Odeh Anas, Sela Mor, Zaffryar-Eilot Shelly, Shemesh Ariel, Saleh Maher Abu, Mizrahi Ido, Coren Lavi, Schroeder Avi, Hasson Peleg
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
The Louis Family Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Department of Chemical Engineering, Technion - Israel Institute of Technology, Haifa 32000, Israel.
iScience. 2025 Apr 2;28(5):112335. doi: 10.1016/j.isci.2025.112335. eCollection 2025 May 16.
Fibrosis, characterized by the deposition of excess and disorganized extracellular matrix (ECM), is a key pathological hallmark of multiple diseases, including Duchenne muscular dystrophy (DMD). Aiming to inhibit fibrosis progression, we generated an antibody-drug conjugate (ADC) that delivers an innovative small molecule conjugate to inhibit the ECM-modifying enzyme Lysyl oxidase (LOX) specifically in fibrotic lesions by targeting M2 macrophages. Administration of the ADC to mice, the murine model of DMD, results in ADC accumulation in fibrotic muscles without affecting healthy tissues. Long-term ADC treatments of adult mice lead to inhibition of the fibrotic process and to significant improvement of cardiac and skeletal muscle function. Our study demonstrates that targeted inhibition of LOX-dependent fibrotic diseases, such as DMD, facilitates improved outcomes for muscular dystrophies.
纤维化的特征是细胞外基质（ECM）过度沉积且排列紊乱，是包括杜氏肌营养不良症（DMD）在内的多种疾病的关键病理标志。为了抑制纤维化进展，我们构建了一种抗体药物偶联物（ADC），该偶联物通过靶向M2巨噬细胞，将一种创新的小分子偶联物递送至纤维化病灶，特异性抑制细胞外基质修饰酶赖氨酰氧化酶（LOX）。将该ADC应用于DMD小鼠模型，结果显示ADC在纤维化肌肉中蓄积，而不影响健康组织。对成年小鼠进行长期ADC治疗可抑制纤维化进程，并显著改善心脏和骨骼肌功能。我们的研究表明，对LOX依赖性纤维化疾病（如DMD）进行靶向抑制，有助于改善肌营养不良症的预后。
