Connective tissue disorders can be caused by pathogenic variants (mutations) in genes encoding extracellular matrix (ECM) proteins. Such disorders typically manifest during development or postnatal growth and result in significant morbidity and mortality. The development of curative treatments for connective tissue disorders is hampered in part by the inability of many mature connective tissues to efficiently regenerate. To be most effective, therapeutic strategies designed to preserve or restore tissue function will likely need to be initiated during phases of significant endogenous connective tissue remodeling and organ sculpting postnatally and directly target the underlying ECM protein mutations. With recent advances in whole exome sequencing, in-vitro and in-vivo disease modeling, and the development of mutation-specific molecular therapeutic modalities, it is now feasible to directly correct disease-causing mutations underlying connective tissue disorders and ameliorate their pathogenic consequences. These technological advances may lead to potentially curative personalized medicine approaches for connective tissue disorders that have previously been considered incurable. In this review, we highlight innovative therapeutic modalities including gene replacement, exon skipping, DNA/mRNA editing, and pharmacological approaches that were used to preserve or restore tissue function in the context of connective tissue disorders. Inherent to a successful application of these approaches is the need to deepen the understanding of mechanisms that regulate ECM formation and homeostasis, and to decipher how individual mutations in ECM proteins compromise ECM and connective tissue development and function.

结缔组织疾病可由编码细胞外基质 (ECM) 蛋白的基因的致病性变异（突变）引起。此类疾病通常在发育或出生后生长期间显现并导致显着的发病率和死亡率。许多成熟结缔组织无法有效再生，部分阻碍了结缔组织疾病治疗方法的发展。为了达到最有效的效果，旨在保护或恢复组织功能的治疗策略可能需要在出生后显着的内源性结缔组织重塑和器官塑造阶段启动，并直接针对潜在的 ECM 蛋白突变。随着全外显子组测序、体外和体内疾病模型的最新进展，以及突变特异性分子治疗方式的发展，现在可以直接纠正结缔组织疾病的致病突变并改善其致病后果。这些技术进步可能会为以前被认为无法治愈的结缔组织疾病带来潜在的治愈性个性化医疗方法。在这篇综述中，我们重点介绍了创新的治疗方式，包括基因替换、外显子跳跃、DNA/mRNA 编辑以及用于在结缔组织疾病中保留或恢复组织功能的药理学方法。成功应用这些方法的本质是需要加深对调节 ECM 形成和稳态的机制的理解，并破译 ECM 蛋白的个体突变如何损害 ECM 和结缔组织的发育和功能。