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.

Recurrent gastric or gastroesophageal junction cancers have poor prognoses and limited treatment options. While archival tumor tissue is commonly used for genomic profiling, it may not reflect molecular changes at recurrence.

Human papillomavirus (HPV) is the cause of most cervical cancers and is released as circulating cell-free tumour HPV DNA (ctHPV DNA) into circulation. Earlier studies have indicated that ctHPV DNA is a promising biomarker for analysing treatment response and for recurrence surveillance. However, factors influencing the release of ctHPV DNA, including HPV type and HPV viral load, have not been extensively studied and additional biomarkers for prognosis are needed. Therefore, here we analysed ctHPV DNA, HPV type and viral load in relation to each other and to progression-free survival in patients with locally advanced or advanced cervical cancer.

Colorectal cancer remains a major global health challenge, necessitating the development of accurate non-invasive diagnostic tools. Circulating and excretory microRNAs (miRNAs) are promising biomarkers owing to their stability and regulatory roles in tumorigenic pathways. While single miRNA assays often lack sufficient diagnostic accuracy, panels combining multiple miRNAs have shown enhanced performance. This systematic review and meta-analysis evaluated the diagnostic accuracy of multi-miRNA panels and explored their mechanistic relevance to colorectal cancer pathogenesis.

Glioblastoma (GBM) is an aggressive primary brain tumor with a median survival of 14-15 months even with standard multimodality treatments. The effectiveness of surgical resection, chemotherapy, and radiation therapy are limited by resistance mechanisms including tumor heterogeneity, immunosuppression, presence of stem-like cells, and inhibited drug delivery due to the blood-brain barrier (BBB). The BBB is composed of endothelial cells with tight junctions and selective transport systems, which prevent drug delivery to the tumor at therapeutic levels. Amino acid (AA) transporters have emerged as promising therapeutic targets for overcoming these limitations and enhancing GBM treatment. This review highlights the role of AA transporters in GBM, emphasizing their potential in enhancing targeted therapy, diagnosis, and disease monitoring. We summarize and discuss the 22 AA transporters which are upregulated in GBM, as well as those that demonstrate prognostic correlation. Among these, LAT1 (SLC7A5) has garnered the most attention for its role in drug delivery and imaging, while other transporters exhibit potential as diagnostic and therapeutic targets. Furthermore, nanoparticle technology has emerged as an innovative strategy to enhance targeted therapy through AA transporters. They can enable extended drug circulation, enhanced BBB penetration, and target-specific localization, offering synergistic therapeutic effects. This review emphasizes the importance of AA transporters as multifaceted tools for improving GBM treatment outcomes and the potential of combining AA transporter-targeted therapies with emerging technologies to address the limitations of current GBM management strategies.

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.

Cardiovascular aging is a complex biological process involving progressive cellular and molecular changes that impair heart and vascular function. This review evaluates both fundamental mechanisms and therapeutic strategies, focusing on how recent advances in pharmacology, gene therapy, and regenerative medicine can be translated into clinical practice to mitigate age-related cardiovascular decline. We conducted a comprehensive analysis of peer-reviewed studies from 2000 to 2023, examining molecular pathways of cardiovascular aging and their modulation through pharmacological, genetic, and lifestyle interventions. The review prioritized clinical trials, translational research, and meta-analyses to assess therapeutic efficacy and safety. Current evidence highlights the effectiveness of senolytic drugs such as dasatinib and quercetin in reducing age-related cardiovascular dysfunction, while rapamycin and metformin show promise in improving cardiac longevity through metabolic regulation. Gene therapies, including clustered regularly interspaced short palindromic repeats (CRISPR)-based interventions, demonstrate potential in preclinical models for cardiac regeneration. Stem cell therapies and nanotechnology-based drug delivery systems are emerging as innovative approaches to enhance tissue repair. In addition, lifestyle modifications such as Mediterranean diet adherence and exercise significantly improve vascular health in aging populations. However, challenges remain in drug delivery, patient-specific responses, and long-term safety of novel therapies. The integration of targeted pharmacological treatments, advanced regenerative techniques, and personalized lifestyle interventions represents a transformative approach to managing cardiovascular aging. Future research should focus on optimizing therapeutic combinations, refining delivery methods, and validating biomarkers for clinical monitoring. A multidisciplinary strategy combining these advances will be essential to improve cardiovascular outcomes in aging populations.

ESR1 gene mutations represent one of the main mechanisms of acquired resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) breast cancer. The introduction of liquid biopsy as a minimally invasive technique for analyzing circulating tumor DNA (ctDNA) has opened new avenues for real-time mutation monitoring and personalized treatment strategies. This review explores the clinical relevance of ESR1 mutations in endocrine resistance, the potential of liquid biopsy for early detection and monitoring, and the integration of advanced sequencing technologies and artificial intelligence to improve diagnostic accuracy. Preclinical and clinical studies on key mutations (D538G, Y537S) were analyzed, emerging technologies [(next-generation sequencing (NGS), digital droplet PCR (ddPCR), Cancer Personalized Profiling by deep Sequencing (CAPP-Seq), Targeted Digital Sequencing (TARDIS)] were compared, and survival data from seven major studies were summarized to assess the impact of ESR1 mutations on progression-free survival (PFS) and overall survival (OS). The results show that these mutations, particularly those affecting the ligand-binding domain, are associated with reduced efficacy of aromatase inhibitors and increased tumor aggressiveness. Liquid biopsy proves useful for early detection of resistance mutations and dynamic disease monitoring, but its clinical implementation is limited by low ctDNA levels, technological variability, and the lack of standardized clinical cut-offs. Integration with tissue biopsy, radiomics, and artificial intelligence (AI)-based platforms enhances its clinical utility and prognostic value. In conclusion, liquid biopsy, when combined with advanced technologies and predictive tools, represents an innovative resource for the personalized management of ER+ breast cancer, with the potential to guide timely therapeutic interventions and improve long-term survival.

