title: A novel lentiviral vector targets gene transfer into human hematopoietic stem cells in marrow from patients with bone marrow failure syndrome and in vivo in humanized mice.
abstract: In vivo lentiviral vector (LV)-mediated gene delivery would represent a great step forward in the field of gene therapy. Therefore, we have engineered a novel LV displaying SCF and a mutant cat endogenous retroviral glycoprotein, RDTR. These RDTR/SCF-LVs outperformed RDTR-LVs for transduction of human CD34(+) cells (hCD34(+)). For in vivo gene therapy, these novel RDTR/SCF-displaying LVs can distinguish between the target hCD34(+) cells of interest and nontarget cells. Indeed, they selectively targeted transduction to 30%-40% of the hCD34(+) cells in cord blood mononuclear cells and in the unfractionated BM of healthy and Fanconi anemia donors, resulting in the correction of CD34(+) cells in the patients. Moreover, RDTR/SCF-LVs targeted transduction to CD34(+) cells with 95-fold selectivity compared with T cells in total cord blood. Remarkably, in vivo injection of the RDTR/SCF-LVs into the BM cavity of humanized mice resulted in the highly selective transduction of candidate hCD34(+)Lin(-) HSCs. In conclusion, this new LV will facilitate HSC-based gene therapy by directly targeting these primitive cells in BM aspirates or total cord blood. Most importantly, in the future, RDTR/SCF-LVs might completely obviate ex vivo handling and simplify gene therapy for many hematopoietic defects because of their applicability to direct in vivo inoculation.
authors: INSERM U758, Human Virology Department, Enveloppe Virale and Ingeniérie du Retrovirus, Ecole Nomrale Supérieure de Lyon, and Université de Lyon, 46 Allée d'Italie, Lyon Cedex 07, France.
authors: Cecilia
authors: C
authors: Frecha
authors: Caroline
authors: C
authors: Costa
authors: Didier
authors: D
authors: Nègre
authors: Fouzia
authors: F
authors: Amirache
authors: Didier
authors: D
authors: Trono
authors: Paula
authors: P
authors: Rio
authors: Juan
authors: J
authors: Bueren
authors: François-Loïc
authors: FL
authors: Cosset
authors: Els
authors: E
authors: Verhoeyen
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D000831:Animals, Newborn; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D018390:Gene Targeting / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014161:Transduction, Genetic
chemical_list: D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; C499308:Rag2 protein, mouse