Clinical and translational discovery最新文献

{"title":"From multi-omics to cancer digital twins: Novel paradigm in cancer research and treatment response","authors":"Sara Sadat Aghamiri, Rada Amin","doi":"10.1002/ctd2.70035","DOIUrl":"https://doi.org/10.1002/ctd2.70035","url":null,"abstract":"<p>Integrating multi-omics in cancer research has expanded our understanding of the intricate molecular mechanisms underlying malignancies. Traditional single-omics approaches, while informative, only capture one molecular layer at a time.<span><sup>1</sup></span> However, cancer is a multifaceted disease driven by genetic, epigenetic, metabolic and signalling interactions. In addition, the crosstalk between tumour cells and their environment, whether occurring during malignancies or modulated through therapy, is inherently multiscale. For instance, the crosstalk spans molecular-, cellular- and systems-level processes, operating across temporal and spatial scales. Such complexity renders the tumour ecosystem an archetype of a hierarchical system, requiring integrative approaches to fully comprehend and address.<span><sup>2</sup></span> Multi-omics bridges this gap by integrating diverse data types from the same patients to provide a multidimensional view of the tumour ecosystem. Each of these modalities contributes unique insights into the core tumour; for example, genomics focuses on the mutational landscape, transcriptomics highlights aberrant gene expression, proteomics elucidates protein interactions, epigenomics reveals regulatory mechanisms, metabolomics uncovers metabolic reprogramming and spatial omics map biomolecules directly onto the physical position of tumour niches.<span><sup>3</sup></span> Together, these multiple modalities resume tumours' molecular and functional dynamics, improving applications such as precision medicine, biomarker discovery, drug target identification and patient stratification (Figure 1).</p><p>Integrating multi-omics requires sophisticated computational methods capable of handling high-dimensional datasets.<span><sup>4</sup></span> To tackle these challenges, artificial intelligence (AI), machine learning (ML) and deep learning (DL) have emerged as powerful tools. The AI- and ML/DL-based models facilitate the fusion of multiple modalities into a unified framework, addressing the challenges of disparate data types that vary in size, scales, formats, distributions and noise levels. Its ability to process and harmonize multi-omics data at scale allows this approach to analyse complex datasets, identify hidden patterns and uncover correlations across multi-omics layers often imperceptible to human analysis.<span><sup>5</sup></span> For example, Zhang et al. developed a comprehensive multi-omics platform called COMOS, designed as a non-invasive approach to enhance the diagnosis and prognosis of diffuse large B-cell lymphoma. The authors utilized cell-free DNA (cfDNA) extracted from a single tube of patient blood to analyse several features simultaneously. Using ML algorithms, authors integrated diverse parameters, including nucleosome positioning, CpG island methylation, DNase hypersensitive sites, methylated regions, and copy number alterations, providing a comprehensive view of the cfDNA landscape. COMOS demonst","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-COVID-19 pulmonary fibrosis: Mechanisms, biomarkers, and therapeutic perspectives","authors":"Urvinder Kaur Sardarni,&nbsp;Siddappa N. Byrareddy","doi":"10.1002/ctd2.70034","DOIUrl":"https://doi.org/10.1002/ctd2.70034","url":null,"abstract":"<p>Post-COVID-19 pulmonary fibrosis (post-CPF) has emerged as a serious complication with profound implications for long-term respiratory health. This short review explores the multifactorial mechanisms underlying post-CPF, emphasising the role of oxidative stress, epithelial-to-mesenchymal transition (EMT), and dysregulated immune responses. Key signalling pathways, such as TGF-β, WNT, and Cadherin, are pivotal in fibrosis progression, offering potential therapeutic targets. Biomarkers, such as MUC4, KRT5, and ATP12A show promise for early detection and therapeutic targeting, as they share molecular features with idiopathic pulmonary fibrosis (IPF) and fibrotic interstitial lung diseases (f-ILDs), suggesting opportunities to repurpose antifibrotic therapies. Despite these advancements, significant gaps remain in understanding the cellular and molecular mechanisms underlying fibrosis progression, hindering effective management of post-CPF. Addressing these challenges through a targeted approach is critical to improving outcomes for survivors of severe COVID-19.