Research needs and unanswered questions
The paradigm shift from treating the downstream consequences of CFTR dysfunction, such as infection with antibiotics, to addressing the fundamental consequences of the molecular defect, is likely to gather momentum, and more designer molecules to treat other classes of mutations are urgently needed.
Currently, the UK CF Gene Therapy consortium (www.cfgenetherapy.org.uk) is carrying out the first therapeutic gene therapy trial (i.e. ‘Does it help the patient?’ rather than ‘Can we get the gene to be expressed in the human airway?’). It seems likely that the results will stimulate further refinements in this area, leading to further big trials.
A huge research need is to find meaningful surrogate end-points for clinical trials. Thankfully, in CF the annual mortality is low and the average decline of spirometric indices is slow, but this implies that neither of these conventional end-points is useful. Other possibilities include: more sophisticated lung function tests, such as lung clearance index; markers of inflammation in blood, induced sputum or breath condensate; expression of CFTR mRNA and protein; and electrophysiological tests. The choice will vary depending on the clinical trial question. Validating these biomarkers is an ongoing and important research task.