This talk has four parts.

• Describe my current understanding of CF.
• Present some of the evidence that leads me to my view of CF.
• Present some recent leads to new treatments for CF.
• A new (?) philosophy for treating CF.

Overview of CF.

• CF stands for cystic fibrosis.
• CF affects our vast internal plumbing system
• The biological pipes in our bodies are lined with special cells.
• These cells keep the inner surfaces of pipes clean and free-flowing.
• This huge inner surface consists of wet epithelia (a special kind of skin).
• CF affects the wet epithelia lining our inner organs.
• CF disrupts the processes that keep our plumbing clean and free-flowing.
• CF affects the:

• 1/4 of the children in CF families will have CF.
• The responsible gene has been identified.
• Genes are named for the diseases they cause when they are broken.
• It is difficult to determine what a gene really does.

• CF arises from one gene, one protein, one basic defect.
• The basic defect is loss of anion conductance.
• The loss occurs across epithelial apical membranes.

• The CF gene makes a protein called CFTR.

• CFTR is an anion channel (a tiny valve that lets (-) ions cross the membrane.
• CFTR is important for secreting water
• CFTR is important for absorbing salt
• In CF, secretions may lack water, or have more salt, or both
• Other important anions, such as bicarbonate and glutathione, are not secreted.

• Hyposecretion of fluid leads to blocked ducts and airways
• Hyposecretion of HCO3^- alters pH.
• Hyposecretion of glutathione increases oxidative stress
• Hypoabsorbtion of salt compromises mucosal defenses
• Hypoabsorbtion of salt leads to salt wasting (sweat)

• Blocked exocrine ducts prevent the secretion of critical enzymes
• The paradigm for this is loss of pancreatic enzymes
• By analogy, antibiotics from lung submucosal glands may be trapped.
• Larger ducts can be blocked, such as the sperm duct.
• Even large structures like intestines can be blocked.

• Blocked ducts can lead to destruction of the blocked organ.
• Blocked intestines are lethal.
• Loss of exocrine secretions has widespread consequences.

CFTR is an anion channel.

• It conducts Cl^- > HCO₃^- >> large, univalent anions >> polyvalent anions.
• Mutations that reduce anion conductance through CFTR cause CF.
• The severity of CF correlates with the degree of anion conductance loss.
• Other anion channels can partially substitute for CFTR.
• Organs with anion channels in parallel with CFTR are less affected.
• People with other anion channels are less affected.
• Animals with other anion channels are less affected.

Gene therapy for CF.

• 16 gene therapy trials underway or completed.
• No clear successes yet.
• Airways have been found to be highly resistant to transfection
• Strategies for circumventing this resistance are being pursued
• The only phase III trial for CF is now nearing completion at Stanford.
• This trial used AAV and the sinus model; it is still blinded.
• Most new gene therapy trials are aimed at cancer.
• A company called Kimerigen has proposed a novel approach.

• Compounds have been found which move D F508 to the membrane.
• These are called chemical chaperones.
• None of these are close to trials yet.
• Other compounds increase the activity of certain CFTR mutants.
• Some of these are already approved for human use.
• Trails of two of these, genistein and CPX, are moving forward.

• Nature has done this experiment for us and it works.
• But, if channels exist, they seem to work
• If they do not exist, we are back to gene therapy.
• ‘Occult channels’ may still be a possibility.

• All increases in CF longevity result from conventional therapies.
• General strategy: reduce challenges, supply what is missing.
• Pancreatic enzymes are again the paradigm.

• Avoidance is the first line of defense.
• Continuous, prophylactic treatments make sense.
• Treatments should be inhaled when possible.
• Monitoring should be improved.
• When infections are detected, eradication is the goal.
• Multiple antibiotics are required.

• Exercise?
• Bronchodilators?
• Physiotherapy?

• Religious pursuit of goals 1 & 2.
• Ibuprofen
• Inhaled antiproteases and antioxidants.

• Better (different) inhaled antibiotics
• Inhaled antifungicides.
• Better (different) inhaled anti-inflammatory agents.
• Inhaled antioxidants and antiproteases.
• Improved delivery systems.
• Improved monitoring of lung structure & function.

• Early treatment for liver disease
• Early treatment for diabetes

• Earlier, earlier, earlier
• More, more, more
• Longer, longer, longer.