloablative conditioning, for whom no other type of suitable donor cells is available.

Zopapogene imadenovec (PAPZIMEOS™; zopapogene imadenovec-drba) is a novel non-replicating adenoviral vector-based immunotherapy that stimulates an immune response against human papillomavirus (HPV) types 6 and 11. It is being developed by Precigen, Inc. for the treatment of recurrent respiratory papillomatosis, as these HPV types are causative agents for this condition. Treatment with zopapogene imadenovec resulted in complete responses in approximately half of treated patients and was associated with a papillary microenvironment that was conducive to T cells in complete responders. This article summarizes the milestones in the development of zopapogene imadenovec leading to this first approval for the treatment of adult patients with recurrent respiratory papillomatosis.

Background: Despite the approval of CFTR modulator (CFTRm) drugs for specific variants, many people with cystic fibrosis with non-eligible genotypes may still benefit from these medications. Indeed, recent studies show that some rare CFTR variants can be rescued by approved CFTRm drugs.

Objective: we assessed the efficacy of CFTRm drugs on eight rare CFTR variants: p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ile507del, p.Ser945Leu, p.Met1137Arg, and p.Asp1152His.

Methods: Patient-derived intestinal organoids with these variants in heterozygosity with other cystic fibrosis-causing ones were analyzed by the forskolin-induced swelling assay. Clinical data from individuals undergoing CFTRm therapy were collected both before and after treatment to evaluate clinical benefit. Furthermore, we characterized the molecular defect of those eight variants individually in cystic fibrosis bronchial epithelial cells.

Results: CFTR function in intestinal organoids with genotypes p.Asp1152His/p.Phe508del, p.Asp1152His/p.Asn1303Lys, p.Pro5Leu/p.Phe508del, p.Leu206Trp/p.Phe508del, p.Ser945Leu/p.Phe508del, p.Pro205Ser/p.Tyr1092Ter, and p.Met1137Arg/c.2657+5G>A was rescued by currently available CFTRm drugs, this was not observed for organoids with genotypes p.Arg347Pro/p.Phe508del (elexacaftor/tezacaftor/ivacaftor was not tested) and p.Ile507del/p.Gln890Ter. People with cystic fibrosis who, based on our data, started CFTRm therapy showed a clinical improvement, including an increase in lung function, and a reduction in sweat chloride levels. A positive correlation was observed between forskolin-induced swelling values and change in forced expiratory volume in 1 second. This study provides evidence that the forskolin-induced swelling assay using patient-derived intestinal organoids can effectively predict the clinical outcome of CFTRm treatment. In CFBE cells, all eight variants were found to have a processing defect and variants p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ser945Leu, and p.Met1137Arg were functionally rescued by the current available CFTRm drug. The CFTRm drug did not elicit the appearance of mature p.Ile507del-CFTR and increased, albeit not significantly, the processing efficiency of p.Asp1152His-CFTR.

Conclusions: This work highlights the importance of using patient-derived intestinal organoids as a theranostic tool to predict the clinical benefit and thus increase the number of people with cystic fibrosis with access to the currently approved CFTRm therapies. While theratyping in cell lines is a valuable approach, additional testing in cystic fibrosis-derived organoids provides more reliable predictions for the individuals carrying rare CFTR variants.

Inhibitors of kinase PI3K have been in clinical development for several years but only two drugs, the alpha catalytic sub-unit specific inhibitor alpelisib and more recently inavolisib, also an inhibitor of the alpha catalytic sub-unit, have been approved for a cancer indication, in metastatic breast cancer. In colorectal cancer, despite a high prevalence of PIK3CA gene mutations, PI3K inhibitors have met with limited success, and development has mostly been halted or stagnated. Inherent resistance of colorectal cancer cells to PI3K inhibitors relate to the molecular alterations of this cancer, which include concomitant mutations and copy number alterations in other key players of the receptor tyrosine kinase pathways, including KRAS and BRAF. These have not been addressed adequately during clinical development of PI3K inhibitors. Most early trials examining PI3K inhibitors did not mandate for molecular alterations of PIK3CA as an inclusion criterion. These trials have sought to potentiate the action of other inhibitors of receptor tyrosine kinase pathways using PI3K inhibitors as a non-specific prevention against feedback resistance development. In addition, trials that included patients with PIK3CA-mutated cancers failed to consider mutations in other genes of the pathway, which may be related to primary or induced resistance. Other factors, such as the specific type of PIK3CA mutations arising in the catalytic domain, the helical domain, or other areas of the gene, which may affect the mutation functional repercussions and the inhibitor effectiveness, have not been fully taken into consideration. This review details the progress of PI3K inhibitors' development in colorectal cancer, addresses hurdles in development, and proposes areas for potential advancement.

Radioligand-antibody conjugates (RadioBodies), also known as radiolabeled antibodies, represent an emerging class that enables targeted delivery of radionuclides to tumor cells using antibodies. Conventional antibodies (full-length antibodies) and nonconventional antibodies (antibody fragments) are ideal agents for targeted delivery of radionuclides to tumor sites, owing to their high affinity and specificity. Antibody guides the radionuclide to a precise target, where it participates in killing of cancer cells (therapy) or helps with imaging (diagnosis). RadioBodies are yet to be effectively employed in cancer theranostics but have the potential for the same. Conventional antibodies have long circulatory half-lives, a feature that limits their application in diagnosis but is desirable for therapy. Using nonconventional antibodies (antibody fragments) offers the advantages of small size and removal of the Fc function, which reduces the serum half-life. In recent years, advances in antibody engineering, chelator chemistry and radionuclide technology have greatly facilitated the development of RadioBodies for desired applications. In this review, we discuss the roles of antibodies, chelators, and radionuclides in the clinical development of RadioBodies for cancer theranostics.