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Chinese Journal of Contemporary Pediatrics logoLink to Chinese Journal of Contemporary Pediatrics
. 2023 Jul 15;25(7):759–766. [Article in Chinese] doi: 10.7499/j.issn.1008-8830.2302048

儿童罕见病药物治疗新进展

Research advances in pharmacotherapy for rare diseases in children

李 佳琦 1,b, 王 慧君 1
Editor: 王 颖
Reviewed by: 周 文浩1
PMCID: PMC10414178  PMID: 37529960

Abstract

罕见病有7 000余种,全球罕见病患者总数约4.75亿,其中儿童占2/3。因每种罕见病的患病人群基数小,制药企业研发资金有限,仍有几千种罕见病还没有获得批准的治疗药物。目前,95%的罕见病患者尚无药可治,因此能够治疗罕见病的药物被称为孤儿药。为引导制药公司加大孤儿药开发力度,多国制定了罕见病药物法案,推进简化孤儿药专利申请程序,积极为孤儿药研发提供科学建议和指导。儿童是罕见病的高发群体,该文将围绕儿童罕见病药物治疗新进展进行综述。

Keywords: 罕见病, 孤儿药生产, 酶替代疗法, 小分子药物, 基因治疗, 儿童


1983年,美国《孤儿药物法》首次提出罕见病的概念1。中国将罕见病定义为新生儿发病率小于1∶10 000或患病率小于1∶10 000,或总的患病人数小于14万的疾病2。截至2022年,美国食品和药物管理局(Food and Drug Administration,FDA)推动的“孤儿产品临床试验资助计划”已使80多种孤儿药获得FDA批准3。目前,我国孤儿药的本土化生产也日益受到重视4。与成人相比,儿童罕见病更常见,且危害更大,常危及生命。本文围绕儿童罕见病药物治疗新进展进行综述,为我国儿童罕见病研究与治疗提供参考。我们将按酶替代疗法(enzyme replacement therapy,ERT)和重组因子、小分子药物、单克隆抗体、基因疗法、超适应证药物等5类罕见病药进行逐一综述。

1. ERT和重组因子

ERT是一种通过重组DNA技术合成重组酶,将其递送至体内替代缺失或功能不全的酶的方法5,常用于治疗溶酶体贮积症(lysosomal storage diseases,LSDs)。

溶酶体是一种负责降解细胞内各种内外源性物质的细胞器,编码各种溶酶体酶的基因的缺陷会引起LSDs。LSDs是50余种溶酶体代谢病的统称,总患病率为1∶7 7006。LSDs主要为常染色体隐性(autosomal recessive,AR)遗传模式致病,以黏多糖贮积症(mucopolysaccharidoses,MPS)较常见,MPS包括MPS Ⅰ、MPS Ⅱ、MPS ⅢA等11型7。MPS主要呈AR遗传,而MPS Ⅱ和Fabry病为X连锁隐性遗传,Danon病为X连锁显性遗传。

LSDs中,溶酶体酶的缺失主要导致糖胺聚糖的堆积,对骨骼、结缔组织、神经系统等器官系统造成损害。MPS Ⅰ由编码α-L-艾杜糖醛酸酶的IDUA基因突变引起8;MPSⅡ由编码艾杜糖醛酸-2-硫酸酯酶的IDS基因突变引起9;MPS ⅢA由SGSH基因突变使heparan-N-sulfamidase缺乏引起10;MPS ⅣA由GALNS基因突变导致N-乙酰半乳糖胺-6-硫酸酯酶缺乏引起11;MPS Ⅶ由编码β-葡糖苷酸酶的GUSB基因突变引起12;Fabry病由GLA基因突变引起13;尼曼-皮克病由编码酸性鞘磷脂酶的SMPD1基因突变引起14;戈谢病由GBA1基因突变引起,使得β-葡糖脑苷脂酶的活性降低15。ERT可有效增加上述疾病酶浓度(表1),早期获得诊断并及时干预可有效延缓此类患儿的疾病进程。

表1.

