How can an oral drug successfully treat the genetic disorder cystic fibrosis?

TeachableMedicalNews article 08142020

Teachable moment in classrooms:

1. chemical basis of life chapter – protein structure and shape is important for proper function
2. cellular basis of life chapter – ion channel proteins in plasma membrane
3. cellular basis of life chapter – concept of gene mutation leading to protein malfunction
4. cellular basis of life chapter – involvement of the smooth endoplasmic reticulum apparatus in protein processing

5. tissue chapter –function of ciliated epithelium
6. respiratory system chapter – anatomy of the conduction zone
7. respiratory system chapter – the lining of bronchi and bronchioles

The news item:  Recently a new treatment was reported for cystic fibrosis:

Studies Yield ‘Impressive’ Results in Fight Against Cystic Fibrosis (Published 2019)

The findings hold promise for a vast majority of those with cystic fibrosis, according to the director of the National Institutes of Health. “This should be a cause for major celebration,” he wrote.

The article mentions that cystic fibrosis is a genetic disorder, and it affects the lungs and bowels of the patients.

So, Why Do I Care??  Over 30,000 people in the USA has cystic fibrosis, and 1000 new cases are diagnosed each year.  The mean life expectancy is age 44 for cystic fibrosis patients.  Only symptomatic treatments have been available until now, because gene therapy has been unsuccessful. Any treatment that reverses the root cause of this disorder is a revolutionary achievement that will literally breathe new life into patients.

Plain English, Please!!! First let’s talk about cystic fibrosis. This disorder causes blockages of the thin ducts – the bronchi and bronchioles of the respiratory system, and the pancreatic duct and the bile ducts of the digestive system. The most imminent threat comes from impairment of air flow to the air sacks. In normal lungs a layer of mucus traps pollutants and microorganisms, and that mucus is swept towards the throat by the microscopic whips called cilia. For cilia to work best, the mucus needs to be a thin, watery liquid that flows easily. In cystic fibrosis the mucus is thick, very viscous like honey, and the cilia cannot move the mucus out of the bronchioles. The accumulating mucus blocks airflow, and prevents the removal of microbes. Breathing problems and persistent lung infections are the result.

Second, let’s talk about the cause of this disease. The thin mucus in normal lungs is created by water flowing from the cells of bronchioles into the mucus. The flow of water from the cells is following the flow of chloride ions from the cells. The chloride ions move through ion channels, which are straw-shaped proteins in the cell membrane. In cystic fibrosis inherited mutations change the shape of the chloride channel into a crumpled straw; the crumpled straw doesn’t allow chloride ions to move through, just like you couldn’t drink through a crumpled straw. Without chloride flow not enough water flows from the cells, so the mucus becomes thick, like honey.

Third, let’s talk about how this new treatment acts.  In cystic fibrosis the cells of bronchioles retain the mutated, crumpled chloride channels in the rough endoplasmic reticulum, and don’t allow them to move to the cell membrane. Trikafta enters the endoplasmic reticulum, and the three drug components tug, pull, and push the crumpled straw, the mutated chloride channels, until they become straight again. Then the channel proteins are allowed to move into the cell membrane, the chloride flow is restored, the mucus becomes watery, and the cilia can resume their cleaning function.