What is Cystic Fibrosis?
 

Cystic Fibrosis (CF) is a rare inherited genetic disorder primarily caused by defects in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene located on the long arm of chromosome 7. This gene defect leads to dysfunction in exocrine glands, affecting organs like the airways, pancreas, gastrointestinal tract, and sweat glands.

A defective CFTR gene impairs the ability of epithelial cells in glands to secrete chloride ions normally, while simultaneously increasing the abnormal reabsorption of sodium ions and water. This reduces the water content in secretions, making them thick and difficult to clear. The thick secretions easily accumulate in the airways, creating a breeding ground for bacteria, thereby increasing the risk of infections and inflammation. Patients frequently suffer from recurrent respiratory infections, and the progression of lung disease is usually the primary cause of mortality. 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.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various CF mouse models according to client needs, such as CFTR knockout mice, CFTRtm1UNC mice, CFTRtm1BAY mice, CFTRtm1EUR mice, CFTRtm1G551D mice, G542X mice, CFTRtm2HGU mice, and β-ENaC mice. We welcome inquiries!
 

References:

[1] Lomunova MA, Gershovich PM. Gene Therapy for Cystic Fibrosis: Recent Advances and Future Prospects. Acta Naturae. 2023 Apr-Jun;15(2):20-31. doi: 10.32607/actanaturae.11708. PMID: 37538805; PMCID: PMC10395777.

[2] Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences. Biomed Res Int. 2016;2016:5258727. doi: 10.1155/2016/5258727. Epub 2016 Jun 1. PMID: 27340661; PMCID: PMC4908263.

[3] Yehui Sun et al. In vivo editing of lung stem cells for durable gene correction in mice. Science 384, 1196-1202 (2024). DOI: 10.1126/science.adk9428

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