刘小红主任谈DMD:多学科管理为治疗基石,3种基因疗法推进上市实为后盾!

2023-06-20 网络 网络 发表于上海

本期专访有幸邀请到来自西安交通大学第一附属医院儿科刘小红主任,让我们一起倾听他对杜氏肌营养不良症诊疗的感悟与思考。

导言

杜氏肌营养不良症(Duchenne Muscular Dystrophy,DMD)又名假肥大型进行性肌营养不良,是一种X连锁隐性遗传病。主要症状包括肌无力、步态异常、爬楼、跑、跳和起立困难、Gowers征以及双侧腓肠肌假性肥大。DMD不仅是进行性肌营养不良症的最严重类型之一,也是最常见的遗传性神经肌肉疾病,约占所有肌营养不良患者的三分之一。

患者多为男性,在存活男婴中发病率约为1/3500,我国每年约有400 ~ 500例DMD患儿出生,累计7万 ~ 9万人确诊,无明显的地域特征,遍布全国各地,是世界上该病患者人数最多的国家。

本期专访有幸邀请到来自西安交通大学第一附属医院儿科刘小红主任,让我们一起倾听他对杜氏肌营养不良症诊疗的感悟与思考。

1. 发病机制

DMD致病基因

DMD的致病基因为抗肌萎缩蛋白基因,位于X染色体短臂Xp21.2区域,是人类最大的基因之一,且结构复杂,致病突变类型多种多样,几乎囊括所有隐性遗传致病突变类型。

图片

该基因全长约2300 kb,cDNA长14 kb,含79个外显子,编码3685个氨基酸,组成427 kD的细胞骨架蛋白抗肌萎缩蛋白。其中,蛋白主要位于骨骼肌和心肌细胞膜的质膜面,具有细胞支架、抗牵拉、防止肌细胞膜在收缩活动时撕裂的功能,同时可以与肌纤维膜上的多种糖蛋白结合为抗肌萎缩蛋白相关蛋白复合体,这些复合体又能与基膜层粘连蛋白连接,以维持肌纤维的稳定性。

DMD患者因基因缺陷而使肌细胞内缺乏抗肌萎缩蛋白,造成肌细胞膜不稳定,进而导致肌细胞坏死和功能缺失而发病。最常见的缺失区为45 ~ 54和第2 ~ 22外显子,通过基因检测,可以为93.1%的患者找到遗传学病因。

2.早期诊断

如前文所述,抗肌萎缩蛋白基因是人类最大的基因之一,结构复杂且突变类型多种多样。因此,采用基因检测追述致病突变时需严谨,尽量避免漏检、错检,这对于DMD的诊断和分型判断至关重要。

抗肌萎缩蛋白基因的突变以外显子缺失/重复为主,基因内部外显子及侧翼区域的点突变次之。

针对外显子缺失/重复,首选多重连接探针扩增(MLPA),高分辨比较基因组微阵列杂交(aCHG)也是可选的方法;

针对基因内部外显子及侧翼区域点突变,常用的方法为Sanger测序。

值得注意的是,即使综合应用MLPA和基因测序,仍有约6.9%的患者找不到致病变异。

应考虑以下可能性:

  • 突变位于内含子深处或表达调控区,此时,可通过RT-PCR直接检测患者DMD基因的表达水平。

  • 患者的临床诊断不明确,需重新进行详细的临床评估,必要时进行肌肉活检。临床体征可见假性腓肠肌肥大、Gower征、步态异常等,同时借助血清酶学、神经肌肉电生理、肌肉活检等辅助检查等手段进行诊断。

3.GS在DMD中的应用现状

糖皮质激素(GS)对治疗DMD有一定积极作用。通常给予患者0.75 mg/kg/d泼尼松,用以改善患者力量和肺功能,减少脊柱手术风险和延缓心肌病的发生。

可能涉及的副作用包括肥胖、Cushing面容、多毛症、骨质疏松等,通常的处置措施是减量至1/3

4.DMD患者的多学科综合管理方案

鉴于DMD治疗效果是多种方法的累积效应,且对患者的多系统损害进行多学科的评估和相应的综合管理,可以延长DMD患者独立行走的时间和生存期,提高患者的生存质量。因此,需要儿科、神经内科、呼吸内科、心脏内科、骨科/脊柱外科、康复医学科医生共同为患儿保驾护航,同时,患者及护理者的知晓和配合也不可或缺,以期达到治疗效果的最大化。

