NEW YORK (Reuters Health) - A lentiviral vector efficiently delivers fetal hemoglobin in a mouse model of beta-thalassemia, according to a report in the October 15th issue of Blood.
Variable gene expression has limited the effectiveness of first-generation gene therapies for beta-thalassemia, the authors explain. Effective gene therapy will likely require vector modifications that result in more consistent globin expression from single-copy vector insertions.
With these limitations in mind, Dr. Derek A. Persons and colleagues from St. Jude Children’s Research Hospital, Memphis, Tennessee developed a second-generation gamma-globin lentiviral vector having more extensive beta-globin locus control region-derived regulatory sequences and tested it in a mouse model of beta-thalassemia.
Transplantation of mice with cells transduced by the new vector resulted in fetal hemoglobin levels above 15% in five of six mice, the authors report, compared with only two of five mice transplanted with cells transduced by the older vector.
The new vector directed an output of 20 g/L of hemoglobin per vector copy, compared with only 8.5 g/L output per vector copy with the older vector. According to the report, this translated into an average 26 g/L improvement in hemoglobin concentration, compared with an average 17 g/L improvement with the first-generation vector.
Both intragenic and intergenic insertions of the new vector expressed well, the researchers note. In contrast, the first-generation vector was more likely to express well with intergenic insertion.
“The use of vectors encoding gamma-globin, rather than beta-globin or beta-globin variants, provides an attractive alternative therapeutic approach for gene therapy of beta-thalassemia and sickle cell disease,” the authors conclude.
“Gene therapy for hematopoietic disorders will be a viable approach in the future for many patients that have no other treatment options,” Dr. Persons told Reuters Health. “For beta-thalassemia and other hemoglobin disorders, where there is very little selective advantage, the challenge is greater and will require much high levels of gene transfer into stem cells.”
“There are two major issues yet to be resolved that are crucial, in my view, to allow clinical trials to begin sooner rather than later with a reasonable possibility of some success,” Dr. Persons continued. “Firstly, we do not yet know what level of human stem cell gene transfer can be achieved with globin lentiviral vectors...The second issue to be addressed is what pre-transplant conditioning will be used in beta-thalassemic patients in a gene therapy trial.”
“I think we shall see human clinical trials within 5 years,” Dr. Persons predicted.
Source: Blood 2004;104:2281-2290. [ Google search on this article ]
MeSH Headings:Animal Diseases: Biological Therapy: Disease Models, Animal: DNA, Recombinant: Genetic Engineering: Genetic Techniques: Genetic Vectors: Investigative Techniques: Therapeutics: Gene Therapy: Lentivirus: Analytical, Diagnostic and Therapeutic Techniques and Equipment: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
