By Rafat Abonour, MD
Gene therapy has had its highs and lows over the last several decades. Excitement was generated around gene transfer into T cell in the setting of graft-versus-tumor trials and into hematopoietic stem cells to treat children with severe combined immune deficiency. Low rate of gene transfer and transient expression and generation of leukemia all prevented the wider application of gene therapy. Dr. Marina Cavazzana-Calvo, from Hôpital Necker – Enfants Malades in Paris, will present exciting data on a hematopoietic stem cell gene therapy trial using lentiviral vector in X-linked adrenoleukodystrophy (abstract #821). Lentivirus has been used to introduce a new gene into human or animal cells. A model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia. Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity. Lentivirus has also been successfully used for transfection of diabetic mice with the gene encoding platelet-derived growth factor (PDGF), a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. Dr. Cavazzana-Calvo will state otherwise. She will present the initial results for a lentiviral vector in the setting of myeloablative bone marrow transplantation, and unlike a previous study in HIV in which lymphocytes were the target for gene transfer, transducer-mobilized stem cells were the target for gene transfer. Dr. Ken Cornetta from Indiana University and the president-elect of the American Society of Gene Therapy expressed his excitement about the trial because of the long-term expression of vector that appears to be stable beyond six months. He thinks this “suggests the claim of higher stem cell gene transfer may be appropriate.”
Dr. Cavazzana-Calvo will report on the preliminary results in three children with cerebral X-linked ALD who received lentiviral, vector-transduced, autologous hematopoietic stem cells (HSCs) in September 2006, January 2007, and June 2008. In the past, they demonstrated that cerebral demyelination associated with cerebral ALD can be stopped or reversed within 12 to 18 months by allogeneic HSC transplantation. The long-term beneficial effects of HCT transplantation in ALD are due to the progressive turnover of brain macrophages (microglia) derived from bone marrow cells. In this trial, mobilized peripheral blood CD34+ cells were transduced ex vivo for 18 hours with a non-replicative HIV1-derived lentiviral vector 1) expressing the ALD cDNA under the control of the MND (myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer binding site substituted) promoter, and 2) in the presence of four human recombinant cytokines (Il-3, Stem Cell Factor, Flt3-ligand, and Megakaryocyte Growth and Differentiation Factor, and CH-296 retronectine). Dr. Cavazzana-Calvo went on to conclude that gene therapy using HIV1-derived lentiviral vector is not associated with the emergence of replication-competent retrovirus and lentivirus. In addition, there was no early evidence of selective advantage of the transduced ALD cells or clonal expansion as seen in previous retroviral gene therapy trials.
Indeed this is an exciting trial demonstrating that two of three patients had improvement in their neurologic dysfunction and presenting first data on lentiviral transduction of HSC in a myeloablative setting. One of the questions raised was in regard to the durability of response, because the infused cells are inherently heterogeneous. A larger cohort of patients and further analysis on the transducer population may answer this question. Despite the small number of patients treated in this trial, it is fair to say that lentivirus has redeemed gene therapy as a viable tool for an efficient and safe modality to treat a variety of illnesses.
Dr. Abonour indicated no relevant conflicts of interest.
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