比如,学龄前康复治疗可以行肌肉阻力训练,不宜进行离心性耐力训练,尽量维持日常活动,可做小运动量的游戏,行走困难时可用呼吸训练器锻炼肺功能,注重手指功能的训练;职能方面可进行运动量小的技艺训练,譬如绘画、雕刻等;运动训练可穿矫形鞋,行动困难时可使用站立床,康复训练注意避免关键挛缩或骨骼变形。

5.聚焦三大研究热点

针对DMD的基因疗法主要包括基于AAV的基因治疗、外显子跳跃、RNA干扰等。

腺相关病毒(Adeno-associated virus,AAVs)是基因治疗常用的人工改造的工具病毒载体之一,其作用是将功能基因直接运送到特定组织的细胞中。PF-06939926疗法SGT-001疗法都是将外源Micro抗肌萎缩蛋白基因传递到体内肌肉组织,从而一次性减缓或阻止DMD患者的肌肉退化。两种疗法均获得美国食品和药物管理局(FDA)和欧洲药品管理局(EMA)的孤儿药认定。

由于DMD是在抗肌萎缩蛋白基因的几个位置上缺失外显子,因而外显子跳跃可用于治疗DMD。外显子是基因表达的关键部分,编码表达蛋白的基因序列。外显子跳跃则是借助反义寡核苷酸,对基因缺失或外显子突变部分的修补。通过外显子跳跃,细胞会产生一种较短的但具有功能的蛋白,以缓解肌营养不良症表征。例如:Exondys 51(eteplirsen)可引发外显子51跳跃,是FDA批准的一种治疗方法。

RNA干扰(RNAi)是抑制或阻断信使RNA(mRNA)功能。该领域目前仍处于研发阶段,代表性药物是Benitec Biopharma的BB-301,利用RNAi阻止突变的PABPN1基因产生异常PABPN1蛋白。同时,它将一个健康的PABPN1基因拷贝导入细胞,完成基因替代,进而达到治疗目的。

图片

刘小红 主任医师

西安交通大学第一附属医院  儿科主任 

中国优生科学协会常务理事

中国优生科学协会妇儿临床分会副主任委员

中华医学会小儿罕见病学组委员

中国抗癫痫协会理事

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    2023-06-29 智慧药 来自上海

    学习了 谢谢

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    2023-06-23 458080332 来自安徽省

    学习#Nat#

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    2023-06-20 医鸣惊人 来自山西省

    认真学习了

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=2145446, encodeId=d17b214544657, content=学习了 谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210901/969603a2377544169c0528539edd5ab7/50bbe992202d43569f6cc40d89829e36.jpg, createdBy=b54c5537441, createdName=智慧药, createdTime=Thu Jun 29 13:18:16 CST 2023, time=2023-06-29, status=1, ipAttribution=上海), GetPortalCommentsPageByObjectIdResponse(id=2144409, encodeId=932921444094b, content=学习<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e4f34732534, createdName=458080332, createdTime=Fri Jun 23 21:55:44 CST 2023, time=2023-06-23, status=1, ipAttribution=安徽省), GetPortalCommentsPageByObjectIdResponse(id=2143936, encodeId=e7752143936ac, content=认真学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6EF3hKja8nER8RMzxQdria9eCYFhgLTLsDOeqnvIYdeLDz5eP6EnicLuE5gibiawgno4zUA0jAR7Nbtp2llQ9fs3Mk/0, createdBy=278f1986883, createdName=医鸣惊人, createdTime=Tue Jun 20 19:10:26 CST 2023, time=2023-06-20, status=1, ipAttribution=山西省), GetPortalCommentsPageByObjectIdResponse(id=2144024, encodeId=57622144024e9, content=学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=940a5479132, createdName=ms2000000702445417, createdTime=Wed Jun 21 06:44:36 CST 2023, time=2023-06-21, status=1, ipAttribution=湖南省), GetPortalCommentsPageByObjectIdResponse(id=2144022, encodeId=b9f0214402296, content=不错,学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=00332233446, createdName=1212ad1cm87暂无昵称, createdTime=Wed Jun 21 06:26:16 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省), GetPortalCommentsPageByObjectIdResponse(id=2144019, encodeId=fcfb214401967, content=不错学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Wed Jun 21 06:23:48 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省)]
    2023-06-21 ms2000000702445417 来自湖南省

