Cellular and gene therapy program designs share similar components and characteristics, including being able to demonstrate simultaneously product safety and support clinical trials. Charles River supports the development of cellular and gene therapies via a strategic and consultative-based approach with great consideration given to scientific and regulatory concerns. Designs for both individual studies and complete programs integrate both safety and efficacy aspects as well as mitigate risk factors inherent in developing these types of therapies. Our multidisciplinary team will accommodate the novel properties of your cellular or gene product, including complications of cross-species reactivity.
Careful choice of a test system for proof-of-concept studies as well as a pharmacologically sensitive species that will serve as a progressive host for the cellular or gene therapeutic is critical with consideration given to the intended clinical route of administration. Animals with competent immune systems can be treated with immunosuppressant agents to enable cell survival after implantation. Surgically altered models (e.g., the middle cerebral artery occlusion (MCAO) stroke model and bone healing models) may be required. Our skilled surgical staff with experience in various surgical implantation methods, including intraocular, intracranial, intraspinal, intrathecal, intracoronary, myocardial, intraprostatic, topical grafting, and infusion, which mimic clinical routes of administration is crucial to program success.
Cell Characterization and Handling
In order to successfully develop a program that meets regulatory expectations, the cell source, type, and degree of manipulation must be considered. Before initiating preclinical studies, the cell line must be well characterized. Characterization of cells should include, but not be limited to, 1) identity and composition; 2) viability and stability; and 3) purity and sterility.
Cell Detection (Identity and Composition)
Cell- and gene-based therapeutics present Chemistry, Manufacturing, and Control (CMC) issues and must be recognized as a heterogeneous mixture of cells. To properly identify the cells, a series of translation biomarkers must be developed. These include morphology, surface, and genetic markers–qualified and optimized for the cell target. GLP-compliant molecular pathology services at Charles River (in situ hybridization and PCR-based evaluations) allow exact identification of cells in tissues. The integration of molecular biology and histopathology capabilities allow for the correlation of gene expression to tissue histomorphology, which provides valuable functional genomics information.
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Pilot Tolerability, Viability, and Biodistribution Studies
Providing preliminary data on the maximum tolerated dose, cell survival, and/or early testing of the cellular or gene therapy product, pilot studies are used to provide a strong proof of concept in the selected animal model(s), including elucidating the route of administration and dosing regimen, dose response, and onset, as well as durability of effects.
The cell or gene therapy product is evaluated for survival, integration in non-target tissues, as well as the ability to endure in the animal model at the target site for durability, differentiation and migration in vivo. Generally, these studies are GLP-compliant. A complete profile of tissues is retained for histopathology, immunohistochemistry, and/or PCR evaluation.
Standard toxicological evaluations are performed, including clinical observations, body weight and feed consumption measurements, ophthalmologic and clinical pathology evaluations, and complete necropsy, organ weight, and histopathology assessments. While systemic toxicity may be less of a concern for cellular therapeutic products, immunogenicity concerns and irreversibility of engraftment must be considered.
These studies assess the potential for cell phenotypic stability or ectopic tissue formation by a cellular therapy product in an immunocompromised rodent. Single subcutaneous or clinical route administration with at least three dose groups (including positive control) are used. Rodents are palpated weekly for mass presence and tissues are retained for histopathology and cell detection (if applicable). Study duration is typically the lifespan of the animal.
Immunohistochemistry techniques allow for the visualization and morphometric analysis of implanted or transformed cells in target tissues. Such techniques identify target antigenic cell components to highly specific antibodies labelled with visible markers for microscopic examination.
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