Saying Goodbye to the Sigh of "65 Roses": Cystic Fibrosis Treatment Enters a New Era of Personalization

Saying Goodbye to the Sigh of "65 Roses": Cystic Fibrosis Treatment Enters a New Era of Personalization

For many patients with cystic fibrosis (CF), the phrase "65 roses" is not unfamiliar. Due to the difficulty in pronouncing "Cystic Fibrosis," young patients use this similar-sounding phrase to refer to their disease. This is both innocent and tinged with helplessness. CF was once considered a fatal genetic disease, but now, with the rapid development of medicine, especially the emergence of revolutionary CFTR modulators, the future of patients is brighter than ever before. A recent review published in Molecular and Cellular Pediatrics systematically describes this exciting transformation.

Research Background: What is Cystic Fibrosis?

Cystic fibrosis is an autosomal recessive genetic disease that affects exocrine glands throughout the body. Its root cause lies in a mutation in a gene called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). The CFTR protein encoded by this gene acts like a "gatekeeper" on the cell surface, responsible for controlling the movement of chloride and bicarbonate ions in and out of cells. When this "gatekeeper" malfunctions, it leads to abnormally thick and dehydrated mucus in multiple organs of the body (especially the lungs and digestive system), thereby causing a series of serious problems.

In the lungs, thick sputum is difficult to clear, becoming a breeding ground for bacteria, leading to recurrent respiratory infections, inflammation, and progressive lung function damage. In the digestive system, mucus blocks pancreatic ducts, preventing digestive enzymes from reaching the intestines, affecting nutrient absorption, and leading to malnutrition and growth retardation in patients. For decades, although symptomatic treatments have continuously improved, extending patients' life expectancy from childhood to adulthood, they have never been able to fundamentally solve the problem. The lives of CF patients are often accompanied by endless treatments and deteriorating physical functions.

Key Findings: Precision Targeting, "Triple Therapy" Changes the Game

All of this changed with the advent of CFTR modulators. These drugs do not simply alleviate symptoms but directly target the malfunctioning CFTR protein itself, correcting the defect at its source. They are mainly divided into two categories:

1. Correctors: Like "production line supervisors," they help CFTR proteins that are misfolded due to mutations to restore their correct shape and successfully "transport" them to the cell surface.
2. Potentiators: Like "door lubricants," they help the CFTR protein "doors" that have already reached the cell surface to open more easily, enhancing their ion channel function.

In recent years, a "triple therapy" drug combination called Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) has achieved great success. It combines two correctors and one potentiator, capable of efficiently repairing the most common F508del mutation (accounting for approximately 60-70% of CF-causing genes worldwide) and other CFTR protein defects caused by various mutations.

Studies have shown that patients receiving triple therapy have experienced significant and sustained clinical improvements:

• Cessation of Lung Function Decline: This is one of the most groundbreaking findings. Previously, patients' lung function would irreversibly decline with age, but triple therapy has been proven for the first time to effectively curb this trend.
• Significantly Extended Life Expectancy: Model-based predictions show that CF patients receiving triple therapy and optimal supportive care can have a median life expectancy of up to 72 years, which was unimaginable in the past.
• Physiological Indicators Tend Towards Normal: One of the gold standards for diagnosing CF is the sweat chloride concentration (SCC) test; patients' sweat is usually very "salty." After treatment, many patients' SCC significantly decreased, even returning to normal or near-normal levels.
• Improved Quality of Life: Patients gained weight, respiratory symptoms were alleviated, and overall health improved.

Method Introduction: From Genes to Clinical Practice, Achieving Individualized Treatment

This article emphasizes the central role of personalized medicine in CF treatment. Since there are thousands of different pathogenic mutations in the CFTR gene, not all patients respond to the same drug. Therefore, "diagnosis before treatment" is crucial.

Doctors use various CFTR biomarkers to assess patients' underlying defects and drug responses, such as:

• Sweat Test: In addition to the traditional sweat chloride concentration test, there is a more refined β-adrenergic sweat secretion rate test, which can more linearly reflect CFTR function.
• Nasal Potential Difference (NPD) Measurement: By measuring the ion transport in nasal epithelial cells, CFTR function in the respiratory tract is directly assessed.
• Organoid Culture: This is a cutting-edge technology. Researchers can obtain rectal biopsy samples from patients and culture miniature "intestinal organoids" in vitro. By testing the effects of different drugs on these organoids, the patient's treatment response in the real world can be predicted, truly achieving "Theratyping."

It is based on these methods that doctors can precisely select effective CFTR modulators for patients with different gene mutations (even those with non-most common F508del mutations), allowing more patients to benefit from treatment.

Limitations: Not a "Miracle Drug" for Everyone

Despite the great success of triple therapy, we still need to be soberly aware of its limitations:

1. Not Universally Applicable: For patients carrying two "minimal function mutations" (i.e., proteins that are almost completely non-produced or completely non-functional), existing CFTR modulators are ineffective. This group of patients accounts for approximately 10-15% of the total, and they urgently need new treatment strategies.
2. Individual Response Variability: Even among patients eligible for medication, there are significant differences in the degree of clinical improvement. Improvement in biomarkers (such as normalization of sweat chloride concentration) does not always perfectly predict individual clinical outcomes (such as the extent of lung function improvement). This indicates that, in addition to the CFTR gene itself, other genetic and environmental factors still play important roles in disease progression.
3. Unknown Long-Term Effects: As a relatively new therapy, its long-term safety and efficacy over decades still need to be observed.

Application Prospects: Towards a Future of Cure

CF treatment has entered a new era, but the pace of science has not stopped. The future direction is even more exciting:

• Next-Generation CFTR Modulators: Scientists are developing more potent, next-generation drugs that can cover more mutation types.
• Gene Therapy: For patients unresponsive to existing modulators, gene therapy holds great promise. Its goal is to directly deliver normal CFTR genes to the patient's cells, fundamentally correcting the genetic defect. The article mentions that the first human clinical trial using recombinant lentiviral vectors is underway, which is a key step towards a genetic cure. Other approaches such as mRNA therapy and gene editing technologies are also being actively explored.
• More Sensitive Biomarkers: As patients' conditions improve significantly, we need more sensitive detection indicators to monitor subtle disease activity, such as assessing long-term changes in airway microbiome, host defense, epithelial homeostasis, and multi-organ metabolism.

Summary

From a fatal pediatric disease to a controllable chronic condition with a life expectancy exceeding 70 years, the treatment journey of cystic fibrosis is a microcosm of modern medical development. CFTR modulators, represented by triple therapy, have ushered CF treatment into a precise and efficient era of personalization, greatly changing the fate of the vast majority of patients. Although challenges remain, such as how to help patients unresponsive to drugs and exploring more fundamental cures, we have reason to believe that in the near future, all CF patients will be able to escape the heavy sigh of "65 roses" and embrace a nearly normal, hopeful life.