Preclinical and clinical progress in hemophilia gene therapy
- 1 September 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Current Opinion in Hematology
- Vol. 17 (5), 387-392
- https://doi.org/10.1097/moh.0b013e32833cd4bd
Abstract
Purpose of review Hemophilia A and B are attractive target diseases for gene therapy, as stable expression of coagulation factor VIII and IX may correct the bleeding diathesis. This review focuses on the recent progress in preclinical and clinical studies in gene therapy for hemophilia A and B. Recent findings Hepatic gene delivery using vectors derived from adeno-associated virus (AAV) resulted in therapeutic but transient functional clotting factor IX (FIX) expression levels in severe hemophilia B patients. Although T-cell-mediated immune responses eliminated the transduced hepatocytes, transient immunosuppression may potentially overcome this limitation. Alternatively, vectors are being developed that result in higher FIX expression levels at lower vector doses. Lentiviral vectors are being explored for in-vivo hepatic gene delivery and for ex-vivo transduction of hematopoietic stem cells. This resulted in stable correction of the bleeding diathesis in hemophilic mice. Finally, nonviral vectors derived from transposons result in sustained clotting-factor expression in rodent models. Translational studies in large animal models are required to move these new approaches forward into the clinic. Summary New insights from clinical trials and advances in preclinical studies may ultimately pave the way toward a cure in patients suffering from hemophilia.Keywords
This publication has 74 references indexed in Scilit:
- Comparative Analysis of Transposable Element Vector Systems in Human CellsMolecular Therapy, 2010
- Proteasome Inhibitors Decrease AAV2 Capsid derived Peptide Epitope Presentation on MHC Class I Following TransductionMolecular Therapy, 2010
- A Preclinical Animal Model to Assess the Effect of Pre-existing Immunity on AAV-mediated Gene TransferMolecular Therapy, 2009
- Directed Engineering of a High-expression Chimeric Transgene as a Strategy for Gene Therapy of Hemophilia AMolecular Therapy, 2009
- Undetectable Transcription of cap in a Clinical AAV Vector: Implications for Preformed Capsid in Immune ResponsesMolecular Therapy, 2009
- Erythroid-specific Human Factor IX Delivery From In Vivo Selected Hematopoietic Stem Cells Following Nonmyeloablative Conditioning in Hemophilia B MiceMolecular Therapy, 2008
- Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower dosesProceedings of the National Academy of Sciences of the United States of America, 2008
- Safety and Efficacy of Gene Transfer for Leber's Congenital AmaurosisThe New England Journal of Medicine, 2008
- Effect of Gene Therapy on Visual Function in Leber's Congenital AmaurosisThe New England Journal of Medicine, 2008
- A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined ImmunodeficiencyThe New England Journal of Medicine, 2003