AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression.
AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression.
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牙周病是一种慢性炎症性疾病，由牙齿相关的微生物生物膜诱导宿主免疫反应引起。对高危患者进行性组织破坏的治疗控制是治疗中的一个重大挑战。肿瘤坏死因子α（TNF-α）拮抗剂的可溶性蛋白递送抑制牙周炎引起的牙槽骨吸收。然而，蛋白质治疗引起了几个问题，如治疗停止和重复给药方案后疾病活动的复发。在这项研究中，我们使用基于血清1型的假型腺相关病毒载体（AAV 2/1）将TNF受体-免疫球蛋白Fc（TNFR：Fc）融合基因递送到实验性牙龈卟啉单胞菌（Pg）-脂多糖（LPS）介导的骨丢失的大鼠中。动物接受每周三次递送至牙龈的Pg-LPS，持续8周，单独的媒介物，Pg-LPS和假型AAV 2/1-TNFR：Fc载体（1×1011 DNA酶I抗性颗粒）或递送至幼稚动物的AAV 2/1-TNFR：Fc载体的肌内递送。AAV 2/1-TNFR：Fc治疗导致血清TNFR蛋白的持续治疗水平，并保护免受Pg-LPS介导的骨体积和密度损失。此外，AAV 2/1-TNFR：Fc给药降低了牙周病变处多种促炎细胞因子和破骨细胞样细胞的局部水平。这些发现表明，AAV 2/1-TNFR：Fc的递送可能是调节牙周疾病进展的可行方法。
Periodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor alpha (TNF-α) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of disease activity after treatment cessation and repeated dosing regimens. In this study, we used pseudotyped adeno-associated virus vector based on serotype 1 (AAV2/1) to deliver the TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene to rats subjected to experimental Porphyromonas gingivalis (Pg)-lipopolysaccharide (LPS)-mediated bone loss. Animals received Pg-LPS delivered to the gingivae thrice weekly for 8 weeks, vehicle alone, Pg-LPS and intramuscular delivery of pseudotyped AAV2/1-TNFR:Fc vector (1×1011 DNase I-resistant particles) or AAV2/1-TNFR:Fc vector delivered to naïve animals. AAV2/1-TNFR:Fc therapy led to sustained therapeutic levels of serum TNFR protein and protected against Pg-LPS-mediated loss of bone volume and density. Furthermore, AAV2/1-TNFR:Fc administration reduced local levels of multiple pro-inflammatory cytokines and osteoclast-like cells at the periodontal lesions. These findings suggest that delivery of AAV2/1-TNFR:Fc may be a viable approach to modulate periodontal disease progression.
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