Toxicologic Pathology最新文献_第5页

Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors. 重组腺相关病毒基因疗法载体的全身毒性。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-01 Epub Date: 2024-11-22 DOI: 10.1177/01926233241298892

Basel T Assaf

{"title":"Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors.","authors":"Basel T Assaf","doi":"10.1177/01926233241298892","DOIUrl":"10.1177/01926233241298892","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) vectors have emerged as a promising tool for gene therapy. However, the systemic administration of rAAV vectors is not without risks, particularly for dose levels >1 × 1014 viral genome per kilogram of body weight (vg/kg). rAAV-associated toxicities can variably manifest either acutely or in a delayed manner. Acute toxicities often present shortly after administration and can include severe immune responses, hepatotoxicity, and thrombotic microangiopathy (TMA). Delayed toxicities, on the other hand, may emerge weeks to months post-treatment, potentially involving chronic liver damage or prolonged immune activation. Thrombotic microangiopathy is often associated with complement activation and endothelial damage. The activation of the complement system can additionally trigger a cascade of inflammatory responses, exacerbating systemic toxicity. While many of these toxicities are reversible with appropriate medical intervention, there have been instances where the adverse effects were severe enough to lead to fatalities. Both human and animal studies have reported these adverse effects, highlighting the critical importance of thorough preclinical testing. However, a differential toxicity profile associated with systemic AAV administration exists between humans and nonhuman primates (NHPs), in which certain toxicities reported in humans are yet to be observed in NHPs, and vice versa. This review aims to explore the recent literature on systemic rAAV toxicities, focusing on dose levels, the role of the complement activation pathway, endothelial injury, TMA, hepatotoxicity, and the bidirectional translational safety profiles from both human and animal studies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"523-530"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Role of Neuropathology Evaluation in the Nonclinical Assessment of Seizure Liability. 神经病理学评估在癫痫发作责任非临床评估中的作用。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-01 Epub Date: 2024-12-05 DOI: 10.1177/01926233241300065

Katie Sokolowski, Judy Liu, Marcus S Delatte, Simon Authier, Owen McMaster, Brad Bolon

{"title":"The Role of Neuropathology Evaluation in the Nonclinical Assessment of Seizure Liability.","authors":"Katie Sokolowski, Judy Liu, Marcus S Delatte, Simon Authier, Owen McMaster, Brad Bolon","doi":"10.1177/01926233241300065","DOIUrl":"10.1177/01926233241300065","url":null,"abstract":"Test article (TA)-induced seizures represent a major safety concern in drug development. Seizures (altered brain wave [electrophysiological] patterns) present clinically as abnormal consciousness with or without tonic/clonic convulsions (where \"tonic\" = stiffening and \"clonic\" = involuntary rhythmical movements). Neuropathological findings following seizures may be detected using many methods. Neuro-imaging may show a structural abnormality underlying seizures, such as focal cortical dysplasia or hippocampal sclerosis in patients with chronic epilepsy. Neural cell type-specific biomarkers in blood or cerebrospinal fluid may highlight neuronal damage and/or glial reactions but are not specific indicators of seizures while serum electrolyte and glucose imbalances may induce seizures. Gross observations and brain weights generally are unaffected by TAs with seizurogenic potential, but microscopic evaluation may reveal seizure-related neuron death in some brain regions (especially neocortex, hippocampus, and/or cerebellum). Current globally accepted best practices for neural sampling in nonclinical general toxicity studies provide a suitable screen for brain regions that are known sites of electrical disruption and/or display seizure-induced neural damage. Conventional nonclinical studies can afford an indication that a TA has a potential seizure liability (via in-life signs and/or microscopic evidence of neuron necrosis), but confirmation requires measuring brain electrical (electroencephalographic) activity in a nonclinical study.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"566-573"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proceedings of the 2024 Division of Translational Toxicology Satellite Symposium. 2024年转化毒理学卫星研讨会论文集。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-01 Epub Date: 2024-12-11 DOI: 10.1177/01926233241298895

Erin M Quist, Shambhunath Choudhary, Typhaine Lejeune, Emily Mackey, Priyanka Thakur, Kristen Hobbie, Amanda Duggan

引用次数: 0

Pathology Findings and In-Life Correlates in the Nonclinical Development of Adeno-Associated Virus (AAV)-Based Retinal Gene Therapies. 基于腺相关病毒（AAV）的视网膜基因治疗的非临床发展的病理发现和生活相关因素

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-01 DOI: 10.1177/01926233241307641

Helen S Booler, Typhaine Lejeune, Oliver Turner, Chandra Saravanan, Joshua T Bartoe, Brad Bolon

