Meta-Analysis and Optimization of the <i>In Vitro</i> Immortalization Assay for Safety Assessment of Retroviral Vectors in Gene Therapy

Antonella Lucía Bastone(Medizinische Hochschule Hannover), Philipp John-Neek(Medizinische Hochschule Hannover), Violetta Dziadek(Medizinische Hochschule Hannover), Friederike Mansel(Medizinische Hochschule Hannover), Maike Hagedorn(Medizinische Hochschule Hannover), Jenni Fleischauer(Medizinische Hochschule Hannover), Bettina Weigel(Medizinische Hochschule Hannover), Gabi Paul(Medizinische Hochschule Hannover), Axel Schambach(Boston Children's Hospital), Michael Rothe(Medizinische Hochschule Hannover)
Human Gene Therapy
April 9, 2025
10.1089/hum.2024.221
Cited by 3Open Access
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Abstract

The underlying risk of retroviral vector-induced insertional oncogenesis in gene therapies requires a reliable preclinical safety assessment. Dysregulation of genes neighboring the vector’s integration sites has triggered hematopoietic malignancies in patients treated with different vector genera and designs. With ca. 18 years in practical use, the in vitro immortalization (IVIM) assay can quantify this mutagenic potential and is actively requested by regulatory authorities during preclinical stages. Here, we present a thorough meta-analysis of IVIM data alongside a step-by-step cell culture protocol. On this basis, we propose clonal outgrowth as the single indicator of mutagenicity, simplifying the IVIM assay cost- and time-wise.

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