晚发性Pompe病糖原储存和肌肉退化的无创光声成像-动脉网

Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease

Nature 等信源发布 2024-09-08 14:13

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AbstractPompe disease (PD) is a rare autosomal recessive glycogen storage disorder that causes proximal muscle weakness and loss of respiratory function. While enzyme replacement therapy (ERT) is the only effective treatment, biomarkers for disease monitoring are scarce. Following ex vivo biomarker validation in phantom studies, we apply multispectral optoacoustic tomography (MSOT), a laser- and ultrasound-based non-invasive imaging approach, in a clinical trial (NCT05083806) to image the biceps muscles of 10 late-onset PD (LOPD) patients and 10 matched healthy controls.

摘要庞贝病（PD）是一种罕见的常染色体隐性糖原贮积病，可导致近端肌肉无力和呼吸功能丧失。虽然酶替代疗法（ERT）是唯一有效的治疗方法，但用于疾病监测的生物标志物却很少。在体模研究中进行离体生物标志物验证后，我们在临床试验（NCT05083806）中应用多光谱光声断层扫描（MSOT），一种基于激光和超声波的非侵入性成像方法，对10例迟发性PD（LOPD）患者和10例相匹配的健康对照者的肱二头肌进行成像。

MSOT is compared with muscle magnetic resonance imaging (MRI), ultrasound, spirometry, muscle testing and quality of life scores. Next, results are validated in an independent LOPD patient cohort from a second clinical site. Our study demonstrates that MSOT enables imaging of subcellular disease pathology with increases in glycogen/water, collagen and lipid signals, providing higher sensitivity in detecting muscle degeneration than current methods.

MSOT与肌肉磁共振成像（MRI），超声波，肺活量测定，肌肉测试和生活质量评分进行比较。接下来，在第二个临床站点的独立LOPD患者队列中验证结果。我们的研究表明，MSOT可以通过增加糖原/水，胶原蛋白和脂质信号来对亚细胞疾病病理学进行成像，从而比目前的方法在检测肌肉变性方面提供更高的灵敏度。

This translational approach suggests implementation in the complex care of these rare disease patients..

这种转化方法建议在这些罕见疾病患者的复杂护理中实施。。

IntroductionPompe disease (PD) is a rare, autosomal-recessive metabolic myopathy caused by mutations in the gene that encodes for acid alpha-glucosidase (GAA)1,2,3. Regularly, GAA catalyzes the hydrolysis of glycogen to glucose, but in PD, its impaired activity results in a generalized build-up of glycogen in metabolic active organs, such as heart, muscle and liver4,5.

简介庞贝病（PD）是一种罕见的常染色体隐性代谢性肌病，由编码酸性α-葡萄糖苷酶（GAA）1,2,3的基因突变引起。通常，GAA催化糖原水解为葡萄糖，但在PD中，其活性受损导致代谢活性器官（如心脏，肌肉和肝脏）中糖原的普遍积累4,5。

The disease progress is variable in age of onset, severity of organ involvement and degree of myopathy6. There is a differentiation in infantile (IOPD) and late-onset (LOPD) forms based on cardiac involvement, age of onset and residual enzyme activity7. IOPD patients may have less than 1% GAA activity, therefore, quickly develop severe symptoms, such as cardiac involvement, resulting in a high mortality rate by year one if untreated1,8.

疾病的进展因发病年龄，器官受累的严重程度和肌病程度而异6。根据心脏受累，发病年龄和残留酶活性，婴儿（IOPD）和迟发（LOPD）形式存在差异7。IOPD患者的GAA活性可能低于1%，因此，如果不治疗，很快就会出现严重症状，例如心脏受累，导致第一年的死亡率很高1,8。

Children and adults with LOPD have residual enzyme activity below 30%, leading to more slowly progressive limb-girdle type weakness and respiratory insufficiency9,10. Replacement therapies (ERT) are available, leading to a slower progression of cardiac and musculoskeletal involvement, prevention of deterioration of pulmonary function and increasing survival11,12,13,14.

