法布雷病（FD）是由X染色体上的GLA基因发生突变引起的，这种突变导致溶酶体半乳糖苷酶A（α-GalA）的活性降低。α-GalA是三己糖酰基鞘脂醇（GL3）代谢过程中的关键酶，当α-GalA缺乏时，GL3会在全身细胞中逐渐积累，往往伴随着早发中风、心律失常、心肌梗死或心力衰竭以及肾功能衰竭的高风险^[1]。FD主要有两种临床表现形式：早发型（典型型）和衰减型（晚发型）。早发型FD的特征是α-GalA功能和活性几乎完全丧失，导致早期出现广泛的多器官并发症，包括肢端感觉异常、出汗异常、角膜轮状和血管角化瘤，以及心血管、脑血管和肾脏疾病，如心肌病、心律失常、中风和蛋白尿。而衰减型FD则由于α-GalA活性部分残留，疾病在晚期出现，且表现各异，主要取决于剩余的α-GalA活性水平^[1-2]。此外，由于致病基因位于X染色体上，FD在男性和女性患者之间存在显著的性别差异，男性患者的症状通常比女性更严重。 

法布雷病（FD）病理生理学机制：不同细胞中鞘糖脂的溶酶体积累是法布雷病（FD）器官损伤的原因^[2] 

法布雷病（FD）的主要治疗方法有两种：一种是每周静脉注射阿加糖酶α或阿加糖酶β的酶替代疗法（ERT），另一种是每日口服米加司他（Migalastat）分子伴侣疗法。然而，这些疗法对疾病进展的影响因素众多，且由于治疗费用高昂（约25万欧元/年），许多患者可能无法承受^[3]。因此，深入研究FD的机制并开发新型有效的疗法成为研究的重点。目前，包括Abeona Therapeutics、UniQure和Spark Therapeutics在内的10多家企业正在开发由腺相关病毒（AAV）载体介导的基因疗法^[4-5]。这类疗法通过AAV载体将GLA基因的健康拷贝送入体内，然后基因进行转录翻译，产生功能性α-Gal A酶。目前，至少有六项AAV-hGLA基因疗法已进入临床试验阶段，这为法布雷病（FD）的治疗带来了新的希望。 

法布雷病（FD）AAV基因疗法4D-310的治疗策略^[6] 

AAV基因疗法是法布雷病（FD）新疗法的重要研究方向。在这些疗法的开发过程中，首先需要对药物的药效和安全性进行动物体内评估。由于法布雷病（FD）主要由GLA基因突变导致α-Gal A酶的功能和活性缺失，Gla基因敲除小鼠（Gla-KO）因此成为这些疗法临床前评价的首选模型。目前，已有多个进入临床阶段的疗法，包括Freeline的FLT190（2期）^[7]、4DMT的4D-310（1/2期）^{[6, 8]}、UniQure的AMT-191（1/2期）^[9]和Sangamo的ST-920（1/2期）^[10-12]，都采用了Gla-KO小鼠进行药效评估。此外，CANbridge和Genzyme等企业也在开发非临床阶段的AAV疗法^[13-14]，并同样采用Gla-KO小鼠进行评估。因此，Gla-KO小鼠被广泛认为是法布雷病（FD）疾病模型的“金标准”，可用于研究疾病机制以及新疗法的临床前疗效评估。 

 Gla-KO小鼠（Fabry mouse）用于AAV基因疗法ST-920的临床前评估^[11] 

Gla-KO小鼠在多种细胞类型中会积累三己糖酰基鞘脂醇（GL3），这种现象随着年龄的增长而加剧。其体内的组织学变化，包括底物的积累性质和时间影响，与法布雷病患者的病理生理过程有着极高的相似性^[15]。因此，Gla-KO小鼠被广泛应用于评估酶替代疗法、AAV基因疗法和底物减少疗法的临床前疗效和安全性。赛业生物开发的Gla-KO小鼠（产品编号：S-KO-00955）同样被广泛用于机制研究和疗法评估。例如，利用肝脏特异性AAV疗法治疗Gla-KO小鼠（Orphanet J Rare Dis, 2023）的研究^[16]，并利用其评估新型ERT疗法效果以及药物代谢（Biomolecules, 2022）^[17]。此外，Gla-KO小鼠还助力溶酶体缺陷与先天性免疫之间的内在联系的揭示和溶酶体贮存病（LSD）新治疗策略的提出（Nature Cell Biology, 2024）^[18]。 

赛业生物Gla-KO小鼠（FD）助力AAV基因疗法的临床前研究^[16] 

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[15] Ohshima T, Murray GJ, Swaim WD, Longenecker G, Quirk JM, Cardarelli CO, Sugimoto Y, Pastan I, Gottesman MM, Brady RO, Kulkarni AB. alpha-Galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2540-4.

[16] Deng M, Zhou H, He S, Qiu H, Wang Y, Zhao AY, Mu Y, Li F, Zhao AZ. Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease. Orphanet J Rare Dis. 2023 Sep 5;18(1):275. 

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[18] Wang A, Chen C, Mei C, Liu S, Xiang C, Fang W, Zhang F, Xu Y, Chen S, Zhang Q, Bai X, Lin A, Neculai D, Xia B, Ye C, Zou J, Liang T, Feng XH, Li X, Shen C, Xu P. Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders. Nat Cell Biol. 2024 Feb;26(2):219-234.