In kidney diseases caused by abnormal complement system activation, the overactivation​ and amplification of chain reactions​ in the alternative complement pathway are the core causes of renal damage. This leads to the accumulation of a protein fragment called C3 in the glomerulus, activating the final damage pathway of the complement system and progressively destroying kidney function. Complement Factor B (abbreviated as CFB) is a key "driver" in this "pathogenic chain" and an indispensable core molecule in the alternative complement pathway. Its main role is to assist in assembling two key "tools" (C3 convertase and C5 convertase), maintaining the "positive feedback loop" of this abnormal reaction and sustaining the damage [1].

 

Existing studies have confirmed that dysregulation of the alternative complement pathway induced by abnormal CFB activation is closely related to various kidney diseases, such as C3 Glomerulopathy and IgA Nephropathy [1,2]. Moreover, therapeutic research targeting CFB has achieved initial breakthroughs: basic pathological mechanisms have been validated, and it is entering the stage of candidate drug development. Multiple clinical studies have shown that drugs capable of inhibiting CFB activity can effectively block the abnormal activation of the alternative complement pathway, holding great promise for translation into clinical treatments to help kidney disease patients [2].

 

However, a key challenge has been encountered in the early development of these candidate drugs (especially nucleic acid-based drugs): the lack of unified, reproducible animal models​ that directly match the human CFB gene sequence. This issue seriously affects the efficient screening of candidate drugs, the determination of dosages, and the establishment of precise relationships between drug dosage and therapeutic effects, slowing down the pace of drug development.

 

Simply put, CFB is a protein primarily produced and released into the blood by the liver, and it is also a "latent enzyme" unique to the alternative complement pathway. Under normal physiological conditions, CFB binds to C3b (a cleavage fragment of the C3 protein), then is cleaved by another complement factor, Complement Factor D (CFD), to form an active Bb fragment. Bb then combines with C3b to assemble into a functional C3 convertase (C3bBb). This convertase continuously drives the "chain amplification" of the alternative complement pathway, maintaining normal immune defense functions [1].

 

The core principle of targeted therapy against CFB is to reduce the "raw material" of C3 convertase in the blood (i.e., CFB), inhibit the excessive amplification of the alternative complement pathway, thereby reducing the cleavage of C3 and C5 proteins and alleviating systemic damage to the kidneys. To accurately test the efficacy of such therapies in animals and determine appropriate dosages, an animal model is needed that can fully demonstrate the complete process of "reduced hepatic CFB expression → decreased CFB protein in blood → reduced alternative complement pathway activity → improved kidney damage."

 

This highlights the importance of humanized CFB gene-modified animal models. Since the current candidate drugs are designed based on the human CFB gene sequence, there are differences in CFB gene sequences among different species (e.g., mice, monkeys). Existing research has found that nucleic acid-based drugs like Antisense Oligonucleotides (ASO) and GalNAc-conjugated small interfering RNA (siRNA) have very strict requirements for target gene sequences: they must be designed for the CFB gene sequence of a specific animal to effectively reduce CFB expression in the animal's liver, lower CFB levels in the blood, and subsequently inhibit the abnormal activation of the alternative complement pathway and alleviate kidney damage [3,4]. If wild-type mice are used to test candidate drugs targeting human CFB, the gene sequence mismatch will make it impossible to accurately assess the drug's efficacy and mechanism of action.

 

Based on this need, the core design concept of the CFB humanized animal model we plan to construct is to replace the mouse's own CFB gene with the complete human CFB gene, while maximally preserving the mouse's normal CFB expression pattern and tissue distribution characteristics dominated by the liver.

 

The applications of this model are extensive: it can be used to test the efficacy of candidate drugs targeting human CFB, validate drug mechanisms, and clearly analyze the correlation between "dosage → CFB inhibition effect → complement activity changes → improved kidney damage." It provides a unified, stable, and reproducible animal testing platform​ for candidate drug screening and dosage optimization, helping accelerate the clinical translation of targeted CFB kidney disease therapies [5].

 

The applications of this model are extensive: it can be used to test the efficacy of candidate drugs targeting human CFB, validate drug mechanisms, and clearly analyze the correlation between "dosage → CFB inhibition effect → complement activity changes → improved kidney damage." It provides a unified, stable, and reproducible animal testing platform​ for candidate drug screening and dosage optimization, helping accelerate the clinical translation of targeted CFB kidney disease therapies [5].
 

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