This Mitochondrial Medicine special issue of the Journal of Inherited Metabolic Disease includes a mini‐symposium of articles based on platform presentations at the 4th International Conference on Mitochondrial Medicine hosted by The Wellcome Trust at Hinxton Hall on the Genome Campus in Cambridge, UK, from 11 to 13 December 2019. The guest editors of this issue include the three organizers of this exciting conference, which brought together critical academic, clinical and corporate stakeholders committed to the development of new treatments for rare mitochondrial disease, as well as patient and family advocacy groups. One hundred and twenty‐one delegates attended from 21 countries around the world, including physicians and laboratory scientists based in hospitals, universities, and the life sciences industry. Formal feedback confirmed our strong impression that the vibrant atmosphere of the conference was pivotal to forging new strategic partnerships and collaborations, particularly between clinicians and academic experts with a suite of new drug developers working in the pre‐clinical and clinical trial space. We believe that nurturing and extending these relationships is pivotal to accelerate the much needed discovery and effective development of new treatments for mitochondrial diseases in the short‐to‐medium term.

This was the fourth of a series of Wellcome Trust Conferences on Mitochondrial Medicine. The first conference in 2013 focused on recent advances in understanding the biology of mitochondrial disorders and how this new knowledge might be harnessed to develop new treatments. At that time, a critically needed step was the development of representative animal models for mitochondrial disease that were becoming feasible based on recent advances in genetics. While some animal models had no phenotype or developed a disease that only loosely resembled the human condition, several showed real promise to help facilitate the pre‐clinical development of new medicines. A number of these models were developed and broadly harnessed by the field.

At the second Conference in 2016, we began to see pre‐clinical treatment effects from repurposed medicines that would subsequently be tested in patients. Throughout this period, the field also witnessed a dramatic advance in diagnostic capabilities, initially through targeted gene panels, then exome sequencing, and eventually genome sequencing. Although not yet providing a comprehensive diagnosis for all patients and families, genomic advances have yielded an extraordinary number of novel mitochondrial disease genes. At the third Conference on Mitochondrial Medicine in 2018, the programme expanded to include several human intervention studies, with early phase trials emerging across the globe, in large part through the establishment of international consortia. By the fourth Conference in December 2019, 102 clinical studies in mitochondrial disease were registered on www.clinicaltrials.gov, 55 of which were testing interventions. Not only is the number of trials increasing, but also the number of distinct therapeutic modalities is growing and includes small molecules, metabolite replacement, gene therapy, and cellular therapy. While there are still no approved medicines for mitochondrial disease by the Food and Drug Administration in the United States, 2019 saw idebenone licensed by the European Medicines Agency for Leber Hereditary Optic Neuropathy and taurine by the Japanese Pharmaceuticals and Medical Devices Agency for Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke‐like Episodes Syndrome (MELAS). The remarkable growth of interest and expertise committed to developing new treatments for mitochondrial disease represents extraordinary progress, increasingly matched with significant government and commercial investment.

The Conference programme in December 2019 took us one step further, embracing and promoting direct engagement between academic scientists, clinicians, and colleagues from diverse aspects of the life sciences industry—interspersing talks from all three communities with poster and discussion sessions specifically aimed to encourage cross‐disciplinary interaction.

This issue of JIMD provides a sampling of the gamut of presentations at this meeting, from fundamental research¹ to addressing practical hurdles in drug development, including how to work with regulatory agencies,² what is required by industry to move from an early concept to a licensed medicine,³ and the critical need to develop reliable noninvasive biomarkers of disease progression⁴ and other outcome measures to allow effective evaluation of new compounds.⁵ Recent developments in animal models were presented,⁶ including high throughput approaches for drug screening.⁷ Novel and known biomarkers were discussed, backed up by large longitudinal studies involving patients with precisely defined molecular diagnoses. Flash presentations from many pharma companies gave a rapid overview of the landscape, including promising work in process. It was particularly rewarding to see new national and international consortia forming to enable adequately powered clinical trials using objective primary end‐points.