。替代疗法（ERT）是可用的，导致心脏和肌肉骨骼受累的进展较慢，预防肺功能恶化并提高生存率11,12,13,14。

However, an early initiation of treatment may positively impact the overall treatment response15.The diagnosis of PD is usually established by confirmation of GAA deficiency, and confirmed by genetic testing16,17. Furthermore, PD patients require regular clinical follow-up monitoring, especially to assess the response to ERT8,9,17,18,19,20.

然而，早期开始治疗可能会对整体治疗反应产生积极影响15。PD的诊断通常通过确认GAA缺乏来确定，并通过基因检测来证实16,17。此外，PD患者需要定期进行临床随访监测，特别是评估对ERT8,9,17,18,19,20的反应。

While rapid determination of GAA in dried blood spots is possible, enzymatic analysis is unable to discriminate between patients with PD and those individuals harboring pseudo deficiency mutations. In this regard, a tetraglucose oligomer (Glc(4)) in the urine and maltotet.

虽然可以快速测定干血斑中的GAA，但酶分析无法区分PD患者和携带伪缺陷突变的个体。在这方面，尿液和麦芽糖中的四葡萄糖低聚物（Glc（4））。

Data availability

数据可用性

The raw (individual, identifiable patient) data are protected and are not available due to data privacy laws. Data sharing requests will be considered on a case-by-case basis. The processed pseudonymized imaging data can be accessed upon request and within the framework of legal regulations from the corresponding author (equivalent purposes to those for which the patients grant their consent to use the data).

原始（个人，可识别的患者）数据受到保护，并且由于数据隐私法而不可用。数据共享请求将根据具体情况予以考虑。可以根据要求并在相应作者的法律法规框架内访问处理后的假名成像数据（与患者同意使用数据的目的相同）。

Access is granted directly after publication for 36 months. The contact is ki-forschung@uk-erlangen.de, and response to request will be provided within 4–6 weeks. The data will be available for 3 months. The remaining data of this study are provided in the Supplementary Information and Source Data file.

出版36个月后直接授予访问权限。联系人是ki-forschung@uk-erlangen.de，并将在4-6周内对请求做出响应。数据将持续3个月。这项研究的其余数据在补充信息和源数据文件中提供。

The study protocols and the statistical analysis plan are provided with this manuscript in the Supplementary information file. Source data are provided with this paper..

。本文提供了源数据。。

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JACC Cardiovasc. Imaging 16, 719–721 (2023).Download referencesAcknowledgementsThe research was supported by a research Grant from Sanofi Aventis (SGZ201912542) for A.L.W., R.R., R.T. and F.K. and an EU-IMI2 JU research grant (www.screen4care.eu) under the grant agreement No. 101034427 for V.D., S.M., J.Z., F.A., R.T., A.L.W., R.R. and F.K.

JACC心血管。成像16719-721（2023）。下载参考文献致谢该研究得到了赛诺菲-安万特（SGZ201912542）的研究资助。五十、 W.，R.R.，R。T、。

The JU receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Association. Further support was provided by the European Research Council under the European Union Horizon H2020 program (ERC Starting Grant No. 101115742-IseeG) for F.K and an Else Kröner Excellence Fellowship from the Else-Kröner Fresenius Stiftung for A.P.R.

JU得到了欧盟地平线2020研究与创新计划和欧洲制药工业与协会联合会的支持。欧洲研究理事会根据欧盟地平线H2020计划（ERC起始资助号101115742 IseeG）为F.K提供了进一步的支持，并为A.P.R.提供了Else Kröner Fresenius Stiftung的Else Kröner卓越奖学金。

A.L.W. was supported by the Rahel Hirsch Program scholarship from the Charité University Hospital Berlin. The present work was performed in (partial) fulfillment of the requirements for obtaining the degree “Dr. med.” for L.T. The sponsors of the study had no influence on study design, data collection and analysis or manuscript writing.FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthor notesThese authors contributed equally: Alexandra L.

A、 L.W.得到了柏林Charité大学医院Rahel Hirsch计划奖学金的支持。目前的工作是（部分）满足L.T.获得“医学博士”学位的要求。该研究的赞助商对研究设计，数据收集和分析或手稿撰写没有影响。资金开放获取资金由Projekt交易启用和组织。作者信息作者注意到这些作者做出了同样的贡献：Alexandra L。

Wagner, Roman Raming, Ferdinand Knieling.Authors and AffiliationsDepartment of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, 91054, G.