Sacituzumab govitecan, an anti-trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate, has been approved by both the US Food and Drug Administration and European Medicines Agency for patients with metastatic triple-negative breast cancer who have received two or more prior systemic therapies, including at least one of them for advanced disease. Although TROP2 evaluation is not required for patient selection, survival data from the ASCENT trial show improved response rates in patients with high TROP2 expression by immunohistochemistry. However, there is no standardized testing assay for these patients. This study evaluated the consistency of TROP2 expression analysis across different immunohistochemistry assays.

Gastric cancer is a highly heterogeneous disease, with substantial variations observed among patients in clinical manifestation, histological characteristics, and drug sensitivities. Achieving precision medicine necessitates a comprehensive understanding of the molecular mechanisms underlying gastric cancer and the establishment of robust preclinical models. Organoids, cultivated from cancer cells within tumor tissues, utilizing three-dimensional tissue culture techniques, faithfully replicate the features and heterogeneity of in vivo tumors and have emerged as a promising platform. This review explores the application of gastric cancer-derived organoids (GCOs) in preclinical research and clinical translation, highlighting current challenges and outlining future prospects. Although this technology remains some distance from direct clinical application, it holds tremendous potential for clinical utilization.

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterised by abnormal ciliary motility, primarily affecting the respiratory tract. Despite its clinical significance, there is currently no gold standard for PCD diagnosis. This study aims to address this diagnostic challenge by evaluating a comprehensive approach in a large cohort of patients with suspected PCD.

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.

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.

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often associated with severe long-term neurocognitive and systemic toxicities. Effective drug delivery across the blood-brain barrier remains a major hurdle, limiting the clinical efficacy of targeted therapies. Drug repurposing offers a promising strategy to accelerate treatment availability by utilizing US Food and Drug Administration-approved agents, including niclosamide, itraconazole, and arsenic trioxide, to target critical oncogenic pathways and overcome therapeutic resistance. However, challenges such as limited blood-brain barrier penetration and the lack of pediatric-specific pharmacokinetic data persist. Future research should focus on integrating comprehensive molecular profiling to guide personalized therapy selection, optimizing drug-delivery systems, and exploring rational drug combinations. Emerging technologies, including nanotechnology-based delivery systems, CRISPR-mediated gene editing, and chimeric antigen receptor-T cell therapies, hold significant potential for transforming medulloblastoma treatment paradigms but require further refinement to address toxicity, off-target effects, and biomarker development. Advancing innovative, less toxic therapeutic strategies through the integration of molecular diagnostics and precision therapies is essential to improving survival outcomes and quality of life for children with medulloblastomas.

Circulating tumor DNA has emerged as a minimally invasive and dynamic tool for providing real-time genetic insights into solid tumors, including breast cancer. Circulating tumor DNA is released into the bloodstream through apoptosis, necrosis, or active secretion, and it reflects tumor heterogeneity, which continues to be a major challenge in breast cancer treatment. Advances in high-sensitivity technologies, such as next-generation sequencing and digital polymerase chain reaction, have enabled the detection of key genetic alterations, offering applications in early diagnosis, monitoring minimal residual disease, identifying drug resistance mechanisms, and predicting relapse. Some circulating tumor DNA-based tests have already received regulatory approval for clinical use in patients with breast cancer, and additional studies are underway to expand their applicability. However, low concentrations of circulating tumor DNA and the necessity for standardization across different platforms remain a challenge for the expanded application. In this review, we present an overview of the genetic variants detected in circulating tumor DNA from patients with breast cancer, emphasizing their potential utility in guiding personalized therapeutic strategies and predicting treatment responses across the diverse molecular subtypes of the disease.

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.

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.

The management of spasticity poses a significant challenge for both physicians and patients. This condition, often characterized by increased muscle tone, clonus, and muscle spasms, can be painful, disrupt daily activities, and increases the risk of injuries. First-line treatment for spasticity includes oral medications, such as baclofen, but these drugs can have significant side effects due to inhibitory effects on neural circuits, such as drowsiness and dizziness. Surgical approaches can be applied to patients for whom oral medications fail. However, these treatments can have life-threatening side effects or are irreversible. An emerging technology, chemogenetics, has the potential to provide targeted relief of spasticity, combining a non-destructive surgical approach with the convenience of an oral medication. This Current Opinion describes the current treatment approaches for spasticity, the pathophysiology of this condition, the current state of chemogenetics, and how this technology may be applied to patients with poorly controlled spasticity. Although the use of this approach is at an early developmental stage, we believe that it shows great promise.

Prademagene zamikeracel (ZEVASKYN™) is an autologous cell sheet-based gene therapy developed by Abeona Therapeutics Inc. for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa. Prademagene zamikeracel contains the patient's own genetically modified cells with functional copies of the COL7A1 gene, as patients lacking functional copies of this gene may develop chronic open wounds caused by the separation of dermal layers. This article summarizes the milestones in the development of prademagene zamikeracel leading to this first approval for treatment of wounds in adult and paediatric patients with recessive dystrophic epidermolysis bullosa.