This special issue of the journal focused on mitochondrial medicine also includes a position paper on the diagnosis and management of mitochondrial neurogastrointestinal encephalomyopathy,⁸ the first description of pathogenic variants in OGDH,⁹ and expansion of the phenotypic description of ECHS1 and HIBCH¹⁰ and TANGO2¹¹ deficiencies. Two novel treatments at a preclinical stage of evaluation are presented: a reactive oxygen species scavenger JP4‐039 for sulfite oxidase deficiency¹² and a nucleotide prodrug CERC‐913 proposed for deoxyguanosine kinase deficiency.¹³ Finally, a phase II open label prospective trial of (+)‐epicatechin in Friedreich ataxia¹⁴ reflects the increasing number of clinical trials being conducted in mitochondrial diseases.

In reflecting on the past four conferences spanning 7 years, it appears that the field of mitochondrial medicine is now at a tipping point. Before 2020, the overwhelming emphasis focused on understanding mitochondrial biology and pathobiology in patients with genetic mitochondrial diseases. Thanks to widespread exome and genome sequencing, many original hurdles have now been overcome. More than 300 genetic forms of mitochondrial disease have now been described, and core mechanistic insights are beginning to emerge thanks to traditional biology and the applications of genomics technologies. The field is beginning to embrace novel therapeutic modalities and moving beyond traditional small molecule therapy. However, great challenges still lie ahead, in part because of how rare and heterogeneous each of these individual genetic diseases is, and the general dearth of patient registries, validated outcome measures specific to mitochondrial disease, and natural history studies with which to empower rigorous clinical trials. Overcoming these challenges requires partnership across the entire ecosystem of biomedicine.

The Wellcome Trust Mitochondrial Medicine Conferences have provided a key venue for sparking new clinical‐academic‐pharma collaborations that are starting to bear fruit. The key role played by patients and their advocacy organizations from across the world was directly endorsed through their active participation throughout the conferences. Now more than ever, there is still much to be done so that patients and families can be offered effective treatment options.

We hope that this special issue of the journal demonstrates the passion of the mitochondrial medicine field in seeking and translating novel treatments to change the therapeutic landscape for primary mitochondrial diseases.

本期《遗传代谢病杂志》线粒体医学特刊包括基于 2019 年 12 月 11 日至 13 日在英国剑桥基因组校区欣克斯顿大厅威康信托基金会主办的第四届线粒体医学国际会议上的平台演讲的文章小型研讨会。本期的客座编辑包括这次激动人心的会议的三位组织者聚集了致力于开发罕见线粒体疾病新疗法的重要学术、临床和企业利益相关者，以及患者和家庭倡导团体。来自全球 21 个国家的 121 名代表出席了会议，其中包括来自医院、大学和生命科学行业的医生和实验室科学家。正式反馈证实了我们的强烈印象，即会议充满活力的氛围对于建立新的战略伙伴关系和合作至关重要，特别是在临床医生和学术专家与一组在临床前和临床试验领域工作的新药开发人员之间。我们认为，培育和扩展这些关系对于在中短期内加速急需的线粒体疾病新疗法的发现和有效开发至关重要。

这是关于线粒体医学的 Wellcome Trust 会议系列中的第四次。2013 年的第一次会议侧重于了解线粒体疾病生物学的最新进展，以及如何利用这些新知识开发新的治疗方法。当时，一个迫切需要的步骤是开发具有代表性的线粒体疾病动物模型，该模型基于遗传学的最新进展而变得可行。虽然一些动物模型没有表型或发展出与人类状况大致相似的疾病，但有一些动物模型显示出真正有望帮助促进新药的临床前开发。许多这些模型被开发并被该领域广泛利用。

