Cystic Fibrosis: From Laboratory To The Clinic

25.5.06

Short history
• Dorothy Andersen - pathologist with special interest in children - carried out post-mortems on children - start of last century - coeliac disease (gluten insensitivity) - found not coeliac disease: "cystic fibrosis of the pancreas" - associated respiratory symptoms.
• Paul di St Agnisi, 1950s New York City.
• High sweat salts - drawing on Medieval folklore - became diagnostic test for CF - pylocarpin applied topically and charge applied to stimulate sweat glands.
• Holistic care:
-chest;
-nutrition;
-social.

Why do children with CF have problems with chest infection?
• Salt transport.

CFTR gene makes ion-transporting protein pore - pores situated in apical surface of epithelium. Lungs sterile due to "mucosillary escalator" - cilia - periciliary aqueous layer helps cilia to beat - mucous layer on top of this - absorbing liquid in respiratory epithelium via sodium transport (ENaC) - water pulled through via osmosis.

CFTR protein:
• 12 transmembrane domains.
• Large R domain.
• 2 NBFs.
• Cl- out of cell, Na+ into cell through difference channel.
• CFTR not Na+ - only regulates Na+ channel - acts as brake on Na+ channel.
• No CFTR protein in CF - lose brake on Na+ channel - increased Na+ absorption - dehydrated periciliary aqueous layer - cilia clamped down - problem with mucosillary clearance.
• Body can form mucosillary transport through other mechanisms - more mucous formed, but becomes dehydrated also - prime breeding ground for bacteria - form chronic infection.

• Difficult bacteria.

• Inflammation - neutrophils enter lungs and become stuck in mucus - explode - release lots of DNA - very sticky.

Paediatric clinic
• Multi-disciplinary team.
• CF nurse specialist.
• Dietician.
• Physiotherapist.
• School teacher.
• Social worker - disability living allowance.
• Psychologist.
• Physicians.

Hope 1: ion transport modulators
• Amiloride - clinical trials - only works for 30 minutes.
• Long-acting Na+ channel blockers.
• Chloride secretagogues.
• Problems:
-dynamic;
-early;
-mucus.

Hope 2: gene therapy
• Somatic gene transfer.
-Replication-deficient viral vector.
§Integrating.
§Non-integrating.
-Liposome vectors.
• Systemic gene transfer.
• Stem cell.
• Foetal gene transfer.

Hope 3: modulators of inflammation
• Steroids.
• NSAIDs - ibuprofen.
• Azithromycin.
• Newer compounds.