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

Huibi Cao,Rongqi Duan,Jim Hu

doi:10.3390/genes11050565

Abstract

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.

Highlights

Cystic fibrosis (CF) is a life-long inherited disease that affects >70,000 patients globally; it is caused by underlying genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)gene [1]
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
Our previous studies have shown that the helper-dependent adenoviral (HD-Ad)-CFTR vector can efficiently transduce epithelial cells, but it induces significant inflammation immune responses to can the efficiently vector intransduce mouse lungs [19]

Summary

Introduction

Cystic fibrosis (CF) is a life-long inherited disease that affects >70,000 patients globally; it is caused by underlying genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). New CFTR-modulator drugs show promise for up to 90% of patients, including patients with. CFTR mutations for which early modulators are ineffective [2,3,4,5]. CFTR modulators show enormous potential for treating most CF patients, they are expensive and patients require lifetime treatments [6]. Some patients may not tolerate the treatments. It is understandable that pharmaceutical approaches may not always effectively fix every malfunctioning human body caused by the same genetic defect [7]. Alternative therapeutic strategies, such as gene therapy, should be explored

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