Gene therapy bio-safety: scientific and regulatory issues

Abstract

We report here the topics discussed during the round table of the 2nd European Conference & Practical Course: Towards Clinical Gene Therapy: Preclinical Gene Transfer Assessment, held in Bellaterra (Spain), 1–14 February, 2004. First, how to predict the risk of pathologies generated by changes of the gene expression after proviral genome integration. In the light of the scientific information that emerged after the SAEs occurred in three X-SCID patients treated in France, (a) it is necessary to take into the account the dose of vector used in transduction protocols, in order to minimize the risk to target potentially pathogenic loci. Namely, low vector doses are recommended to minimize the number of vector genomes inserted per cell. (b) The potency of vector elements (ie promoter and transgene), in terms of activation of undesired cell function(s), should be elucidated to devise safe transduction protocols. (c) Target cells should be better characterized before and after transduction to avoid reinfusion into patients' cells, with proviral integration that may be pathogenic. (d) The possibility of replacing onco-retroviruses with other vector systems should be envisaged, for example, nonintegrative gene correction strategies. Second, adequate animal models are required in preclinical experimentation before going to clinics. Although animal models are not yet predictive for risk assessment of proviral insertion, they allow validation of the proof of principle of gene therapy strategies and pharmacological characterization of gene transfer products. Third, a dialogue between researchers and members of regulatory agencies is necessary to implement the regulatory frame where gene therapy products are to be used as new bio-pharmaceuticals. This will implement the whole gene therapy process development at both preclinic (research, development and clinical designs) and postclinic (follow-up of patients) stages. Hence, a European cooperation between professionals (researchers, physicians, industries, patients' associations, investors, etc) will allow implementation of gene therapy regulation in Eastern European countries.