Therapeutic approaches to CFTR dysfunction: From discovery to drug development

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
• CFTR mutations impair protein processing, stability, and chloride channel function.
• Current treatments focus on managing symptoms, but CFTR-targeting therapies are emerging.

Purpose of the Study:

• To review current and innovative therapeutic strategies for CF.
• To discuss approaches for overcoming defective CFTR processing and stability.
• To highlight the need for combination therapies and novel bypass strategies.

Main Methods:

• Literature review of CFTR protein function and therapeutic interventions.
• Analysis of strategies targeting CFTR processing, stability, and function.
• Exploration of proteostasis regulators and artificial anion transporters.

Main Results:

• CFTR mutations have pleiotropic effects on protein biogenesis and function.
• Combination therapy with multiple pharmacological chaperones may be necessary.
• Proteostasis regulators offer a route to enhance mutant CFTR plasma membrane expression.
• Artificial anion transporters present an innovative bypass strategy for CFTR dysfunction.

Conclusions:

• Restoring CFTR function requires addressing multiple defects caused by mutations.
• Combination therapies are likely essential for rescuing mutant CFTR expression.
• Targeting proteostasis and developing artificial transporters are promising therapeutic avenues.
• Developing therapies that rescue all CF mutations remains a critical priority.