酶替代疗法治疗溶酶体贮积症总结

疾病 致病基因 药物 发表年份
MPS Ⅰ IDUA 拉罗尼酶 (Laronidase) [8] 2019
MPS Ⅱ IDS Pabinafusp alfa [16] 2021
Intrathecal idursulfase [9] 2022
阿糖苷酶α (Alglucosidase alfa) [17] 2021
MPS ⅢA SGSH Recombinant human heparan-N-sulfatase [10] 2021
MPS ⅣA GALNS Elosulfase alfa [11] 2022
MPS Ⅶ GUSB UX003 (Vestronidase alfa) [12] 2019
戈谢病 GBA1 Velaglucerase alfa [15] 2021
Fabry病 GLA JR-051 [13] 2020
Agalsidase beta [5] 2020
尼曼-皮克病 SMPD1 Olipudase alfa [14] 2021

Pabinafusp alfa可穿过血脑屏障,治疗MPS Ⅱ16。但是,大多数ERT药物仍难以穿过血脑屏障,且存在静脉注射产生抗药物抗体的风险7

2. 小分子药物治疗

小分子药物的优势是能够到达包括中枢神经系统在内的所有组织,并且成本低、可口服,易于制作18,占上市罕见病药物的80%~90%19

2.1. 囊性纤维化

囊性纤维化(cystic fibrosis,CF,MIM:219700)是一种AR遗传的进行性多系统疾病,患病率为1∶6 000~1∶3 000,新生儿期即可起病20。CF因囊性纤维化跨膜传导调节因子(cystic fibrosis transmembrane conductance regulator,CFTR)的门控突变导致CFTR蛋白异常,引起细胞膜对氯化物的运输障碍21,最常见的门控突变体是G551D22

第一个被用于治疗CF的是CFTR增效剂Ivacaftor,该药主要通过增加G551D-CFTR氯离子通道开放以增强CFTR蛋白功能23。2022年,Liu等24研发出一种新型CFTR增效剂CP-628006,这种小分子药有更高的单个G551D-CFTR激活效率和更持久的F508del-CFTR激活效应,与Ivacaftor联合使用疗效更强。

2.2. Hutchinson-Gilford早老症

Hutchinson-Gilford早老症(Hutchinson-Gilford progeria syndrome,HGPS,MIM:176670)呈常染色体显性(autosomal dominant,AD)遗传,患病率为1∶4 000 000,致病基因是LMNA基因25。HGPS患者多于1岁前发病,面容酷似老人,寿命一般不超过14岁25LMNA基因编码核纤层蛋白A、C,纤层蛋白A可与早老蛋白结合。基因突变产生的早老蛋白一方面在核膜被法尼基化和甲基化产生堆积26,另一方面使微管与细胞核过度耦联阻止肌动蛋白移动27,这些改变共同造成细胞核结构和功能的损害。

2020年11月,法尼基转移酶抑制剂洛那法尼(ZokinvyTM)获得FDA治疗HGPS的批准28,通过阻止早老蛋白法尼基化发挥作用29。化合物UCM-13207使早老蛋白从核膜分离以降低其浓度,并有效减少细胞DNA损伤以恢复细胞功能30。结合抑制剂JH4通过阻止早老蛋白-纤层蛋白A结合以改善核变性31。Remodelin是N-乙酰转移酶-10的新型强效选择性抑制剂,通过抑制N-乙酰转移酶-10介导微管重组而补救细胞核形状的破坏32,可延长HGPS患儿的寿命33

3. 单克隆抗体治疗

治疗性单克隆抗体(monoclonal antibody,mAb)是一种由B淋巴细胞产生的能高度特异识别抗原的抗体类药物,包括抗体片段、Fc融合蛋白及抗体-药物耦合物,通过递送细胞毒素、募集细胞和蛋白质及调节信号通路等发挥作用34

自身免疫性多内分泌腺病综合征I型伴或不伴可逆性干骺端发育不良(autoimmune polyendocrine syndrome, type I, with or without reversible metaphyseal dysplasia, APS1, MIM: 240300)呈AD或AR遗传,患病率为1∶1 000 000~9∶1 000 00035。APS1表现为慢性皮肤黏膜念珠菌病、甲状旁腺功能减退症和肾上腺皮质功能衰竭三联征,常常导致患儿的过早死亡36

APS1的致病基因为AIRE基因,表达于胸腺CD45-MHC-Ⅱ+细胞35AIRE基因突变导致自体反应性T细胞逃避免疫细胞的阴性选择,引起多系统自身免疫37。一项研究发现抗CD45RC mAb可抑制T细胞毒效应和恢复Treg细胞,有效延缓APS1进程,揭示了CD45RC mAb药物在APS1预防性治疗中的重要性38

