scholarly journals Overcoming Immunological Challenges to Helper-Dependent Adenoviral Vector-Mediated Long-Term CFTR Expression in Mouse Airways

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 565
Author(s):  
Huibi Cao ◽  
Rongqi Duan ◽  
Jim Hu
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Immune Responses ◽  
Mouse Lung ◽  
Host Immune Responses ◽  
Gene Therapy Vectors ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Cluster Of Differentiation ◽  
Mouse Lungs

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and CF patients require life-long treatment. Although CFTR modulators show a great potential for treating most CF patients, some individuals may not tolerate the treatment. In addition, there is no effective therapy for patients with some rare CFTR mutations, such as class I CF mutations, which lead to a lack of CFTR protein production. Therefore, other therapeutic strategies, such as gene therapy, have to be investigated. Currently, immune responses to gene therapy vectors and transgene products are a major obstacle to applying CF gene therapy to clinical applications. In this study, we examined the effects of cyclophosphamide on the modulation of host immune responses and for the improvement of the CFTR transgene expression in the repeated delivery of helper-dependent adenoviral (HD-Ad) vectors to mouse lungs. We have found that cyclophosphamide significantly decreased the expression of T cell genes, such as CD3 (cluster of differentiation 3) and CD4, and reduced their infiltration into mouse lung tissues. We have also found that the levels of the anti-adenoviral antibody and neutralizing activity as well as B-cell infiltration into the mouse lung tissues were significantly reduced with this treatment. Correspondingly, the expression of the human CFTR transgene has been significantly improved with cyclophosphamide administration compared to the group with no treatment. These data suggest that the sustained expression of the human CFTR transgene in mouse lungs through repeated vector delivery can be achieved by transient immunosuppression.

Immune responses to gene therapy vectors in the context of corneal transplantation

2009 ◽  
Vol 87 ◽  
pp. 0-0
Author(s):  
T RITTER ◽  
M WILK ◽  
N GONG ◽  
U PLEYER ◽  
M NOSOV
Keyword(s):  
Gene Therapy ◽  
Immune Responses ◽  
Corneal Transplantation ◽  
Gene Therapy Vectors

scholarly journals Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 538 ◽  
Author(s):  
Ashley Cooney ◽  
Paul McCray ◽  
Patrick Sinn
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Anion Channel ◽  
Gene Replacement ◽  
Cystic Fibrosis Gene ◽  
Cftr Gene ◽  
System Disease ◽  
Cftr Mutations ◽  
Infection And Inflammation

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality.

scholarly journals Gene delivery systems—gene therapy vectors for cystic fibrosis

2004 ◽  
Vol 3 ◽  
pp. 203-212 ◽  
Author(s):  
Daniel Klink ◽  
Dirk Schindelhauer ◽  
Andreas Laner ◽  
Torry Tucker ◽  
Zsuzsanna Bebok ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Gene Delivery ◽  
Delivery Systems ◽  
Gene Therapy Vectors

Gene therapy for Cystic Fibrosis: Improved delivery techniques and conditioning with lysophosphatidylcholine enhance lentiviral gene transfer in mouse lung airways

2017 ◽  
Vol 43 (9-10) ◽  
pp. 426-433 ◽  
Author(s):  
Patricia Cmielewski ◽  
Nigel Farrow ◽  
Sharnna Devereux ◽  
David Parsons ◽  
Martin Donnelley
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Mouse Lung ◽  
Lung Airways ◽  
Delivery Techniques

scholarly journals Overcoming the Cystic Fibrosis Sputum Barrier to Leading Adeno-associated Virus Gene Therapy Vectors

2014 ◽  
Vol 22 (8) ◽  
pp. 1484-1493 ◽  
Author(s):  
Benjamin S Schuster ◽  
Anthony J Kim ◽  
Joshua C Kays ◽  
Mia M Kanzawa ◽  
William B Guggino ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Adeno Associated Virus ◽  
Virus Gene ◽  
Cystic Fibrosis Sputum ◽  
Gene Therapy Vectors

scholarly journals Designing gene therapy vectors: avoiding immune responses by using tissue-specific promoters

Gene Therapy ◽  
2001 ◽  
Vol 8 (24) ◽  
pp. 1872-1878 ◽  
Author(s):  
RD Weeratna ◽  
T Wu ◽  
SM Efler ◽  
L Zhang ◽  
HL Davis
Keyword(s):  
Gene Therapy ◽  
Immune Responses ◽  
Tissue Specific ◽  
Gene Therapy Vectors

scholarly journals Progress Toward The Synthesis Of Labeled Derivatives Of The Cystic Fibrosis Drug Ivacaftor

2021 ◽  
Author(s):  
Salma Elmallah
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Genetic Diseases ◽  
Early Death ◽  
Open Probability ◽  
Gene Encoding ◽  
Short Period ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Orally Bioavailable

Cystic fibrosis (CF) is one of the most common genetic diseases, affecting approximately 70,000 people worldwide causing severe complications and often leading to early death. CF is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is responsible for fluid and ion transport through epithelial membranes maintaining the formation of a thin slippery mucous layer. CFTR mutations either lead to a trafficking defect where the CFTR protein does not reach the plasma membrane or a gating defect where CFTR protein at the plasma membrane does not function properly. Treatment of cystic fibrosis usually addresses the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Vertex pharmaceuticals has been interested in developing small molecules that have the ability to interact with mutated CFTR proteins, aiding in their delivery to the cell membrane and/or restoring their channel function. VX-770 is an orally bioavailable potentiator that has the ability to improve the gating activity and increasing the open probability of CFTR protein in patients carrying the G551D mutation. VX770, Ivacaftor, was recently approved by the US FDA after showing very good improvements in the lung function in CF patients with good safety profile. Our research is focusing on the synthesis of VX770 under mild conditions and formation of labeled derivatives to help in the understanding of its exact mode of action. Different methods were developed toward the synthesis of the two main components, LHS and RHS, of VX770 by using less harsh conditions for a short period of time. We were successfully able to make two photoaffinity labeled derivatives, aryl azide and benzophenone derivatives, which will be beneficial in tracking the drug molecule and revealing the exact site of interaction between the drug and the protein. Synthesis of VX770 fragments was is another focus of interest in our research as they will provide us with information about the best positions for further derivatization.

Sign in / Sign up

Export Citation Format

Share Document