Therapy for beta-globinopathies: a brief review and determinants for successful and safe correction.
ABSTRACT Gene therapy for beta-globinopathies, particularly beta-thalassemia and sickle cell anemia, hold much promise for the future, as a one time cure for these common and debilitating disorders. Correction of the beta-globinopathies using lentivirus vectors (LV) carrying the beta- or gamma-globin genes and elements of the locus control region has been well established in murine models, and a good idea of "what it will take to cure these diseases" has been developed in the first decade of the twenty-first century. A clinical trial using one such vector has been initiated in France while other trials are in development. Vector improvements to enhance the safety and efficiency of LV are being explored, while newer strategies, like homologous recombination in induced pluripotent cells for correction of sickle cell anemia, has been shown as a proof-of-concept. Here we provide a review of current progress in genetic correction of beta-globin disorders.
SourceAvailable from: Garyfalia Karponi[Show abstract] [Hide abstract]
ABSTRACT: We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34+ HPCs in adults with β-thalassemia major. We further assessed whether thalassemia patient CD34+ HPCs could be transduced with a globin lentiviral vector under clinical conditions at levels sufficient for therapeutic implementation. All patients tolerated G-CSF well with minimal side effects. All cell collections exceeded 8x10(6) CD34+ cells/kg. Using clinical grade TNS9.3.55 vector, we demonstrated globin gene transfer averaging 0.53 in three validation runs performed under cGMP conditions. Normalized to vector copy, the vector-encoded β-chain was expressed at a level approximating normal hemizygous protein output. Importantly, stable vector copy number (0.2-0.6) and undiminished vector expression were obtained in NSG mice 6 months post-transplant. We thus validated a safe and effective procedure for β-globin gene transfer in thalassemia patient CD34+ HPCs, which we will implement in the first US trial in patients with severe inherited globin disorders (NCT01639690).Blood 01/2014; 123(10). DOI:10.1182/blood-2013-06-507178 · 9.78 Impact Factor
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ABSTRACT: Nonviral systems for nucleic acid delivery offer a host of potential advantages compared with viruses, including reduced toxicity and immunogenicity, increased ease of production and less stringent vector size limitations, but remain far less efficient than their viral counterparts. In this article we review recent advances in the delivery of nucleic acids using polymeric and inorganic vectors. We discuss the wide range of materials being designed and evaluated for these purposes while considering the physical requirements and barriers to entry that these agents face and reviewing recent novel approaches towards improving delivery with respect to each of these barriers. Furthermore, we provide a brief overview of past and ongoing nonviral gene therapy clinical trials. We conclude with a discussion of multifunctional nucleic acid carriers and future directions.Therapeutic delivery 04/2011; 2(4):493-521. DOI:10.4155/tde.11.14
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ABSTRACT: Abstract The goals of the National Heart, Lung, and Blood Institute (NHLBI) Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases are to conduct gene transfer studies in monkeys to evaluate safety and efficiency; and to provide NHLBI-supported investigators with expertise, resources, and services to actively pursue gene transfer approaches in monkeys in their research programs. NHLBI-supported projects span investigators throughout the United States and have addressed novel approaches to gene delivery; "proof-of-principle"; assessed whether findings in small-animal models could be demonstrated in a primate species; or were conducted to enable new grant or IND submissions. The Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases successfully aids the gene therapy community in addressing regulatory barriers, and serves as an effective vehicle for advancing the field.Human gene therapy 09/2012; DOI:10.1089/hum.2012.178 · 3.62 Impact Factor