{"title":"Pathology Findings and In-Life Correlates in the Nonclinical Development of Adeno-Associated Virus (AAV)-Based Retinal Gene Therapies.","authors":"Helen S Booler, Typhaine Lejeune, Oliver Turner, Chandra Saravanan, Joshua T Bartoe, Brad Bolon","doi":"10.1177/01926233241307641","DOIUrl":"https://doi.org/10.1177/01926233241307641","url":null,"abstract":"Adeno-associated virus (AAV)-based vectors are the most frequently used platform for retinal gene therapy. Initially explored for the treatment of loss-of-function mutations underpinning many inherited retinal diseases, AAV-based ocular gene therapies are increasingly used to transduce endogenous cells to produce therapeutic proteins, thus producing site-specific biofactories. Relatively invasive ocular routes of administration (ROA) mean prominent procedure-related in-life, and histopathological findings may be observed with some regularity. Test article-related findings may vary with the ROA and cell populations transduced, with retinal pigmented epithelium (RPE) changes prominent (ranging from pigment alteration through degeneration, with or without associated degeneration of the overlying retina) with subretinal ROA, and more anterior changes (iris, ciliary body) generally observed with the intravitreal ROA. Ocular inflammation is the most frequent finding that occurs nonclinically and in patients, and is particularly pronounced with intravitreal administration. Extraocular findings may be observed in extraocular muscles, regional ganglia, or central visual pathways with multiple ocular ROA. Work is still needed to understand the mechanisms underpinning many of these ocular and extraocular findings. Emerging patient data is helping to clarify both the potential for translating nonclinical findings to predict possible human responses and the applicability of nonclinical biomonitoring methods to the clinical setting.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"52 8","pages":"506-522"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products. 过继细胞治疗产品的非临床安全性评估病理学家指南。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-01 Epub Date: 2024-12-06 DOI: 10.1177/01926233241298570

Alessandra Piersigilli, Vinicius S Carreira, Frédéric Gervais, Keith Mansfield, Brian E McIntosh, Ingrid Cornax

{"title":"A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.","authors":"Alessandra Piersigilli, Vinicius S Carreira, Frédéric Gervais, Keith Mansfield, Brian E McIntosh, Ingrid Cornax","doi":"10.1177/01926233241298570","DOIUrl":"10.1177/01926233241298570","url":null,"abstract":"Through two decades of research and development, adoptive cell therapies (ACTs) have revolutionized treatment for hematologic malignancies. Many of the seven US Food and Drug Administration (FDA)-approved products are proven to be a curative last line of defense against said malignancies. The ACTs, known more commonly as chimeric antigen receptor (CAR) T-cells, utilize engineered lymphocytes to target and destroy cancer cells in a patient-specific, major histocompatibility complex (MHC)-independent manner, acting as \"living drugs\" that adapt to and surveil the body post-treatment. Despite their efficacy, CAR T-cell therapies present unique challenges in preclinical safety assessment. The safety and pharmacokinetics of CAR T-cells are influenced by numerous factors including donor and recipient characteristics, product design, and manufacturing processes that are not well-predicted by existing in vitro and in vivo preclinical safety models. The CAR therapy-mediated toxicities in clinical settings primarily arise from unintended targeting of non-tumor cells, potential tumorigenicity, and severe immune activation syndromes like cytokine release syndrome and immune effector cell-associated neurotoxicity. Addressing these issues necessitates a deep understanding of CAR target expression in normal tissues, inclusive of the spatial microanatomical distribution, off-target screening, and a deep understanding CAR cell manufacturing practices and immunopathology.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"531-544"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicologic Pathology Forum*: Opinion on Assessing and Communicating Adversity for Implantable Medical Devices. 毒理病理学论坛*：关于评估和通报植入式医疗器械不良反应的意见。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-11-27 DOI: 10.1177/01926233241300313

L M Wancket, B Bolon, K A Funk, J C L Schuh

{"title":"Toxicologic Pathology Forum*: Opinion on Assessing and Communicating Adversity for Implantable Medical Devices.","authors":"L M Wancket, B Bolon, K A Funk, J C L Schuh","doi":"10.1177/01926233241300313","DOIUrl":"https://doi.org/10.1177/01926233241300313","url":null,"abstract":"Medical devices are a product class encompassing many materials and intended uses. While adversity determination is a key part of nonclinical safety assessments, relatively little has been published about the unique challenges encountered when determining adversity for implantable medical devices. The current paper uses the Society of Toxicologic Pathology (STP)'s \"Scientific and Regulatory Policy Committee Recommended ('Best') Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies,\" which were crafted for conventional bio/pharmaceutical products (small and large molecules, cell and gene therapies, etc), as a framework for making adversity decisions for medical devices. Some best principles are directly translatable to medical devices: (1) adversity indicates harm to the animal; (2) effects should be assessed on their merits without speculation regarding future or unmeasured implications; (3) adversity decisions apply only to the test species under the specific conditions of the nonclinical study; and (4) adversity decisions and supporting evidence should be clearly stated in reports. However, unique considerations also apply for evaluating implanted medical devices, including testing of multiple articles in the same animal and the unavoidable tissue trauma during device implantation. This opinion piece offers suggestions for applying previously published STP best practice recommendations for assigning adversity to implantable medical devices.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300313"},"PeriodicalIF":1.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of Nonrodent Ocular Tissues. 国际协调命名和诊断标准（INHAND）：非啮齿动物眼部组织的非增殖性和增殖性病变。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-10-01 DOI: 10.1177/01926233241283708

