PKC activators improve the function of biogenesis-deficient CFTR channels

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CFTR gene.
• The common F508del mutation leads to misfolded CFTR protein degradation, necessitating new therapeutic approaches.
• Current CFTR modulators require adjunctive therapies for comprehensive treatment.

Purpose of the Study:

• To investigate novel therapeutic agents that enhance F508del-CFTR function.
• To explore the synergistic effects of protein kinase C (PKC) activators with existing CFTR correctors.
• To evaluate the anti-inflammatory and broad-spectrum efficacy of PKC activators in CF models.

Main Methods:

• Utilized PKC activators ingenol-3,20-dibenzoate (IDB) and 12-Deoxyphorbol 13-phenylacetate 20-acetate (DOPPA).
• Assessed F508del-CFTR channel function in immortalized human airway epithelial cells and Cftr^{F508del/F508del} mouse lungs.
• Investigated the impact of PKC activators on pulmonary inflammation and CFTR mutations refractory to current therapies.
• Examined the role of PKCε-mediated phosphorylation in CFTR biogenesis.

Main Results:

• PKC activators IDB and DOPPA enhanced F508del-CFTR function as monotherapies and in combination with CFTR correctors.
• These agents largely restored CFTR channel function in cell and mouse lung models.
• PKC activators attenuated pulmonary inflammation in Cftr^{F508del/F508del} mice.
• Enhanced function of CFTR with rare missense mutations, previously unresponsive to therapies.
• PKCε-mediated phosphorylation stabilized CFTR transcripts, promoting channel synthesis.

Conclusions:

• PKC activators represent a novel therapeutic strategy for cystic fibrosis, distinct from current correctors.
• These compounds demonstrate potential for combinatorial therapy to achieve more complete CFTR functional rescue.
• PKCε signaling plays a critical role in CFTR biogenesis, offering new therapeutic targets.