Chondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC1D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo leading to degradation of CSPGs. Compared to a contusion only group, AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to a contusive spinal cord injury. Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to functional recovery after SCI compared to a contusion only group. Thus, long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a candidate for further preclinical development.

中文翻译：

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星形胶质细胞选择性AAV-ADAMTS4基因疗法与后肢康复相结合可促进脊髓损伤后的功能恢复。

硫酸软骨素蛋白聚糖（CSPG）是轴突再生和可塑性的抑制剂。具有血小板反应蛋白基序4的双整合蛋白和金属蛋白酶（ADAMTS4）是一种人类酶，可催化CSPG蛋白核心的蛋白水解。先前已证明将ADAMTS4输注到受损的脊髓可以改善SCI的功能恢复，但是，这种疗法的酶形式受到限制。腺相关病毒（AAV）载体基因治疗已成为中枢神经系统中安全，稳定和长期转基因表达的首选载体。在此，将在星形细胞GfaABC1D启动子控制下的包含ADAMTS4的AAV表达盒包装到AAV5载体中。在体外和体内均实现了ADAMTS4的持续表达，从而导致CSPG降解。与仅挫伤组相比，AAV-ADAMTS4导致病变大小显着减小，后肢皮质脊髓束突突的发芽增加，尾部对挫伤性脊髓损伤的血清素能纤维密度增加。后肢特定运动康复被用来推动神经可塑性朝着改善功能连接的方向发展。与仅挫伤组相比，后肢康复与AAV-ADAMTS4的结合导致SCI后功能恢复。因此，通过AAV-ADAMTS4基因疗法与康复相结合的方法，CSPG的长期降解代表了进一步临床前开发的候选者。后肢特定运动康复被用来推动神经可塑性朝着改善功能连接的方向发展。与仅挫伤组相比，后肢康复与AAV-ADAMTS4的结合导致SCI后功能恢复。因此，通过AAV-ADAMTS4基因疗法与康复相结合的方法，CSPG的长期降解代表了进一步临床前开发的候选者。后肢特定运动康复被用来推动神经可塑性朝着改善功能连接的方向发展。与仅挫伤组相比，后肢康复与AAV-ADAMTS4的结合导致SCI后功能恢复。因此，通过AAV-ADAMTS4基因疗法与康复相结合的方法，CSPG的长期降解代表了进一步临床前开发的候选者。