introduction
Duchenne muscular dystrophy (DMD) is a progressive muscular dystrophy disease first reported by France neuropathologist Guillaume Duchenne, with an incidence of about 1 in 3500. Genetic studies have found that the disease is an X-linked recessive genetic disease caused by a mutation in the DMD gene that causes a loss of dystrophin. The patients are mainly boys, usually at the age of 2-4 years with progressive muscle weakness such as walking and wrestling, and gradually lose mobility, most of them die of cardiopulmonary failure at the age of 20-30 years. Due to the insidious onset, long course of DMD and the lack of effective treatment drugs, it has brought a heavy burden to the patient's family and society.
Gene therapy research for DMD has made significant progress in the past few years, with drugs such as exon skipping and micro-dystrophin protein supplementation on the market, bringing new hope to patients. However, existing animal models such as mice, dogs, and pigs cannot realistically simulate the disease progression of DMD patients, resulting in a limited understanding of disease progression, especially the early mechanism of the disease. Therefore, it still faces challenges in clinical application, such as large side effects, limited efficacy, narrow scope of application, and high treatment cost. In order to find more effective treatments, there is an urgent need to study the molecular and cellular mechanisms of DMD at various disease stages.
Non-human primates are highly similar to humans in terms of genome sequence, muscle structure and function, physiology and pathology, and growth and development process, making them ideal laboratory animals for studying the occurrence and development of DMD diseases. Since 2014, the team of Chen Yongchang and Ji Weizhi of Kunming University of Science and Technology has made a series of outstanding progress in non-human primate gene editing and disease model construction, and in 2015, the DMD gene was edited for the first time in monkeys. However, due to the limitations of the technology at the time, most of the F0 generations obtained were in a chimeric state, and it was difficult to present a typical disease phenotype. After nearly 8 years of hard work, the team has successfully cultivated an F1 generation DMD monkey model, in which the male hemizygous mutant individuals meet the DMD genotype and show progressive pathological changes similar to those of clinical patients.
Based on the DMD monkey model, the team of Yongchang Chen/Weizhi Ji and Ping Hu first focused on the pathogenesis of the early stage of the disease. Due to the difficulty of muscle biopsy in DMD patients at this stage, and the commonly used mouse models of DMD are very different from clinical patients in terms of pathogenesis and pathological phenotype, the mechanism of early DMD pathogenesis is still not well understood. Therefore, in-depth analysis of the molecular and cellular changes in the early stage of DMD is of great significance for exploring the regulatory mechanism of the disease process and developing early treatment options.
2024年9月20日， 陈永昌/胡苹/季维智团队在Cell发表题为Profound cellular defects attribute to muscular pathogenesis in rhesus monkey model of Duchenne muscular dystrophy的研究论文。 研究首次发现在DMD的早期阶段，肌肉退化往往首先表现在肌肉组织的微环境和细胞组成上，而这些变化主要涉及单核细胞群，如免疫细胞（Immune cells）、成纤维/成脂肪祖细胞（Fibro-adipogenic progenitors, FAPs）和肌肉干细胞（Muscle stem cells, MuSCs）等。 这些单核细胞的动态变化对疾病的进展至关重要。 利用单细胞测序技术，研究团队揭示了严重的细胞缺陷是早期肌肉组织病变和再生异常的关键原因，并深入解析了该阶段肌肉组织中单核细胞的变化。
模式图（Credit: Cell）
The results of this study provide new insights into the pathogenesis of DMD, especially the molecular and cellular changes in the early stages of the disease. The dynamic changes of immunity, fibrosis and muscle stem cells in the early stage of DMD were revealed, which provided a scientific basis for early intervention and targeted therapy. The rapid increase in immune cells worsens the living environment of muscle cells, suggesting that inhibition of inflammatory response is crucial in DMD treatment. In addition, the DMD monkey model showed that FAPs fibrosis did not depend on the TGFβ pathway, which provided a new direction for new drug development. More importantly, the dysfunction of muscle stem cells leads to muscle repair disorders, suggesting that DMD is a stem cell disease, and the development of cell therapy or intervention therapy for muscle stem cells may be an important direction for future research.
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https://doi.org/10.1016/j.cell.2024.08.041
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