Toxicologic Pathology最新文献

The unprecedented speed of developing vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has propelled mRNA technologies into the public eye. The versatility of mRNA technology, often referred to as "plug and play," offers immense promise for rapidly updating vaccines to address newer variants of respiratory diseases and combat emerging infectious diseases and lethal pathogens, such as the Ebolavirus. However, the potential applications of mRNA technology extend well beyond prophylactic vaccines. This session explored the two primary mRNA platforms: nonreplicating mRNA and self-amplifying mRNA (variably referred to as saRNA, samRNA, or SAM). Presentation topics were on current research efforts aimed at broadening the applications of mRNA modalities beyond vaccines. Topics included opportunities for delivering mRNA via intra-tumoral and inhalational routes, immunological and systemic inflammatory responses elicited by these modalities, and regulatory considerations involved in the development and licensing of these technologies.

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.

The 2024 annual Division of Translational Toxicology (DTT) Satellite Symposium, entitled "Pathology Potpourri," was held in Baltimore, Maryland, at the Society of Toxicologic Pathology's 42nd annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced nonneoplastic lesions in the mouse kidney, induced and spontaneous neoplastic lesions in the mouse lung, infectious and proliferative lesions in nonhuman primates, an interesting inflammatory lesion in a transgenic mouse strain, and a lesson on artifact recognition.

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.

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.

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.

One of the emerging concepts on the reduction of animal use in non-clinical studies is the use of virtual control group (VCG) to replace concurrent control group (CCG). The VCG involves the generation of a control data from historical control data to match a specific study design. This review focuses on two recently published proof-of-concept (POC) studies conducted in rats. One major issue that was consistently seen across these POC studies was the non-reproducibility of some quantitative endpoints between the CCG and the VCG, with clinical pathology parameters being the most affected. The inconsistencies observed with the clinical pathology parameters when using VCGs may lead to: (1) misconception about the accuracy and sensitivity of traditional clinical pathology biomarkers and its implications on safety monitoring in the clinic; (2) inability to correctly identify and characterize organ dysfunctions; (3) interference with the weight-of-evidence approach used in identifying hazards in toxicologic clinical pathology and toxicology studies at large; and (4) wrong interpretations and data reproducibility issues. Other alternatives to reduce animal use in toxicology studies are also discussed including blood microsampling for toxicokinetics, scientifically justified use of recovery animals, and appropriate use and continuous investments in new alternative methods.

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.

Sharing pathology data is critical for educational and scientific purposes. Since most pharmaceutical or (agro)chemical companies outsource nonclinical safety assessment studies to contract research organizations (CROs), the pathology data of those studies are not owned by the investigator but is the legal property of the respective company sponsoring the work. Although some companies have installed policies that govern sharing of pathology data, many companies generally do not allow the external use of data by either the CRO-based study pathologist or the sponsor pathologist. Policies for governing the external use of data vary significantly. In this article, we present an overview of the different approaches taken across different companies (CROs, pharmaceutical/chemical companies, or other institutes) for sharing pathology material for educational and/or scientific purposes. The results of a survey and interviews with legal departments of different companies will be presented (anonymously) and discussed. In addition, the importance of sharing pathology data is addressed, as well as the challenges and opportunities this presents. Suggestions will be provided regarding what material should be made available and what will be needed to achieve agreement for this to happen.

Microscopic observation data collected from approximately 1800 male and female Sprague Dawley (SD) control rats used on 104-week carcinogenicity studies performed at North American Labcorp Early Development, Inc, Madison, WI, were retrospectively evaluated for spontaneous nonneoplastic findings. This study provides incidence of the most common spontaneous nonneoplastic microscopic findings in each organ system of SD rats encountered during 104-week carcinogenicity studies. Some of the most common spontaneous background findings were cardiomyopathy; chronic progressive nephropathy; uterine cystic endometrial hyperplasia; prostate inflammation; pulmonary alveolar macrophage infiltrates; hepatocyte vacuolation, bile duct hyperplasia, and basophilic foci in the liver; pancreatic fibrosis; splenic extramedullary hematopoiesis and pigment; decreased lymphocytes and epithelial hyperplasia in the thymus; ventral brain compression; cystic degeneration and hyperplasia of the adrenal cortex; and mammary gland hyperplasia. The most common nonneoplastic findings in male SD rats were chronic progressive nephropathy (80.9%) and rodent progressive cardiomyopathy (73.2%). The most common nonnenoplastic findings in female SD rats were cystic degeneration of the adrenal cortex (64.7%) and ventral compression of the brain due to pituitary neoplasms (62.7%).