Dataset Information

Careful adjustment of Epo non-viral gene therapy for beta-thalassemic anaemia treatment.

ABSTRACT:

Background

In situ production of a secreted therapeutic protein is one of the major gene therapy applications. Nevertheless, the plasmatic secretion peak of transgenic protein may be deleterious in many gene therapy applications including Epo gene therapy. Epo gene transfer appears to be a promising alternative to recombinant Epo therapy for severe anaemia treatment despite polycythemia was reached in many previous studies. Therefore, an accurate level of transgene expression is required for Epo application safety. The aim of this study was to adapt posology and administration schedule of a chosen therapeutic gene to avoid this potentially toxic plasmatic peak and maintain treatment efficiency. The therapeutic potential of repeated muscular electrotransfer of light Epo-plasmid doses was evaluated for anaemia treatment in beta-thalassemic mice.

Methods

Muscular electrotransfer of 1 microg, 1.5 microg, 2 microg, 4 microg or 6 microg of Epo-plasmid was performed in beta-thalassemic mice. Electrotransfer was repeated first after 3.5 or 5 weeks first as a initiating dose and then according to hematocrit evolution.

Results

Muscular electrotransfer of the 1.5 microg Epo-plasmid dose repeated first after 5 weeks and then every 3 months was sufficient to restore a subnormal hematrocrit in beta-thalassemic mice for more than 9 months.

Conclusion

This strategy led to efficient, long-lasting and non-toxic treatment of beta-thalassemic mouse anaemia avoiding the deleterious initial hematocrit peak and maintaining a normal hematocrit with small fluctuation amplitude. This repeat delivery protocol of light doses of therapeutic gene could be applied to a wide variety of candidate genes as it leads to therapeutic effect reiterations and increases safety by allowing careful therapeutic adjustments.

SUBMITTER: Fabre EE

PROVIDER: S-EPMC2276190 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Publications

Careful adjustment of Epo non-viral gene therapy for beta-thalassemic anaemia treatment.

Fabre Emmanuelle E EE Bigey Pascal P Beuzard Yves Y Scherman Daniel D Payen Emmanuel E

Genetic vaccines and therapy 20080311

<h4>Background</h4>In situ production of a secreted therapeutic protein is one of the major gene therapy applications. Nevertheless, the plasmatic secretion peak of transgenic protein may be deleterious in many gene therapy applications including Epo gene therapy. Epo gene transfer appears to be a promising alternative to recombinant Epo therapy for severe anaemia treatment despite polycythemia was reached in many previous studies. Therefore, an accurate level of transgene expression is required ...[more]

PMID: 18334017

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Project description:BackgroundTransfusion-associated microchimerism implies the presence of allogeneic hematopoietic cells in an individual, following the transfusion of a blood product. It is a transfusion-related adverse effect/long-term consequence, which has not been well-investigated among regularly transfused patients with thalassemia.Patients and methodsWe investigated 64 regularly transfused, homozygous β-thalassemic patients and 21 never-transfused healthy volunteer blood donors (controls) for the presence of microchimerism in their sera, using real-time PCR targeting circulating allogeneic, both, Human Leukocyte Antigen-DR isotype (HLA-DR) and non-HLA alleles. The investigation was longitudinally repeated in patient subsets for more than 2 years. Results were correlated with clinical and laboratory parameters, peripheral blood lymphocyte immunophenotype, blood storage time, and donor's gender to identify potential contributing factors for microchimerism generation.ResultsOverall, microchimerism was detected in 52 of the 64 patients (81.2%) and in 6 of the 21 controls (28.5%, p = 0.0001). Forty-four patients (68.7%) exhibited long-term microchimerism (persisted for more than 6 months), confirmed at all time-points investigated. Microchimerism was more frequent among elderly, women, splenectomized and more heavily transfused patients, and among those who exhibit higher serum ferritin levels. In these patients, a distinct descending pattern of CD16dim+CD56dim+ natural killer (NK)-cells (p < 0.001) and an ascending pattern of CD4+CD25brightCD127- regulatory T-cells (p = 0.022) for increasing allelic burden were noticed, suggesting the establishment of recipient immune tolerance against the donor-derived chimeric alleles. Both splenectomized and non-splenectomized thalassemic patients exhibited the same trend. The storage time of transfused blood products and donor/gender mismatch had no impact on the development of microchimerism.Discussion-conclusive remarksTransfusion-associated microchimerism appears to be a very common complication among multi-transfused thalassemic patients. The potential clinical consequences of this phenomenon remain as yet unclear. Immune tolerance attributed to disease itself and to repeated transfusions might at least in part explain its appearance.

Dataset Information

Careful adjustment of Epo non-viral gene therapy for beta-thalassemic anaemia treatment.

Background

Methods

Results

Conclusion

Publications

Careful adjustment of Epo non-viral gene therapy for beta-thalassemic anaemia treatment.

Similar Datasets

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