    学习学习

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=2145446, encodeId=d17b214544657, content=学习了 谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210901/969603a2377544169c0528539edd5ab7/50bbe992202d43569f6cc40d89829e36.jpg, createdBy=b54c5537441, createdName=智慧药, createdTime=Thu Jun 29 13:18:16 CST 2023, time=2023-06-29, status=1, ipAttribution=上海), GetPortalCommentsPageByObjectIdResponse(id=2144409, encodeId=932921444094b, content=学习<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e4f34732534, createdName=458080332, createdTime=Fri Jun 23 21:55:44 CST 2023, time=2023-06-23, status=1, ipAttribution=安徽省), GetPortalCommentsPageByObjectIdResponse(id=2143936, encodeId=e7752143936ac, content=认真学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6EF3hKja8nER8RMzxQdria9eCYFhgLTLsDOeqnvIYdeLDz5eP6EnicLuE5gibiawgno4zUA0jAR7Nbtp2llQ9fs3Mk/0, createdBy=278f1986883, createdName=医鸣惊人, createdTime=Tue Jun 20 19:10:26 CST 2023, time=2023-06-20, status=1, ipAttribution=山西省), GetPortalCommentsPageByObjectIdResponse(id=2144024, encodeId=57622144024e9, content=学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=940a5479132, createdName=ms2000000702445417, createdTime=Wed Jun 21 06:44:36 CST 2023, time=2023-06-21, status=1, ipAttribution=湖南省), GetPortalCommentsPageByObjectIdResponse(id=2144022, encodeId=b9f0214402296, content=不错,学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=00332233446, createdName=1212ad1cm87暂无昵称, createdTime=Wed Jun 21 06:26:16 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省), GetPortalCommentsPageByObjectIdResponse(id=2144019, encodeId=fcfb214401967, content=不错学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Wed Jun 21 06:23:48 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省)]
    2023-06-21 1212ad1cm87暂无昵称 来自吉林省

    不错,学习了。

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=2145446, encodeId=d17b214544657, content=学习了 谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210901/969603a2377544169c0528539edd5ab7/50bbe992202d43569f6cc40d89829e36.jpg, createdBy=b54c5537441, createdName=智慧药, createdTime=Thu Jun 29 13:18:16 CST 2023, time=2023-06-29, status=1, ipAttribution=上海), GetPortalCommentsPageByObjectIdResponse(id=2144409, encodeId=932921444094b, content=学习<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e4f34732534, createdName=458080332, createdTime=Fri Jun 23 21:55:44 CST 2023, time=2023-06-23, status=1, ipAttribution=安徽省), GetPortalCommentsPageByObjectIdResponse(id=2143936, encodeId=e7752143936ac, content=认真学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6EF3hKja8nER8RMzxQdria9eCYFhgLTLsDOeqnvIYdeLDz5eP6EnicLuE5gibiawgno4zUA0jAR7Nbtp2llQ9fs3Mk/0, createdBy=278f1986883, createdName=医鸣惊人, createdTime=Tue Jun 20 19:10:26 CST 2023, time=2023-06-20, status=1, ipAttribution=山西省), GetPortalCommentsPageByObjectIdResponse(id=2144024, encodeId=57622144024e9, content=学习学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=940a5479132, createdName=ms2000000702445417, createdTime=Wed Jun 21 06:44:36 CST 2023, time=2023-06-21, status=1, ipAttribution=湖南省), GetPortalCommentsPageByObjectIdResponse(id=2144022, encodeId=b9f0214402296, content=不错,学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=00332233446, createdName=1212ad1cm87暂无昵称, createdTime=Wed Jun 21 06:26:16 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省), GetPortalCommentsPageByObjectIdResponse(id=2144019, encodeId=fcfb214401967, content=不错学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Wed Jun 21 06:23:48 CST 2023, time=2023-06-21, status=1, ipAttribution=吉林省)]
    2023-06-21 仁术2021 来自吉林省

    不错学习了。

    0