What is Cystic Fibrosis?
 

Introduction to CFTR and Disease Association​
 

Cystic fibrosis (CF) is a rare autosomal recessive disorder caused by mutations in the CFTR gene located on chromosome 7 (7q31.1). The CFTR protein functions as a chloride channel critical for maintaining fluid balance across epithelial surfaces. Defects in CFTR lead to abnormal ion transport, resulting in thickened mucus in multiple organs. Pulmonary manifestations—such as chronic airway obstruction and recurrent infections—are the most life-threatening features of CF and directly stem from CFTR dysfunction.
 

According to statistics, the global incidence of CF is approximately 1 in 3,500 to 1 in 5,000 live births. In China, the incidence is about 1 in 64,000, with only about 200 CF cases reported to date.
 

Pathogenesis

 

(Image: PubMed)
 

CF is an autosomal recessive disorder, with its core etiology being mutations in the CFTR gene. Located at 7q31.1, the CFTR gene spans approximately 250 kb, contains 27 exons, and encodes a chloride channel protein responsible for regulating chloride ion and water transport across epithelial cell surfaces. Over 2,000 CFTR gene mutations have been identified, including missense (39%), frameshift (16%), splicing (11%), nonsense (8%), and large deletions or insertions (2%).

 

(Image: PubMed)
 

Based on the mechanism of their effect on CFTR function, CFTR mutations are classified into six categories. Among these:
 

Class II Mutations: Class II missense mutations (e.g., F508del, I507del, N1303K, S541I, S549R) are the most common in CF patients. F508del is the most prevalent mutation; it causes protein misfolding, leading to its degradation in the endoplasmic reticulum and failure to reach the cell surface, severely impairing CFTR function.
 

Class III Mutations: Class III missense mutations (e.g., G551D, G1224E, S1255P) disrupt the gating function of the CFTR channel, preventing it from opening properly.
 

Class IV Mutations: Mutations like R117H, R334W, and R347P reduce chloride ion conductance through the open CFTR channel, decreasing its permeability to chloride and bicarbonate.
 

Gene Therapy
 

1.CFTR Modulators: Therapies like the triple-combination Trikafta (elexacaftor/tezacaftor/ivacaftor) work by correcting the functional defect in the CFTR protein caused by mutations like F508del, covering approximately 90% of patients.
 

2.Gene Editing: In 2024, a team from the University of Texas published a study in the journal Science demonstrating successful editing of CFTR mutations (e.g., R553X) in lung stem cells via lung-targeted lipid nanoparticles (LNPs). The correction lasted for 22 months (equivalent to a mouse's lifespan). A single intravenous injection enabled long-term gene repair, particularly suitable for patients with rare mutations unresponsive to current drugs.
 

3.mRNA Therapy: The mRNA therapy VX-522, co-developed by Vertex Pharmaceuticals and Moderna, delivers CFTR mRNA via lipid nanoparticles (LNPs) to express functional CFTR protein in target airway cells. It is currently in Phase 1/2 clinical trials.
 

4.Antisense Oligonucleotide (ASO) Therapy: Approaches like SPL84 aim to correct specific splicing mutations in CFTR mRNA or inhibit the overactivity of the epithelial sodium channel (ENaC).
 

5.Gene Replacement Therapy: Strategies like AAV vector delivery of a normal CFTR gene copy are applicable for patients with rare mutations resulting in complete absence of CFTR protein.
 

Mouse Models
 

CFTR Knockout Mice: Generated by knocking out the mouse Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, successfully modeling the human genetic disease Cystic Fibrosis (CF). Key phenotypes include abnormal secretion in respiratory and intestinal mucosal epithelia, mucosal thickening, and viscous mucus, making this a necessary animal model for pathological research and drug development related to pulmonary fibrosis and severe COVID-19 in CF patients.
 

CFTRtm1UNC Mice: Exon 10 replacement (S489X mutation). Severe intestinal complications (obstruction, mucus plugging), mild pancreatic lesions, gallbladder dilation/rupture, increased susceptibility to lung infection.
 

CFTRtm1BAY Mice: Insertion duplication in exon 3. Defective intestinal mucus secretion, growth retardation, crypt dilation.
 

CFTRtm1EUR Mice: ΔF508 (Class II mutation). Non-lethal intestinal abnormalities, nasal epithelial sodium hyperabsorption, absence of pancreatic lesions.
 

CFTRtm1G551D Mice: G551D (Class III mutation). Mild intestinal obstruction, gallbladder abnormalities, no spontaneous lung disease.
 

G542X Mice: Carry a Class I nonsense mutation (G542X), resulting in complete absence of CFTR protein.
 

CFTRtm2HGU Mice: G480C (Class II mutation). Mild abnormal intestinal mucus secretion, nasal epithelial electrophysiological defects.
 

β-ENaC Mice: Overexpress the ENaC β subunit, leading to sodium hyperabsorption and mucus dehydration, modeling CF-like pulmonary mucus obstruction and inflammation.

 

In the future, the development of CFTR mouse models—and thus rare disease research—will be revolutionized by new genetic technologies, with tetraploid technology being the most impactful for efficiency and reliability. Traditional ES cell targeting avoids off-target risks but takes 6 to 12 months to prepare a single model—far too slow for urgent rare disease research. Fortunately, tetraploid technology solves this dilemma: it is both fast and reliable, bypassing long breeding cycles to turn genetically edited stem cells into complete mice in as little as 35 days, boosting efficiency from 1%-5% to 30%-60%. Notably, Guangzhou Mingceler Biotech is the only company in the world using this tetraploid technology to accelerate CFTR gene mouse model production. This unique advantage allows for the rapid creation of high-quality, custom CFTR mouse models at lower cost, perfectly addressing the pain points of slow, unreliable traditional methods. For rare disease research—where speed and accuracy are critical—this means faster progress, more efficient therapy testing, and quicker breakthroughs for patients. Combining these high-quality, rapidly prepared models with other technologies will further speed up our understanding of rare diseases and the development of targeted treatments.