瓦格纳、罗曼·拉明、费迪南德·克尼林。作者和附属机构埃尔兰根大学医院儿科和青少年医学系，弗里德里希·亚历山大大学（FAU）埃尔兰根-纽伦堡，埃尔兰根，91054，G。

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PubMed Google ScholarContributionsL.T., A.L.W., J.Z., A.P.R., V.D., R.R., and F. K. designed, performed experiments, and clinical studies. J.J., V.D., and S.S., S.M., A.S., and H.B. performed clinical studies. J.Z., M.T., U.R., Y.L., W.L., A.H., R.T., A.M., M.W., J.W., and R.H.

PubMed谷歌学术贡献l。T、，A.L.W.，J.Z.，A.P.R.，V.D.，R.R。和F.K.设计，进行实验和临床研究。J、 J.，V.D。和S.S.，S.M.，A.S。和H.B.进行了临床研究。J、。

provided essential support to the clinical study. U.R., F.A., M.V., and L.S. provided essential materials or technical expertise. L.T., R.R., A.L.W., M.C., and F.K. analyzed and interpreted the data. F.K. conceived and supervised the project. L.T., R.R., and F.K. wrote the first draft of the manuscript.

为临床研究提供了必要的支持。U、 R.，F.A.，M.V.和L.S.提供了必要的材料或技术专业知识。五十、 T.，R.R.，A.L.W.，M.C。和F.K.分析并解释了数据。F、 K.构思并监督了该项目。五十、 T.，R.R。和F.K.撰写了手稿的初稿。

All authors edited and approved the final draft.Corresponding authorCorrespondence to.

所有作者都编辑并批准了最终草案。对应作者对应。

Ferdinand Knieling.Ethics declarations

费迪南德·克尼林。道德宣言

Competing interests

相互竞争的利益

A.P.R. and F.K. are co-inventors together with iThera Medical GmbH, Germany, on an EU patent application (EP 19 163 304.9) relating to a device and a method for analyzing optoacoustic data, an optoacoustic system and a computer program. F.K. is a member of the advisory board of iThera Medical GmbH, Munich, Germany.

A、 P.R.和F.K.与德国iThera Medical GmbH共同发明了一项欧盟专利申请（EP 19 163 304.9），涉及一种用于分析光声数据、光声系统和计算机程序的装置和方法。F、 K.是德国慕尼黑iThera Medical GmbH咨询委员会成员。

A.P.R. and F.K. received travel support from iThera Medical GmbH, Germany. A.P.R., A.L.W., and F.K. report travel support from Sanofi Aventis, Germany. A.P.R. and F.K. report lecture fees from Sanofi Genzyme. F.K. reports lecture fees from Siemens Healthcare GmbH. The other authors declare no competing interests..

A、 P.R.和F.K.获得了德国iThera Medical GmbH的旅行支持。A、 P.R.、A.L.W.和F.K.报告了来自德国赛诺菲-安万特的旅行支持。A、 P.R.和F.K.报告赛诺菲基因酶的讲座费用。F、 K.报道了西门子医疗保健有限公司的讲座费用。其他作者声明没有利益冲突。。

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To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

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Reprints and permissionsAbout this articleCite this articleTan, L., Zschüntzsch, J., Meyer, S. et al. Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease.

转载和许可本文引用本文Tan，L.，Zschüntzsch，J.，Meyer，S。等人。迟发性庞贝病糖原储存和肌肉变性的无创光声成像。

Nat Commun 15, 7843 (2024). https://doi.org/10.1038/s41467-024-52143-6Download citationReceived: 09 December 2023Accepted: 26 August 2024Published: 08 September 2024DOI: https://doi.org/10.1038/s41467-024-52143-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157843（2024）。https://doi.org/10.1038/s41467-024-52143-6Download引文接收日期：2023年12月9日接收日期：2024年8月26日发布日期：2024年9月8日OI：https://doi.org/10.1038/s41467-024-52143-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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