Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994

From Biol557

Contents 1 Abstract 2 Introduction 2.1 I also decided to add in the notes I took in class just for completeness 2.2 Results in the human study:

[edit] Abstract

• They administered a recombinant adenovirus vector (AdCFTR) containing the normal human CFTR cDNA into the nasal and bronchial epithelium of 4 individuals with CF.
• They found the vector expresses the CFTR cDNA in the respiratory epithelium in vivo.
• At 2x10⁹ pfu there was no recombination, complementation, shedding of the vector, or rise in antibody titres. Although, there was a transient and systemic pulmonary syndrome observed (possibly mediated by IL-6)
• They saw no long term effects

[edit] Introduction

• CF is a common lethal hereditary disorder caused by a mutation on CFTR on chromosome 7
• The disorder is characterized by airway and gastrointestinal disease, the lung manifestations dominate
• The pathogenesis is clearly linked to the lack of CFTR in the respiratory epithelia
• Symptoms in first decade:
  • Thick mucus, colonization with infectious bacteria, and chronic airway inflammation
• One approach to prevent respiratory manifestations of CFTR is gene therapy (talked about in abstract)
• Gene therapy must be carried out in vivo, cannot be done ex vivo

[edit] I also decided to add in the notes I took in class just for completeness

• One of the four human gene therapy trials approved and initiated at the same time
• Based on the results of this trial, the others were halted
• Used CF patients who were in remarkably good health
• Did multiple dosing to find effecting concentration

[edit] Results in the human study:

• Treatment evoked an immune response
• Inflammation accompanied the immune response
• Results are short lived-- at most 6 weeks
• Because of the immune response, will not be able to do multiple dosing
• Very inefficient transfer of gene of interest-- will do nothing to correct the defect
• "Correction of the CF phenotype of the airway epithelium might be achieved with this strategy"
• "To maintain chronic expression, adenovirus vectors will probably have to be administered repeatedly"
  • This is not possible with an immune response