Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

Dalle, B; Payen, Emmanuel; Régulier, Etienne; Déglon, Nicole; Rouyer-Fessard, P; Beuzard, Yves; Aebischer, Patrick

doi:10.1038/sj.gt.3300812

Cited by 48 publications

(29 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…41 In fact, recent approaches to overcome gene silencing include either lentivirus-encoded 'shaveddown' ␤-globin gene locus transcription units or circumvention of the ␤-globin gene locus entirely by erythropoietin delivery in myoblasts, by electrotransfer, and by adeno-associated virus gene transfer. [48][49][50][51][52] Although these approaches have had limited success, there remain unresolved safety issues using lentivirus and adeno-associated virus in human applications. In addition, there are concerns about encapsulated myoblast technology and longevity, as well as the cost and efficacy of repeated electrotransfers of erythropoietin in diseased humans.…”

Section: Stable Episomal Persistence Of Pbh148mentioning

confidence: 99%

Establishment of an oriP/EBNA1-based episomal vector transcribing human genomic β-globin in cultured murine fibroblasts

Black

2002

Gene Ther

View full text Add to dashboard Cite

Section: Stable Episomal Persistence Of Pbh148mentioning

confidence: 99%

Establishment of an oriP/EBNA1-based episomal vector transcribing human genomic β-globin in cultured murine fibroblasts

Black

2002

Gene Ther

View full text Add to dashboard Cite

“…This is because the EPO gene has been delivered to healthy animals [5][6][7][8][9][10] or has been used in models such as ␤-thalassemic mice 11,12 or mice with acute renal failure. 13 In these studies, any response in the hematocrit level has been taken as a measure of successful gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy

Binley

Askham

Iqball

et al. 2002

Blood

View full text Add to dashboard Cite

Anemia is a common clinical problem, and there is much interest in its role in promoting left ventricular hypertrophy through increasing cardiac workload. Normally, red blood cell production is adjusted through the regulation of erythropoietin (Epo) production by the kidney. One important cause of anemia is relative deficiency of Epo, which occurs in most types of renal disease. Clinically, this can be corrected by supplementation with recombinant Epo. Here we describe an oxygen-regulated gene therapy approach to treating homozygous erythropoietin-SV40 T antigen (Epo-TAg h ) mice with relative erythropoietin deficiency. We used vectors in which murine Epo expression was directed by an Oxford Biomedica hypoxia response element (OBHRE) or a constitutive cytomegalovirus (CMV) promoter. Both corrected anemia, but CMVEpo-treated mice acquired fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit level in anemic mice to a normal physiologic level that stabilized without resulting in polycythemia. Importantly, the OBHRE-Epo vector had no significant effect on the hematocrit of control mice. Homozygous Epo-TAg h mice display cardiac hypertrophy, a common adaptive response in patients with chronic anemia. In the OBHRE-Epo-treated EpoTAg h mice, we observed a significant reversal of cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit level is corrected to healthy in anemic Epo-TAg h mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved, and it makes EPO gene therapy more attractive and safer in clinical settings. We envisage that this control system will allow regulated delivery of therapeutic gene products in other ischemic settings. IntroductionAn important cause of anemia is relative deficiency in the production of the glycoprotein hormone erythropoietin (Epo), which regulates the formation of red blood cells (RBCs). Relative Epo deficiency occurs in almost all patients with chronic renal failure. 1,2 Decreased RBC production reduces the oxygen-carrying capacity of the blood, resulting in tissue hypoxia. Pathophysiologic consequences correlate with the severity of the anemia and range from fatigue and reduced exercise tolerance to cardiac hypertrophy. Erythropoietin deficiency in renal disease can be treated remarkably effectively by regular administration of recombinant human Epo (rhEpo) several times a week. Erythropoietin can also be used to treat anemia in patients with cancer and chronic inflammatory diseases such as rheumatoid arthritis. 3,4 Although it is safe, treatment with erythropoietin is relatively costly and entails some inconvenience in monitoring and administration. Hence, there has been considerable interest in developing a gene therapy strategy for the delivery of Epo whereby single administration of the EPO gene would ensure the long-term delivery of Epo.Although the EPO gene has been delivered to animals using various plasmid and viral vectors, the ...

show abstract

“…In a mouse model, a major histocompatibility complex-negative allogeneic cell line genetically engineered to produce GM-CSF was shown to afford an anti-tumor immune response that was equivalent to or better than those achieved using genetically modified autologous tumor cells. 26 Furthermore, the investigators reported the generation of the modified K562 human erythroleukemia cell line, which produces large quantities of GM-CSF, for use in clinical applications. However, using allogeneic tumor cells engineered to produce a stable amount of the cytokine leads to the rapid destruction of the cells, and it does not allow for a sustained delivery of the adjuvant over several days.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the properties of the permeable membrane of the capsule ensures a selective influx of molecules essential for cell survival, and a selective outflow of metabolic byproducts and the cytokine of interest. This strategy has been studied extensively as a sustained delivery system to provide biologically active molecules like erythropoietin, [26][27][28][29] coagulation factors 30 and neurotrophic factors. 31,32 Clinical trials have been conducted in diabetic patients 33 and patients suffering from amyotrophic lateral sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy

et al. 2011

View full text Add to dashboard Cite

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based cancer immunization

show abstract

Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

Cited by 48 publications

References 24 publications

Establishment of an oriP/EBNA1-based episomal vector transcribing human genomic β-globin in cultured murine fibroblasts

Establishment of an oriP/EBNA1-based episomal vector transcribing human genomic β-globin in cultured murine fibroblasts

Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy

Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy

Contact Info

Product

Resources

About