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilising single-cell sequencing in clinical nutraceutical research: Recent progress and perspectives","authors":"Xiaoqiang Wang,&nbsp;Yin S. Chan,&nbsp;David Sadava,&nbsp;Shiuan Chen","doi":"10.1002/ctd2.70032","DOIUrl":"https://doi.org/10.1002/ctd2.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Single-cell sequencing technologies have revolutionised pharmaceutical research by providing in-depth insights into human biology at the single-cell level. These tools enable researchers to identify rare cell types and analyse cellular diversity within tissues, facilitating the discovery of new therapeutic targets and biomarkers. However, their application in nutraceutical research is still in its early stages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>Unlike pharmaceuticals, which have well-defined chemical structures and mechanisms, nutraceuticals are food-based materials intended for specific medical purposes and often contain complex and diverse food chemicals. These molecules can work synergistically, producing multi-targeted effects in various tissues. Traditional bulk profiling methods for tissues and tumours do not adequately capture cellular heterogeneity or specific cellular responses to treatments. Therefore, advanced single-cell sequencing is crucial for dissecting tissues into distinct cell types, helping to clarify the underlying mechanisms at the cellular level. Many derivatives of functional foods have been marketed or assessed, demonstrating health benefits. However, mechanistic insights are lacking, with most current data derived from observational studies or traditional in vitro and in vivo models. Human clinical trials are needed to validate these nutraceutical effects and determine effective and safe dosages. Edible mushrooms have gained attention as nutraceuticals due to their medicinal properties. They have been observed to enhance immunity, reduce inflammation, and combat cancer. These effects have been attributed to their unique bioactive components and historical uses in traditional medicine. Epidemiological studies show that higher consumption of edible mushrooms is linked to a reduced risk of certain cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In this review, we share important lessons learned in the design and execution of clinical trials focusing on white button mushrooms as anti-cancer nutraceuticals. We demonstrate the use of single-cell RNA sequencing (scRNA-seq) in nutraceutical research to capture the nuanced biological responses and health effects of dietary foods and their constituents.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143118527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrarenal pressure monitoring via flexible and navigable suction ureteral access sheath in retrograde intrarenal surgery: A preclinical animal study and a pilot clinical study","authors":"Wei Zhu,&nbsp;Steffi Kar Kei Yuen,&nbsp;Jianwei Cao,&nbsp;Chu Ann Chai,&nbsp;Shusheng Liu,&nbsp;Jingzeng Du,&nbsp;Wen Zhong,&nbsp;Zhijian Zhao,&nbsp;Yongda Liu,&nbsp;Guohua Zeng","doi":"10.1002/ctd2.70031","DOIUrl":"https://doi.org/10.1002/ctd2.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated intrarenal pressure (IRP) during retrograde intrarenal surgery (RIRS) can lead to deleterious complications. Emerging non-invasive, real-time IRP monitoring tools are proving crucial for enhancing procedural safety. This study evaluates a newly developed flexible and navigable suction ureteral access sheath (FANS) with IRP monitoring capabilities through animal study and a clinical trial, assessing its accuracy and operational benefits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A preclinical animal study and a prospective clinical trial involving 100 patients were conducted. The animal study confirmed the accuracy of IRP-monitoring FANS, whilst the clinical trial compared its performance to conventional FANS in RIRS. The evaluated outcomes included the accuracy of IRP measurements, the irrigation flow rate, the duration of the operation, and the stone-free rate (SFR). Statistical comparisons were performed using appropriate tests with a significant threshold of <i>p</i> &lt; .05. Registration for this study is recorded under the identifier NCT06729801 at ClinicalTrials.gov.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the animal study, IRP-monitoring FANS demonstrated high accuracy in real-time IRP measurement, comparable to percutaneous nephrostomy-based monitoring. In the clinical study, IRP-monitoring FANS enabled increased irrigation flow whilst maintaining safe IRP levels within 30 mmHg. Operative time was significantly shortened in IRP-monitoring FANS group (50.9 vs. 67.6 min, <i>p</i> &lt; .01), with similar SFRs between groups. No notable discrepancies in the rates of complications were observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The IRP-monitoring FANS improves stone retrieval efficiency and shortens operative time whilst ensuring safety through real-time IRP monitoring. This novel device marks a major improvement in both the safety and effectiveness of RIRS for managing large renal stones.