Immune Responses to Gene Product of Inducible Promoters

Abstract

Efficient gene transfer has been achieved in several animal models using different vector systems, leading to stable transgene expression. The tight control of this expression is now an important outcome for the field of gene therapy. Such regulation is likely to be required for therapeutic applications and in some instances for safety reasons. For this purpose, several regulatable systems depending on small molecules have been developed. Among these, the tetracycline and the rapamycin dependent systems have been largely used. However, if long-term regulation of the transgene has been obtained in small animal models using these inducible systems, when translational studies were initiated in larger animals, the development of an immune response against proteins involved in transgene regulation were often observed. Such immune response was especially documented when using the TetOn tetracycline regulatable system in nonhuman primates (NHP). Humoral and destructive cellular immune responses against the transactivator involved in this regulation system were documented in a large majority of NHP leading to the complete loss of the transgene regulation and expression. This review will describe the immune responses observed in these different model systems applied for transgene regulation. Focus will be finally given on future directions in which such immune responses might be surmounted, enabling long-term transgene regulation in future clinical developments of gene transfer.

Modulation of Transgene Expression in Retinal Gene Therapy by Selective Laser Treatment

“…15 Systems that seem to avoid this problem, such as the Tet-On system, suffer from other shortcomings that prevent widespread clinical use, such as documented immune response to the gene product in large animals. 17 Another shortcoming is that these systems are often ''leaky,'' leading to a low level of background expression persisting in the ''off'' state. Finally, for such a system to reach widespread clinical use, substantial barriers would need to be overcome in the clinical trial design phase of drug development; such an approach would necessitate independent arms to demonstrate safety of the gene therapy agent alone, the inducible agent alone, and the combination, and in the later phases would need to employ a randomization scheme to switch off the therapy.…”

“…15 Systems that seem to avoid this problem, such as the Tet-On, suffer from an immune response to the gene product. 17 The primary target for genetic therapy of AMD and many other retinal diseases is the RPE, a supportive monolayer of cells underneath the neural retina. We have developed a method for downregulation of the transgene expression in RPE that selectively destroys a designated fraction of RPE cells using a rapidly scanning laser.…”

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

“…In addition, in contrast to rodents, the tetracycline regulator has been proven immunogenic in nonhuman primates. 90 For these reasons, the use of these regulatable systems has so far been confined to preclinical applications.…”

Constitutive and inducible co-expression systems for non-viral osteoinductive gene therapy

“…However, their translatability to the clinic remains questionable given the complexity of such systems and the need to additionally express a heterologous transactivator transgene with potential immunogenicity (Le Guiner et al, 2007). Simple constitutive co-expression systems, ideally backbonedevoid minicircle (Chen et al, 2003) variants, on the other hand are more likely to be clinically translated.…”