NFP37 SOMATIC GENE THERAPY Texts for Laypersons

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Prof. Nicolas Mermod;	Lab. Biotechnologie; moléculaire; Département de chimie; EPFL; 1015 Lausanne; CH; Tel 021 693 6151; Fax 021 693 6140; e-mail: mermod@iba.unil.ch
Title:	Development of vectors for regulated expression in gene therapy.
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ABSTRACT FOR LAYPERSONS 1997:

Somatic gene therapy protocols usually do not allow for the regulation of the therapeutic gene in vivo. However, it would be most desirable to control the expression of the transgene in the patient, using medically acceptable drugs. This would significantly contribute to safer somatic gene therapies, as the treatment could be interrupted or resumed without invasive procedures. Furthermore, this would allow for the more efficient fine tuning of transgene expression, so as to respond to the patient's physiological needs, while decreasing the likelihood of adverse secondary effects. In this project, we have started developing genetic vectors to efficiently regulate the expression of neurotrophic factors in response to tetracycline antibiotic derivatives. These vectors are developed with the perspective of an ex vivo gene therapy of amyotrophic lateral sclerosis (ALS) using encapsulated cultured cells, in collaboration with partners at the CHUV hospital in Lausanne and at the University of Geneva.

The expression system currently being developed relies on a network of regulatory proteins that can activate or repress gene transcription, and on a target promoter engineered to faithfully control the expression of the transgene. So far, we have constructed over 20 different synthetic proteins that act as repressors of gene transcription. Using molecular genetics techniques, we engineered these repressors so that their DNA binding activities would be controlled by the administration of tetracycline analogs. These regulatory proteins have been evaluated in the laboratory with a cell line currently used in clinical trials for the treatment of the ALS disease in ex vivo gene therapy. Two highly potent repressors of transcription were identified, allowing activation of a target gene by 2 to 3 orders of magnitude upon administration of the tetracycline analog in short term (transient) evaluations. This system thus functions as an efficient «molecular switch», allowing precise control of the expression of a transgene. This genetic system is currently being fine tuned with respect to the expression of the activators and repressors of transcription, before long term studies are carried on.

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