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143117827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilisation of a national database to characterise renal function in patients with COVID19 infection","authors":"Nicholas R. Nelson,&nbsp;Nicholas Farina,&nbsp;Denise H. Rhoney,&nbsp;the N3C consortium","doi":"10.1002/ctd2.70027","DOIUrl":"https://doi.org/10.1002/ctd2.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>The incidence of renal function alterations among patients with COVID19 is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine the incidence of acute kidney injury (AKI) or augmented renal clearance (ARC) in patients hospitalised with COVID19 and identify risk factors for patients who may exhibit each renal alteration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Retrospective, observational cohort analysis of hospitalise, adult patients within the National COVID Cohort Collaborative (N3C) database with laboratory confirmed COVID19 and available data to calculate creatinine clearance using the Cockcroft–Gault equation from 1 January 2020 through 9 April 2022.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Measurements</h3>\u0000 \u0000 <p>Incidence of AKI or ARC and patient demographics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main results</h3>\u0000 \u0000 <p>15 608 patients were included for renal function characterisation where 20.9% experienced AKI and 34.8% exhibited ARC. ARC lasted longer than AKI; however, AKI was associated with increased hospital length of stay and mortality. 11 274 patients were included in logistic regression analysis. Height and White race were the only variables associated with decreased risk of AKI while male sex and diabetes were associated with increased risk. Male sex, Black race and hypertension were associated with decreased risk of ARC. Age was associated with decreased risk of both AKI and ARC while weight and Hispanic ethnicity were associated with increased risk in both renal alterations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>A significant proportion of patients exhibit renal alterations during their hospitalisation for COVID19. These results provide initial evidence of identifying patients at risk of AKI or ARC, but more research is needed, especially with respect to use of biomarkers for renal alteration risk stratification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroglobulin mRNA ectopic expression was an excellent marker to detect lymph node metastasis for patients with papillary thyroid cancer","authors":"Wen-Hua Du,&nbsp;Ying-Chao Chen,&nbsp;Ning Jin,&nbsp;Yuan-yuan Zhang,&nbsp;Bao-Lan Ji,&nbsp;Jing Wu,&nbsp;Feng-Yao Wu,&nbsp;Shuang-Xia Zhao,&nbsp;Bing Han,&nbsp;Huai-Dong Song,&nbsp;Mei Dong","doi":"10.1002/ctd2.70029","DOIUrl":"https://doi.org/10.1002/ctd2.70029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate whether the mRNA expression of thyroglobulin (<i>TG</i>) and TSH receptor (<i>TSHR</i>) in lymph node could be used to diagnose lymph node metastasis in patients with papillary thyroid cancer (PTC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Subjects and methods</h3>\u0000 \u0000 <p>Around 156 paraffin samples of lymph nodes from 89 patients with PTC after surgery were collected, and the expressions of <i>TG</i> and <i>TSHR</i> mRNA were detected by nested qPCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with the results of confirmed histopathology, 86 out of 87 tissues of lymph nodes metastasis ectopically expressed <i>TG</i> mRNA, while 66 out of 69 tissues of non-metastasis lymph nodes did not express the <i>TG</i> mRNA. The specificity and sensitivity of <i>TG</i> mRNA measurement for detecting the lymph node metastasis were 95.65% and 98.85%, as effective as the first postoperative histopathology. However, the specificity and sensitivity of <i>TSHR</i> mRNA measurement were 92.75% and 85.06%, respectively. The accuracy of <i>TG</i>, <i>TSHR</i> mRNA measurement and the first postoperative histopathology were 97.44%, 88.46% and 95.51%, with the positive predictive rate (PPR) 96.63%, 93.67%, and 98.78%, respectively, negative predictive rate (NPR) 98.51%, 83.12% and 91.89%, respectively, as well as Youden's index 0.95, 0.78 and 0.92.