title: [Gene therapy for hereditary and acquired human diseases].
abstract: Cystic Fibrosis (CF) and AIDS are primary candidate disorders to be treated by gene therapy, owing to their lethality and the absence of efficient clinical treatments. Treatment of CF by gene therapy will require the transfer of the functional CFTR cDNA into the diseased human airway epithelia since mutations within the CFTR gene are responsible for CF. We have therefore cloned the human CFTR cDNA and developed a recombinant E1-deleted adenoviral vector carrying a CFTR expression cassette. We demonstrated in vitro the ability of this vector to efficiently transduce human lung cells isolated from CF patients and to correct their phenotype. Efficient in, vivo delivery of the CFTR cDNA to the airways of cotton rats and rhesus monkeys was also obtained and no dissemination of the recombinant viral vector in other tissues than the airways was observed. We have therefore designed a phase I clinical trial involving CF patients. In contrast to the monogenic CF disease, the mechanisms of AIDS pathogenesis still remain poorly understood. Such limited knowledge of the disease constitutes a serious restriction to the development of a rational gene therapy strategy for AIDS. Since HIV, the causative agent of AIDS, predominantly infects cells of the hematopoietic system, pluri- or multipotent stem cells may constitute potential targets for the introduction of a foreign anti-HIV gene that will inhibit HIV replication and/or spread. Reimplantation of the genetically modified stem cells into asymptomatic HIV-infected patients should theoretically allow the repopulation of the host's immune system with mature CD4+ cells expressing novel molecules that interfere with viral replication, thus slowing the progression of AIDS. We identified several new transdominant inhibitors derived from the viral TAT and REV proteins and showed their ability to confer to human CD4 lymphocytes resistance against HIV1 infection. Retroviral vectors carrying these potential therapeutic genes have been developed and are currently being tested in vivo in newly developed transgenic animal models, in humanized SCID mice and in macaques.
authors.affiliation: TRANSGENE S.A., Strasbourg.
authors.forename: M
authors.initials: M
authors.lastname: Mehtali
authors.forename: J L
authors.initials: JL
authors.lastname: Imler
authors.forename: T
authors.initials: T
authors.lastname: Sorg
authors.forename: A
authors.initials: A
authors.lastname: Pavirani
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000628:therapy*; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans
vernacular_title: Thérapie génique de maladies humaines héréditaires et acquises.