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Adenovirus-mediated in utero expression of CFTR does not improve survival of CFTR knockout mice
Lee A Davies1, Anusha Varathalingam, Hazel Painter
1Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Abstract:
Gene therapy is being investigated in the treatment of lung-related aspects of the genetic disease, Cystic fibrosis (CF). Clinical studies have demonstrated CF transmembrane conductance regulator (CFTR) expression in the airways of adults with CF using a variety of gene transfer agents. In utero gene therapy is an alternative approach that facilitates vector transduction of rapidly expanding populations of target cells while avoiding immune recognition of the vector. In CF, in utero gene transfer could potentially delay the onset of disease symptoms in childhood and compensate for the role, if any, that CFTR plays in the developing organs. Previously published studies have suggested that transient expression of CFTR in utero was sufficient to rescue the fatal intestinal defect in S489X Cftr(tm1Unc)/Cftr(tm1Unc) knockout mice. We replicated these studies using an identical CFTR-expressing adenoviral vector and CF mouse strain in sufficiently large numbers to provide robust Kaplan-Meier survival data. Although each step of the procedure was carefully controlled and vector-specific CFTR expression was confirmed in the fetal organs after treatment, there was statistically no significant improvement in the survival of mice treated in utero with AdCFTR, compared with contemporaneous control animals.
Insights
In utero gene therapy using AdCFTR did not improve survival in Cystic Fibrosis (CF) mice, despite confirmed CFTR expression. This study did not replicate previous findings of rescue in CF mouse models.
Area of Science:
- Medical Genetics
- Molecular Biology
- Developmental Biology
Background:
- Gene therapy is explored for Cystic Fibrosis (CF), focusing on CF transmembrane conductance regulator (CFTR) expression in airways.
- In utero gene therapy offers potential to target developing organs and avoid immune responses, possibly delaying CF symptom onset.
Purpose of the Study:
- To investigate if in utero gene transfer of CFTR can rescue fatal intestinal defects and improve survival in a CF mouse model.
- To replicate previous findings suggesting transient in utero CFTR expression is sufficient for rescue.
Main Methods:
- Utilized an identical CFTR-expressing adenoviral vector (AdCFTR) and the S489X Cftr(tm1Unc)/Cftr(tm1Unc) mouse strain.
- Administered in utero gene transfer and confirmed vector-specific CFTR expression in fetal organs.
- Collected robust survival data using Kaplan-Meier analysis for treated and control groups.
Main Results:
- Vector-specific CFTR expression was confirmed in fetal organs post-treatment.
- No statistically significant improvement in survival was observed in mice treated with AdCFTR compared to control animals.
- The study failed to replicate previous findings of rescue in this CF mouse model.
Conclusions:
- In utero gene therapy with AdCFTR did not demonstrate efficacy in improving survival for the tested CF mouse model.
- Further research is needed to understand the limitations and potential of in utero gene therapy for Cystic Fibrosis.
- The discrepancy with prior studies highlights the complexity of gene therapy applications in genetic diseases.