在 2016 年的第二次会议上，我们开始看到重新利用药物的临床前治疗效果，这些药物随后将在患者身上进行测试。在此期间，该领域还见证了诊断能力的巨大进步，最初是通过靶向基因组，然后是外显子组测序，最后是基因组测序。尽管尚未为所有患者和家属提供全面的诊断，但基因组的进步已经产生了大量新的线粒体疾病基因。在 2018 年第三届线粒体医学会议上，该计划扩大到包括几项人类干预研究，早期试验在全球范围内出现，主要是通过建立国际联盟。到 2019 年 12 月的第四次会议，在 www.clinicaltrials.gov 上注册了 102 项线粒体疾病临床研究，其中 55 项是测试干预措施。不仅试验数量在增加，而且不同治疗方式的数量也在增加，包括小分子、代谢物替代、基因治疗和细胞治疗。虽然美国食品和药物管理局仍然没有批准用于线粒体疾病的药物，但 2019 年，艾地苯醌获得了欧洲药品管理局的莱伯遗传性视神经病许可，牛磺酸获得了日本药品和医疗器械局的许可，用于线粒体脑病，乳酸酸中毒和中风样发作综合征（MELAS）。

2019 年 12 月的会议计划让我们更进一步，拥抱和促进来自生命科学行业不同方面的学术科学家、临床医生和同事之间的直接接触——穿插来自所有三个社区的演讲和专门旨在鼓励交叉‐学科互动。

本期 JIMD 提供了本次会议演讲的样本，从基础研究¹到解决药物开发中的实际障碍，包括如何与监管机构合作，²行业从早期概念转变为获得许可的药物^{3以及开发可靠的疾病进展的非侵入性生物标志物4}和其他结果测量的迫切需要，以便对新化合物进行有效评估。⁵介绍了动物模型的最新进展，⁶包括用于药物筛选的高通量方法。⁷讨论了新的和已知的生物标志物，并得到了涉及具有精确定义的分子诊断的患者的大型纵向研究的支持。来自许多制药公司的 Flash 演示快速概述了前景，包括有前景的在制品。看到新的国家和国际联盟成立，以使用客观的主要终点来进行充分有力的临床试验，这尤其令人欣慰。

本期专注于线粒体医学的期刊还包括一篇关于线粒体神经胃肠道脑肌病诊断和管理的立场文件，⁸ OGDH致病变异的首次描述，⁹以及 ECHS1 和 HIBCH ¹⁰和 TANGO2表型描述的扩展¹¹不足之处。介绍了处于临床前评估阶段的两种新疗法：活性氧清除剂 JP4-039 用于亚硫酸氧化酶缺乏症¹²和核苷酸前药 CERC-913 用于脱氧鸟苷激酶缺乏症。¹³最后，一项针对 Friedreich 共济失调的 (+)-表儿茶素的 II 期开放标签前瞻性试验^图14反映了越来越多的线粒体疾病临床试验。

回顾过去 7 年的四次会议，线粒体医学领域似乎正处于一个转折点。2020 年之前，压倒性的重点集中在了解遗传性线粒体疾病患者的线粒体生物学和病理生物学。由于广泛的外显子组和基因组测序，现在已经克服了许多最初的障碍。现在已经描述了 300 多种遗传形式的线粒体疾病，并且由于传统生物学和基因组学技术的应用，核心机制见解开始出现。该领域开始接受新的治疗方式并超越传统的小分子疗法。然而，巨大的挑战仍然存在，部分原因是这些个体遗传疾病中的每一种都非常罕见和异质，以及患者登记的普遍缺乏、针对线粒体疾病的经过验证的结果测量，以及支持严格临床试验的自然史研究。克服这些挑战需要在整个生物医学生态系统中建立伙伴关系。

Wellcome Trust 线​​粒体医学会议为激发新的临床-学术-制药合作提供了一个重要场所，这些合作开始取得成果。来自世界各地的患者及其倡导组织所发挥的关键作用通过他们在整个会议中的积极参与得到了直接认可。现在比以往任何时候都需要做很多工作，才能为患者和家属提供有效的治疗选择。

我们希望本期特刊能展示线粒体医学领域在寻求和转化新疗法以改变原发性线粒体疾病治疗领域的热情。