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>TG</i> mRNA ectopic expression in the lymph node might be an excellent marker to diagnose the lymph node metastasis for patients with PTCs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in mitochondrial replacement therapy and its future expectations","authors":"Qifeng Lyu,&nbsp;Weiwei Zou,&nbsp;Taosheng Huang","doi":"10.1002/ctd2.70010","DOIUrl":"https://doi.org/10.1002/ctd2.70010","url":null,"abstract":"<p>The prevention of mitochondrial diseases is particularly important due to the lack of specific therapies. Therefore, mitochondrial replacement therapy (MRT) is expected to be a technology to prevent mitochondrial diseases. Admittedly, this technology sparked a lot of controversy and discussion. In this article, we review the recent advances in MRT, discuss its safety and ethical issues, and finally explore its potential to completely block the inheritance of mitochondrial diseases.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roads diverged in a wood: Proteins and RNAs encoded by cytochrome b (CYTB) gene in health and disease","authors":"Cijie Du,&nbsp;Baodan Chen,&nbsp;Yile Huang,&nbsp;Wenxi Liang,&nbsp;Ying Hua Su,&nbsp;Xingguo Liu","doi":"10.1002/ctd2.70026","DOIUrl":"https://doi.org/10.1002/ctd2.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The cytochrome b (<i>CYTB</i>) gene, a crucial component of the mitochondrial genome, plays a multifaceted role in cellular metabolism, energy production and various biological processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>It is well known that the <i>CYTB</i> gene encodes a subunit of complex III in the electron transport chain, which is vital for the oxidative phosphorylation process and ATP generation. Various studies report that the <i>CYTB</i> gene not only encodes a core protein in the mitochondrial respiratory chain but also produces a long non-coding RNA called lncCYTB, which participates in a variety of physiological and pathological processes. Inspiringly, a study has recently revealed that the <i>CYTB</i> gene also encodes a novel 187 amino acid long polypeptide, CYTB-187AA, a mitochondrial DNA-encoded protein produced by cytosolic translation and important for early mammalian development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review will provide insight into the functional and expression properties of the <i>CYTB</i> gene, as well as its unique non-coding RNA signature, and describe the diseases associated with the <i>CYTB</i> gene, ranging from mitochondrial dysfunction to more complex genetic disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The FACTs trial for Fabry disease highlights the promise and challenges of gene therapy","authors":"Jeffrey A. Medin,&nbsp;Michael L. West","doi":"10.1002/ctd2.70028","DOIUrl":"https://doi.org/10.1002/ctd2.70028","url":null,"abstract":"&lt;p&gt;Gene therapy studies in Fabry disease (FD) are proceeding utilising either lentivirus (LV) or adeno-associated virus (AAV) vectors with either ex vivo or in vivo transductions, respectively. In the FACTs (Fabry Disease Clinical Research and Therapeutics) gene therapy trial,&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; five male patients with classical FD (aged 29–48 years) received autologous LV-transduced CD34+ haematopoietic stem/progenitor cells (HSPCs). Cells were transduced ex vivo with a recombinant LV harbouring the cDNA for human α-galactosidase A (α-gal A) and returned to non-myeloablated hosts who had received low-dose melphalan. Cells engrafted well and polyclonal haematopoiesis was observed.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In FD, as with a number of lysosomal storage disorders (LSDs), the overexpressed hydrolase can be used by primary corrected cells and can also be secreted, enabling uptake via a mannose-6-phosphate receptor into bystander cells. This was the rationale for targeting HSPCs as they, and their progeny, can circulate and thereby deliver the corrective enzyme systemically. In contrast to enzyme therapy (ET), this approach utilised a single infusion rather than continual biweekly treatments. This single infusion of LV-transduced cells led to continuous production of the α-gal A&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; rather than variable peaks and troughs of activity as is seen with ET. The promise and challenges in gene therapy for amelioration of single-gene defects are highlighted by this study (See Figure 1).&lt;/p&gt;&lt;p&gt;The 5-year data show that this LV-based gene therapy was safe and impactful.