4. 基因疗法

基因疗法以替换、转入或编辑疾病基因等方式操纵遗传物质39,成为近年来孤儿药的重点研究方向之一40。另外,二代测序在临床遗传诊断中广泛应用,CRISPR技术迅猛发展,也极大地推动了基因治疗在孤儿药研发领域中的应用。CRISPR是原核生物基因组内的一段重复序列,通过Cas酶特异性切割和修复目标DNA序列,实现目标基因敲除和碱基编辑,是一种更为经济、迅速且简单的基因编辑工具41

基因治疗按治疗途径的不同可分为体内治疗和体外治疗2种42。体内治疗指通过局部注射携带目的基因的病毒载体进行基因编辑,病毒载体多用非整合型病毒[如腺相关病毒(adeno-associated virus,AAV)]43。体外治疗利用自体细胞或同种异体细胞在体外转入目的基因并进行修饰,也称为细胞疗法44

4.1. 基因治疗

4.1.1. Leber先天性黑蒙

Leber先天性黑蒙(Leber congenital amaurosis,LCA)是基因治疗最早成功的案例37。LCA是严重的遗传性视网膜营养不良症,患病率为1∶81 000~1∶30 000,多于儿童早期发病45。LCA已知至少有28种基因突变参与致病,遗传病因占全部病例的75%46RPE65基因是LCA的重要致病基因,RPE65基因编码类视黄醇异构酶,负责维生素A在类视黄醇循环中的代谢45

Voretigene neparvovec是AAV2载体相关的基因治疗药物46,于2017年被FDA正式批准用于RPE65双等位基因突变引起的LCA47。AAV2载体可将有编码类视黄醇异构水解酶功能的RPE65基因导入LCA患者体内,该药物通常通过玻璃体切割术注入视网膜间隙47

4.1.2. 杜氏肌营养不良

杜氏肌营养不良(Duchenne muscular dystrophy,DMD,MIM:310200)是一种X连锁肌肉萎缩性疾病,在男性新生儿中的患病率为1∶5 00043。DMD通常于3岁前发病,出现进行性肌无力和肌疲劳,最终发展为呼吸衰竭和心肌病,常于20岁前死亡48。该病由DMD基因突变引起其编码的抗肌萎缩蛋白(dystrophin,Dys)缺乏44,Dys是抗肌萎缩蛋白结合蛋白复合物的关键成分,对维持肌纤维刚度至关重要49

Gange等47设计了一种微抗肌萎缩蛋白转基因(AAVrh74.MHCK7.micro-dystrophin),该药物以AAV作为载体进行基因转移,可有效恢复Dys的表达。另一项研究设计出一种经密码子优化的合成转基因,编码微型化的Dys相关蛋白utrophin(μUtro),μUtro具有与Dys相似的结构和功能50。该研究对Dys缺陷的新生mdx小鼠应用AAV-μUtro,发现DMD小鼠模型肌坏死、再生组织和生化标志物的异常在成年之前得到完全控制51

随着AAV基因治疗向人体临床试验的逐步推进,其在转导效率、组织趋向性及免疫原性等方面的要求也不断增加,这推动了更为安全、高效的AAV载体的研发。

4.2. 细胞治疗

Wiskott-Aldrich综合征(Wiskott-Aldrich syndrome,WAS,MIM:301000)是一种X连锁免疫缺陷病,由WAS基因失功能突变引起,患病率为1∶100 00052。WAS表现为免疫缺陷、血小板减少和湿疹三联征,常在10岁之前死亡52WAS基因编码WAS蛋白,对细胞信号转导和免疫突触形成至关重要53

WAS的一线治疗是同种异体造血干细胞移植53,但常由于供体不匹配使得患儿病死率增加54,移植物抗宿主病对此类疾病的治疗效果有着巨大影响55-56

一项研究首次开发了一种基于CRISPR/Cas9基因编辑平台的造血干细胞和祖细胞药物,在患者来源的造血干细胞和祖细胞中敲入治疗性WAS cDNA及其内源性翻译起始密码子,在60%的患者中得到满意效果54