K A Schafer, E Atzpodien, U Bach, J Bartoe, H Booler, J Brassard, C Farman, M Kochi, T Lejeune, E Meseck, T Nolte, M Ramos, B Short, S Sorden, L Teixeira, O Turner, B Walling, K Yekkala, K Yoshizawa

{"title":"International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of Nonrodent Ocular Tissues.","authors":"K A Schafer, E Atzpodien, U Bach, J Bartoe, H Booler, J Brassard, C Farman, M Kochi, T Lejeune, E Meseck, T Nolte, M Ramos, B Short, S Sorden, L Teixeira, O Turner, B Walling, K Yekkala, K Yoshizawa","doi":"10.1177/01926233241283708","DOIUrl":"10.1177/01926233241283708","url":null,"abstract":"The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/ inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in ocular tissues (eyes and glands and ocular adnexa) from laboratory nonrodent species (rabbits, dogs, minipigs, and nonhuman primates) used in nonclinical safety studies with an emphasis on ocular-targeted dosing. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes descriptions and visual depictions of spontaneous lesions and lesions induced by exposure to various test materials. A widely accepted and utilized internationally harmonized nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"52 7","pages":"368-455"},"PeriodicalIF":1.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exogenous Growth Hormone Exacerbates Post-Irradiation Atherosclerosis in Susceptible Epicardial Coronary Arteries 外源性生长激素加剧易受辐射影响的心外膜冠状动脉辐射后动脉粥样硬化

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2024-09-10 DOI: 10.1177/01926233241277454

Krystal J. Vail, J. Daniel Bourland, Gregory O. Dugan, Benny J. Chen, Thomas B. Clarkson, J. Mark Cline, Giselle C. Meléndez

{"title":"Exogenous Growth Hormone Exacerbates Post-Irradiation Atherosclerosis in Susceptible Epicardial Coronary Arteries","authors":"Krystal J. Vail, J. Daniel Bourland, Gregory O. Dugan, Benny J. Chen, Thomas B. Clarkson, J. Mark Cline, Giselle C. Meléndez","doi":"10.1177/01926233241277454","DOIUrl":"https://doi.org/10.1177/01926233241277454","url":null,"abstract":"Cardiac exposure to ionizing radiation can damage both the microvasculature and coronary arteries, as well as increase the long-term risk of heart disease, myocardial fibrosis, and conduction abnormalities. Therapeutic agents capable of promoting recovery from radiation injury to the heart are limited. Growth hormone is linked to improved cardiac function following injury. Here, we leveraged a cynomolgus macaque model to determine the long-term outcomes of recombinant human growth hormone (rhGH) therapy on the heart following low-dose ionizing radiation. Macaques were exposed to 2 Gy radiation, treated with rhGH for one month, and assessed after 2 years. Overall, plasma lipid profile, cardiac function, and coronary artery disease were similar between rhGH and placebo treated animals. However, a subgroup of rhGH-treated animals exhibited more extensive atherosclerotic plaques in the coronary arteries. Together, these findings indicate that transient human growth hormone therapy subsequent to a single low dose of ionizing radiation involving the heart does not result in long-term changes to plasma cholesterol but may promote exacerbated coronary artery disease in a subset of individuals.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"64 1","pages":"1926233241277454"},"PeriodicalIF":1.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicologic Pathology Forum*: mRNA Vaccine Safety–Separating Fact From Fiction 毒理病理学论坛*：mRNA 疫苗安全性--分清事实与虚构

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2024-09-10 DOI: 10.1177/01926233241278298

Rani S. Sellers, Philip R. Dormitzer

{"title":"Toxicologic Pathology Forum*: mRNA Vaccine Safety–Separating Fact From Fiction","authors":"Rani S. Sellers, Philip R. Dormitzer","doi":"10.1177/01926233241278298","DOIUrl":"https://doi.org/10.1177/01926233241278298","url":null,"abstract":"SARS-CoV-2 spread rapidly across the globe, contributing to the death of millions of individuals from 2019 to 2023, and has continued to be a major cause of morbidity and mortality after the pandemic. At the start of the pandemic, no vaccines or anti-viral treatments were available to reduce the burden of disease associated with this virus, as it was a novel SARS coronavirus. Because of the tremendous need, the development of vaccines to protect against COVID-19 was critically important. The flexibility and ease of manufacture of nucleic acid–based vaccines, specifically mRNA-based products, allowed the accelerated development of COVID-19 vaccines. Although mRNA-based vaccines and therapeutics had been in clinical trials for over a decade, there were no licensed mRNA vaccines on the market at the start of the pandemic. The rapid development of mRNA-based COVID-19 vaccines reduced serious complications and death from the virus but also engendered significant public concerns, which continue now, years after emergency-use authorization and subsequent licensure of these vaccines. This article summarizes and addresses some of the safety concerns that continue to be expressed about these vaccines and their underlying technology.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"4 1","pages":"1926233241278298"},"PeriodicalIF":1.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intra-abdominal Abscesses in Two Göttingen Minipigs. 两只哥廷根小型猪的腹内脓肿

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-08-01 Epub Date: 2024-10-17 DOI: 10.1177/01926233241289112

Nanna Grand, Gitte Jeppesen, Abraham Nyska

引用次数: 0