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Four of the five patients went home the same day as their cell infusions. Febrile neutropenia was observed in one patient; another developed a PICC line infection. These were the only two severe adverse events. All patients achieved sufficient α-gal A activity that they technically did not have FD and were eligible to pause their ET. Three patients stopped ET and remained off for between 3 and 5 years duration. Other benefits were also observed: three of the patients had IgG-based antibody titres against α-gal A. In each case, these titres were reduced to background following the gene therapy and remained there for all 5 years. This was likely due to the conditioning regimen or to tolerisation generated by continual production of low levels of α-gal A from LV-transduced cells. Plasma globotriaosylsphingosine, an important biomarker, was also decreased in four of five patients. Further, estimated glomerular filtration rate, proteinuria and left ventricular mass index stabilised in most patients.&lt;/p&gt;&lt;p&gt;After 5 years, no haematopoietic (or any other) malignancies have been seen in our study. This mirrors data to March 2022 in the entire gene therapy field when recombinant LV were employed.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; However, three recent trials contrast this situation.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Haematological cancers developed in seven out of 67 pat","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143110950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes and machine perfusion as a therapy to improve organ transplantation","authors":"Wayne J. Hawthorne,&nbsp;Rajith Amaratunga,&nbsp;Ahmer Hameed","doi":"10.1002/ctd2.70025","DOIUrl":"https://doi.org/10.1002/ctd2.70025","url":null,"abstract":"&lt;p&gt;Cellular therapies are cutting-edge technologies that are now expanding into all spheres of medicine including transplantation. We are increasingly reliant upon marginal or less optimal donor organs for transplantation, however, to close the ever-widening gap between organ demand and supply. Such organs have higher discard rates and less ideal short and longer-term outcomes and ideally require improved organ preservation and resuscitation methods which can be utilised regardless of the jurisdiction.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Various cellular therapies are gaining significant momentum as a novel approach to reducing transplant organ ischemia/reperfusion injury (IRI), and potential improvement in graft outcomes. As seen in Figure 1, machine perfusion of organs provides the ideal setting to specifically deliver many targeted therapies to individual grafts, including therapies such as; stem cells, organoids, viral transduction, nanoparticles, and the use of exosome-based treatments.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Exosomes are small extracellular vesicles (30–150 nm in diameter), that play a unique role in cellular communication, derived from the endosomal pathway, with intraluminal vesicles being formed in multivesicular bodies and subsequently released with fusion of the plasma membrane. Unlike traditional cell-based therapies, exosomes do not contain live cells, reducing concerns about immune interaction in both the organ and subsequently recipient. In the study by Burdeyron et al.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; innovatively delivered exosomes derived from porcine urine progenitor cells (UPCs) to kidneys using hypothermic and normothermic machine perfusion (HMP and NMP).&lt;/p&gt;&lt;p&gt;IRI is a critical challenge in transplantation, particularly impacting organs from extended criteria donors and those from donors after circulatory death. These types of organs are generally more sensitive to ischemia, with attendant magnification of injury during reperfusion, and a subsequent higher incidence of graft dysfunction/rejection.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Technologies such as HMP and NMP are variably employed by different centres to improve organ quality prior to transplantation. HMP involves the continuous circulation of a cold preservation solution through the kidney, whilst NMP involves perfusing the kidney with a warm, oxygenated solution to simulate physiological conditions. While these methods offer some protective effects, they do not completely ameliorate IRI, and significant further work is required to enhance their efficacy.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Exosomes carry bioactive molecules, including microRNAs (miRNAs), mRNAs, and proteins, which can influence cellular interaction and regulate immune activity. Exosome-based therapy can leverage the potential for intercellular communication, signalling cascades, and other physiological effects without the complexity and risks associated with administering whole cells. Studies have shown that exosomes derived f","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143118160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}