Libertini, Silvana, Martus, Hans-Joerg, Kimber, Ian, Rothe, Michael, Themis, Michael, Cathomen, Toni, Gao, Guangping, Ertl, Hildegrund, Salk, Jesse, Brugmann, Martijn, Onodera, Masafumi, Micklethwaite, Ken, Lanz, Tom, Pizzurro, Daniella, Jadlowsky, Julie, Yuan, Jing, Bushmann, Rick, Del Rio, Alberto, Vickers, Catherine, Klapwijk, Jan, Lynch, Anthony, Zeller, Andreas, Jobling, Susan, Vickers, Cathy, Collin, Philippe and Fellows, Mick (2024) Scientific principles and experimental approaches for the assessment of risk factors relevant to potential carcinogenicity of gene therapies: consensus statements. Molecular Therapy, 35 (15). pp. 527-542.

Abstract

There is an urgent need to improve the non-clinical evaluation of potential carcinogenicity of gene therapies (GTs), including the use of more human-relevant models, that can inform and help reduce the risk of clinical adverse events. Regulatory agencies and the pharmaceutical industry are actively seeking improvements and alternatives to current models and approaches. Progress is, however, hampered by the lack of promising experimental platforms to address potential risks, and an apparent lack of consensus among scientists regarding how the potential carcinogenicity of GTs should be identified and measured in a regulatory context. Questions remain as to the most appropriate platforms and toxicological principles to support robust, scientific, and reliable risk assessment of vector safety.
Motivated by these concerns, a meeting of international scientific experts was organised by NC3Rs/UKEMS (London, March 2023) to discuss principles and open questions on the assessment of vector-mediated carcinogenicity. This paper describes the scientific background and consensus reached amongst delegates on the definition of vector genotoxicity in non-clinical testing, sources of uncertainty, suitable toxicological endpoints for genotoxic assessment of GTs, and future research needs. It addresses the challenges in predicting carcinogenesis, the insufficient range of validated test systems, and other issues that impact the evaluation of vector-mediated carcinogenicity risks, such as understanding the “background noise” (both technical and biological) of proposed endpoints and avoidance of tests that are prone to misleading and/or uninformative results.
The recommendations in this consensus paper should inform the further development of regulatory guidelines for the non-clinical toxicological assessment of GT products.

Item Type:	Article
Date Deposited:	20 Nov 2024 00:45
Last Modified:	20 Nov 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52186