Jan Klapwijk

hInGeTox: a human-based in vitro platform to evaluate lentivirus/host interactions that contribute to genotoxicity

Saqlain Suleman, Sharmin Alhaque, Andrew Guo, Huairen Zhang et autres

Abstract Lentivirus vectors are effective for treatment of genetic disease. However, safety associated with vector related genotoxicity is of concern and currently available models are not reliably predictive of safety in humans. We have developed h InGeTox as the first human in …

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Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article

Jan Klapwijk, Alberto Del Rio Espinola, Silvana Libertini, Philippe Collin et autres

Regulators and industry are actively seeking improvements and alternatives to current models and approaches to evaluate potential carcinogenicity of gene therapies (GTs). A meeting of invited experts was organized by NC3Rs/UKEMS (London, March 2023) to discuss this topic. This article describes the …

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hInGeTox: A human-based in vitro platform to evaluate lentivirus contribution to genotoxicity

Michael Themis, Saqlain Suleman, Sharmin Al Haque, Andrew Guo et autres

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The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure

Rodolfo Cadilla, David N. Deaton, Young Do, P.A. Elkins et autres

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Imaging drugs, metabolites and biomarkers in rodent lung: a DESI MS strategy for the evaluation of drug-induced lipidosis

Alex Dexter, Rory T. Steven, Aateka Patel, Lea Ann Dailey et autres

Within drug development and pre-clinical trials, a common, significant and poorly understood event is the development of drug-induced lipidosis in tissues and cells. In this manuscript, we describe a mass spectrometry imaging strategy, involving repeated analysis of tissue sections by DESI MS, …

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Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis

Aateka Patel, Ewelina Hoffman, D.I. Ball, Jan Klapwijk et autres

‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that …

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Evolving the Role of Discovery-focused Pathologists and Comparative Scientists in the Pharmaceutical Industry

Sunish Mohanan, Sean Maguire, Jan Klapwijk, Rick R. Adler et autres

GlaxoSmithKline has recently made significant organizational changes to its nonclinical safety, drug metabolism and pharmacokinetic, and laboratory animal science/veterinary functions, with the goal to increase our focus on scientific partnership with the discovery part of the organization. One specific change was bringing …

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A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 2 of 2)

James R. Hailey, Beverly E. Maleeff, Heath C. Thomas, Gail Pearse et autres

To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study …

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A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 1 of 2)

James R. Hailey, Beverly E. Maleeff, Heath C. Thomas, Gail Pearse et autres

Spontaneous rodent progressive cardiomyopathy (PCM) in the Sprague Dawley rat may confound identification and/or interpretation of potential test article (TA)-related cardiotoxicity. Pathologists apply diagnostic term(s) and thresholds for diagnosing and assigning severity grades for PCM and/or PCM-like (PCM/like) lesions consistently within a …

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Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis

Ewelina Hoffman, Aateka Patel, D.I. Ball, Jan Klapwijk et autres

PURPOSE: Progress to the clinic may be delayed or prevented when vacuolated or "foamy" alveolar macrophages are observed during non-clinical inhalation toxicology assessment. The first step in developing methods to study this response in vitro is to characterize macrophage cell lines and …

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Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice

Nicola Carriglio, Jan Klapwijk, Raisa Jofra Hernández, Michela Vezzoli et autres

GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is …

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Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses

Ben Forbes, Raegan O’Lone, Philippa Pribul Allen, Anthony Cahn et autres

Alveolar macrophage (AM) responses are commonly induced in inhalation toxicology studies, typically being observed as an increase in number or a vacuolated 'foamy' morphology. Discriminating between adaptive AM responses and adverse events during nonclinical and clinical development is a major scientific challenge. …

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