Rewriting the rules for rare diseases

Illustration of a dna str和 into a timer

Rare diseases often take a back seat when it comes to public awareness 和 advocacy. But a team of researchers have made it their mission to find treatments. Their genetic discoveries are extending lives.

Duchenne muscular dystrophy was long considered untreatable. The most common 和 serious form of childhood muscle wasting, the disease arises from mutations in the dystrophin gene. 患有这种疾病的人通常在12岁之前就依赖轮椅,许多人活不过25岁左右. 


And while a cure is still a distant hope, 他们开发了一种新的治疗方法,使疾病的自然进展变得更好. 

Their research team has now delivered the three U.S. Food 和 Drug Administration approved treatments for the disease. 这些药物利用细胞机制诱骗细胞“跳过”基因中的致病错误, acting as genetic ‘whiteout’. 

The eureka moment


“通过欺骗细胞跳过遗传错误来治疗杜氏肌营养不良症的概念,是在我开发神经肌肉疾病的诊断筛查过程中产生的,” said Professor Wilton. 

“我发现,自然外显子跳跃和缺失蛋白质的恢复是在非常低的水平上零星发生的. 我们已经找到了一种方法,可以在一定程度上减缓肌肉萎缩.” 

Steve 和 Sue图片说明:苏·弗莱彻教授(左)和史蒂夫·威尔顿教授(右)奔驰宝马大学.

最初的想法是与弗莱彻教授和Sarepta Therapeutics合作研究,历时20年,开发出第一个DMD的治疗方法, approved in 2016. This heralded a new frontier in the treatment of DMD.  

Until that point, there hadn’t been any approved therapy that addressed the underlying genetic defect.

Clinical trials of the first drug, Exondys 51, 美国的研究人员发现,这种疗法通过延缓肌肉功能的丧失来减缓疾病的发展.

“通过试验,我们看到这些患有DMD的孩子在做他们通常不会做的事情. 通常需要坐轮椅的男孩在十几岁的时候仍然能够走路,” said Professor Wilton.  

Their respiratory function stabilized, 他们可以打开一罐饮料或把手机放在耳边——这些我们认为是理所当然的事情,但在DMD的后期阶段是不可能的.”
A second drug, Vyondys 53, received accelerated approval by the U.S. Food 和 Drug Administration in 2019. While this means ongoing evaluation of its benefits, both the treatments are now accessible to patients in the United States. 

A third treatment, Casimersen, 已获得美国食品和药物管理局(FDA)的加速批准,并已在美国上市. 该药物在营养不良蛋白表达过程中跳过45外显子,有可能治疗8%的杜氏病患者.

每种药物都是针对不同的肌营养不良蛋白基因突变量身定做的,现在的目标是尽可能多地治疗不同的患者. 据估计,大约80%的DMD患者对这种治疗有反应, if all the potential drugs can make it to the clinic. 

Changing life trajectories

“This could be any family’s disease,” explained Professor Fletcher. “这种疾病可能袭击任何有男孩的家庭,你不需要有DMD的家族史. The gene is unstable 和 easily mutated.”

埃尔斯沃斯一家就是那些因治疗而改变生活的家庭之一, 他的儿子比利曾在美国参与过最初的临床试验.

“At the age of 11, 在他的家乡匹兹堡,如果两边都没有人来扶他,比利就无法在一个灌木丛生的小斜坡上上下行走,” said Professor Wilton.

“Two years after starting the treatment, 比利不仅能在应该坐在轮椅上的时候独立地走在同一条路上, his breathing stabilised 和 he could whistle as he walked up hill.”

Steve Sue 和 BillyImage caption: Professor Steve Wilton, 比利·埃尔斯沃斯和苏·弗莱彻教授在来自美国的比利访问期间奔驰宝马的校园里散步.

丧失行走能力是这种疾病发展过程中的一个重要里程碑, so keeping boys on their feet is crucial.

“If we can keep these young men walking, this reduces contractures 和 other complications of the disease; improves their breathing; 和 maintains their independence 和 health 和 wellbeing,” said Professor Fletcher. 


Today, Billy is still able to walk 和 is attending college in the United States. He turns 20 in January, 2021. 

Steve Sue 和 BillyImage caption: Professor Sue Fletcher, Professor Steve Wilton, Billy Ellsworth 和 Terri Ellsworth.

Redefining what’s possible with rare diseases

罕见病领域的进展历来集中在基因发现和鉴定上. Diagnosis has typically been delayed because of how complex they are. 

Once the genetic basis of a disease has been defined, 对致病途径的探索可以开始,潜在的治疗可以计划.

这是分子医学和创新疗法中心的弗莱彻教授和威尔顿教授等团队关注的焦点, which is dedicated to advancing the treatment of these rare diseases.

这一重点的最大优势之一是他们开发的治疗平台, such as that for DMD, could be applicable to many rare diseases.

威尔顿教授说:“这真的只是这种类型治疗的开端。. “Depending on the type of mutation 和 the gene, 理论上,我们可以治疗,在某些情况下,我们可以纠正各种以前被认为无法治疗的疾病.

“这种精准医疗有潜力在规模上改变医疗保健,就像抗生素改变对抗传染病的斗争一样. Indeed, 我们正在与莫纳什大学的同事合作,重新设计我们的药物,以应对COVID-19感染。”.

有7000多种遗传疾病,这种疗法可以应用于其中的许多疾病, depending on the type of mutation. 

The team continues to work on treatments for spinal muscular atrophy, Marfan syndrome, Stargardt’s disease, epidermolysis bullosa, inherited blindness, cystic fibrosis, Pompe disease, Huntington’s disease 和 other types of muscular dystrophy.


“And we believe we are doing that.” 

This research supports the United Nations Sustainable Development Goal 310.

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Posted on:

28 Apr 2021


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