4.3. 寡核苷酸治疗

寡核苷酸治疗通过设计特定寡核苷酸序列,以沃森-克里克碱基配对原则为基础,下调或修饰致病基因、阻断RNA翻译相关蛋白等发挥作用57

寡核苷酸治疗可分为2种药物,包括反义寡核苷酸(antisense oligonucleotide,ASO)和小干扰RNA。ASO又可分为核糖核酸酶H1(ribonuclease H1,RNase H1)依赖性ASO和gapmer58。ASO是一种人工合成的单链小分子核酸聚合物,可激活RNase H1裂解目标mRNA以改变mRNA的表达59。RNase H1是一种内源性核酸内切酶,结合同源性mRNA后在ASO结合位点切割靶mRNA调节基因表达58。小干扰RNA的作用机制是引导沉默复合物中的Argonaute 2蛋白结合目标转录物,引起基因沉默58

4.3.1. DMD

2016年9月,Eteplirsen(Exondys51)获得FDA的加速批准,是第一种获批治疗DMD的磷酸二酰胺吗啡寡聚物,其机制与51号外显子的跳跃有关60。Eteplirsen可操纵DMD的Dys转录本剪接并使阅读框得到恢复61。一项观察性研究证明了Eteplirsen对无法行走或在治疗过程中失去行走能力的患儿的潜在益处60

Golodirsen(SRP-4053)是一种新型磷酸二酰胺吗啡寡聚物,于2019年被FDA批准,与Dys的前体mRNA互补并恢复该mRNA的阅读框,与53号外显子的跳跃有关,其安全性、药代动力学和生物活性均得到了验证62

4.3.2. Batten病

Batten病也称神经元蜡样质脂褐质沉积症,是一组包含13种神经退行性疾病的遗传性疾病,是儿童痴呆症最常见的形式63

对于该疾病的特定基因突变,研究者为一位神经元蜡样质脂褐质沉积症7型儿童制定了为期一年的“N-of-1”个性化治疗方案64。研究团队设计出了一种ASO药物——Milasen,该药物靶向患儿6号外显子剪接到6号内含子的隐秘剪接位点及其附近剪接增强剂64。经过Milasen治疗,患儿癫痫发作频率和持续时间都下降至少50%。该药物的使用为孤儿药的个性化治疗提供了可参考依据,也为个性化基因组医学提供了范例。

5. “超适应证”使用治疗药物和老药新用

“老药新用”指发现了某已知药品的新性质或功能并用于新领域。再利用药物的安全性和质量在先前研究和长期使用中均已得到验证,其不良反应发生的风险相对较低,可更快开始临床试验,对于罕见病的治疗更加有利。

5.1. 普萘洛尔治疗Lafora肌阵挛性癫痫

Lafora肌阵挛性癫痫(Lafora disease,LD,MIM:254780)是一种致命的神经退行性疾病,患病率小于1∶1 000 00065,特征是患儿全身癫痫发作和快速进展为植物状态。LD由EPM2AEPM2B基因突变引起66

普萘洛尔最初用于高血压、特发性震颤和焦虑。证据表明,普萘洛尔抗血管生成、促凋亡和抗炎特性也可应用在不同的罕见病中67-68。一项动物实验研究表明,普萘洛尔作为炎症调节剂,可减少星形胶质细胞和小胶质细胞炎症化,对LD早期治疗有潜在效果66

5.2. 除草剂治疗尿黑酸尿症

尿黑酸尿症(alkaptonuria,AKU,MIM:203500)呈AR遗传,患病率为1∶250 00069,由编码尿黑酸1,2双加氧酶的HGD基因突变引起,婴儿期即可起病70。该病主要为酪氨酸代谢障碍引起,酪氨酸参与儿茶酚胺神经递质的生物合成,对神经的兴奋和抑制起重要作用71

尼替西农最初被作为除草剂开发,后来被发现可以用于抑制尿黑酸堆积并延缓AKU的疾病进展。一项研究报告了一组AKU患者在尼替西农治疗试验前后24 h的变化,发现用药后患者尿液中神经代谢物去甲肾上腺素减少,肾上腺素、3-甲氧酪胺增多,证明尼替西农可使AKU患者的神经递质代谢得到改善69

6. 小结

综上,在过去的十年中,生物制药行业在为罕见病群体提供新疗法方面取得了一定进展。但孤儿药的开发仍然受有限的罕见病人数限制,也受高昂的研发和治疗费用掣肘。为加快开发罕见病新疗法的进程,未来需要投入更多关注和出台更好的激励措施。

利益冲突声明

所有作者均声明不存在利益冲突。

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