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Biotech / Medical : ARIAD Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: Mike McFarland who wrote (385)	12/8/1998 4:38:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 4474

Well, someone certainly wanted a big hunk of the company today. They must believe that a bottom is in place and that things will turn up. Here's the ARIA-related abstract that was presented at ASH, embargoed until today...... Abstract #2752 - Monday, December 7, 1998 - Hall C, 5:00-6:30 pm Posterboard 609-IV, GENE THERAPY - Clinical and Pre-Clinical Studies I A NEW SUICIDE SYSTEM BASED ON GENE TRANSFER OF FAS INTO DONOR LYMPHOCYTES FOR CONTROLLED GVL S. Marktel, F. Ciceri, C. Bonini, D. Thomis, J.F. Amara, E. Zappone, P. Servida, S. Rossini, C. Traversari, M. Gilman, C. Bordignon Telethon Institute for Gene Therapy (TIGET), Istituto Scientifico H.S. Raffaele, Milan, Italy ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA In allogeneic marrow transplantation (BMT), donor lymphocytes play a central therapeutic role in both graft-versus-leukemia and immune reconstitution. However, their use is limited by the risk of severe graft-vs-host disease (GvHD). We and others have demonstrated the efficacy of infusion of Herpes Simplex virus thymidine kinase (HSV-tk) genetically-engineered donor lymphocytes in patients who relapsed for chronic myelomonocytic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma and multiple myeloma or developed an Epstein-Barr virus-induced lymphoma after BMT (Bonini C. et al., Science 276: 1719, 1997). Despite the encouraging clinical results, two vector-related limitations were observed: the induction of a strong immune response against genetically-modified cells and partial resistance to ganciclovir-mediated elimination of transduced cells in chronic GvHD (Verzeletti et al., Human Gene Therapy, in press). Based on these limitations, we approached the possibility to utilize a new, non immunogenic, non cell cycle-dependent suicide gene strategy. This is based on gene transfer into donor lymphocytes of a modified intracitoplasmic domain of FAS. Subsequently, the administration of a syntetic ligand leads to activation of transgenic FAS and cell death. FAS is part of the apoptotic pathway of programmed cell death. The interaction between the death domains of the intracytoplasmic tail of FAS leads to activation of the signal downstream via intracellular caspases and finally to proteolysis of cytosolic substrates and chromosomal fragmentation. T cells genetically modified for the FAS vectors express the cell surface marker DLNGFR fused with two copies of a modified FK506-binding-protein (FKBP) and the intracytoplasmic domain of FAS. A cell permeable synthetic ligand binds the modified FK506 binding-proteins producing oligomerization of FKBPs resulting in activation of the intracytoplasmic domain of FAS and apoptosis-mediated cell death. Synthetic ligands for FKBPs successfully trigger FAS-mediated apoptosis in several human tumors and in human PBLs, with a killing efficacy and kinetic comparable to the best HSV-tk/GCV vectors. Ligand administration results also in a dose dependent in vivo elimination of human PBLs in SCID mice. These data suggest that the FAS vectors, based on expression of human products and therefore less or non immunogenic, represent a promising suicide gene strategy, able to circumvent the intrinsic limitations of the HSV-tk based system.