These results suggest a possible alteration in the carbohydrate moiety of alpha 2-macroglobulin in cystic fibrosis, presumably due to a defective posttranslational process.
alpha 2-Macroglobulin (alpha 2M) is a major plasma protease inhibitor that has been studied because of its suggested role in the pathology of cystic fibrosis (CF).
Areas covered: Herein, the authors focus on AAV gene therapy for CF, evaluating past experience with this approach and identifying ways forward, based on the progress that has already been made in identifying and overcoming the limitations of AAV gene therapy.
A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.
These studies provide novel insights into AAV gene expression, and this newly described promoter allows for the production of AAV vectors expressing CFTR in those differentiated cells affected in CF.
A study was conducted to assess health care worker exposure to tgAAVCF during the aerosolized administration of this experimental gene transfer agent in clinical trials for the treatment of cystic fibrosis (CF). tgAAVCF is a recombinant adeno-associated virus (AAV) genetically engineered to contain the human CF transmembrane conductance regulator cDNA.
We investigated whether CF sputum acts as a barrier to leading adeno-associated virus (AAV) gene vectors, including AAV2, the only serotype tested in CF clinical trials, and AAV1, a leading candidate for future trials.
After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution.
We also demonstrate that novel corrector compounds that are being tested as treatment for cystic fibrosis, such as VX-809, can rescue the processing of the ABCA4 mutants, particularly their expression at the cell surface, and can reduce their binding to HDAC6.
If present among humans, polymorphic expression of MDR1 in lung parenchyma may explain part of the differences in lung symptomatology observed in the CF patients carrying the same mutation.
In addition, overexpression of native Pgp in sigmaCFTE29ó could also be achieved by long-term treatment with colchicine, a drug, which may be of great interest in CF therapy.
These results demonstrate that both the CF and MDR1 genes are expressed in the human placenta at all stages of development and differentiation, although the expression of the CF, but not the MDR1, gene appears to be much weaker in the undifferentiated JAr cells in comparison with cytotrophoblast cells.
Heterologous expression of wild-type or mutated MDR1 revealed similar mRNA transcript levels in Chinese hamster ovary K1 recipients, but the subsequent processing was defective for all mutations that give rise to severe cystic fibrosis in the case of CFTR.
The results show parallel mRNA expression for the CF and MDR1 genes, with the signal detected in the syncytiotrophoblast and cytotrophoblast cells of the placental villi.
P-glycoprotein (MDR1), that confers multidrug resistance in cancer, and the cystic-fibrosis transmembrane-conductance regulator (CFTR), that is causative defective in cystic fibrosis, belong to the family of ATP-binding transport proteins.
In addition, overexpression of native Pgp in sigmaCFTE29ó could also be achieved by long-term treatment with colchicine, a drug, which may be of great interest in CF therapy.
The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, an ATP binding cassette (ABC) protein whose defects cause the deadly genetic disease cystic fibrosis (CF), encompasses two nucleotide binding domains (NBD1 and NBD2).