FINAL PROGRAM - American Society of Gene & Cell Therapy

13 th AnnUAL MEETing | Washington, DC USA May 19-22, 2010 31Program ScheduleScientific Symposium 1121:00 pm - 3:00 pmRoom: Marriott Ballroom Salon 1Barriers to HSC Gene TherapyCo-ChairsManuel Grez, PhD & Harry L. Malech, MDSpeakersMary C. Dinauer, MD, PhDNew Approaches for Marrow Conditioning in HSC Gene TherapyIn many genetic blood disorders, there is no selective advantage for hematopoietic stem cells following gene correction. Hence, in addition to expression of adequatelevels of the therapeutic protein, successful use of HSC gene therapy in these disorders will require efficient transduction, homing and engraftment of transduced HSC, aswell as cytoreduction of uncorrected HSC. It is highly desirable to develop effective conditioning regimens that reduce marrow content of uncorrected HSC yet minimizeexposure of patients to genotoxic agents and acute and long-term multiorgan toxicities. This talk will present new approaches for marrow conditioning for transplantationin HSC gene therapy, including more selective targeting of HSC in their niche.Luigi M. Naldini, MD, PhDExploiting and Antagonizing miRNA in Gene TherapyC. Anthony Blau, MDPharmacologically Regulated Cell TherapyHematopoietic stem cells (HSC) compete for the opportunity to contribute to various mature cell lineages in the blood, however little is known about the rules that governthis competition. Eight years ago, two dogs were transplanted with autologous CD34+ cells that had been transduced with an gammaretrovirus vector encoding greenfluorescent protein (GFP) and a conditionally activatable derivative of the thrombopoietin receptor (F36VMpl). Responses to F36VMpl signaling, elicited through administrationof a chemical inducer of dimerization (CID), were reported previously. Now long-term monitoring shows no spontaneous rises in GFP+ cells over time, suggestingthat F36VMpl is inert in the absence of CID. Stably higher frequencies of GFP+ B and T cells relative to other lineages suggests that CID administration within the first 18months post-transplantation generates stable increases in transduced lymphocytes, whereas only myeloid lineages responded when later courses of CID were administeredin one animal. Clonal tracking identified functionally distinct categories of hematopoietic stem cells: those that persisted and remained CID responsive, those that persistedbut were CID unresponsive, and those that did not persist.Christopher Baum, MDApproaches to Avoid Adverse Events in the Genetic Modification of Hematopoietic CellsAdverse events related to insertional mutagenesis or ectopic transgene expression may compromise the therapeutic prospects of gene therapy in the hematopoietic system.Over the past years, major progress has been made in the understanding of the underlying mechanisms, opening rational approaches to increase the therapeutic index. Wehave established sensitive nonclinical models, in transplanted C57BL/6J mice or using cultured cells, to reveal the transforming capacity of insertional activation of cellularproto-oncogenes such as Evi1 or Prdm16, and developed integrating gene vectors designed to reduce the risk of insertional transformation by altering the insertion patternand the expression cassette of the transgene. In a murine model of Mpl deficiency, major adverse events related to ectopic protein expression could be controlled bytranscriptionally targeted vectors. Two important principles emerge to ensure undisturbed long-term hematopoiesis from gene-modified cells. The first is the establishmentof polyclonal hematopoiesis using vectors with an untargeted integration profile and “physiological” transgene cassettes. The second is the generation of clonally definedhematopoiesis derived from induced pluripotent cells with genetic modification in bona fide safe harbours.Wednesday, May 19 th