延长基于蛋白质治疗药物的半衰期可以提高药物疗效。然而，基因治疗本质上是提供了长期表达所需的治疗性蛋白，药物半衰期对基因治疗疗效的影响尚不清楚。在这项腺相关病毒（adeno-associated virus, AAV）基因治疗研究中，通过与免疫球蛋白G1（immunoglobulin G 1, IgG1）可溶性单体Fc 区（soluble monomeric IgG1 fragment crystallizable, sFc）或Fc 区融合，设计了几种能够延长半衰期的蛋白质。研究表明，延长AAV递送的小分子双功能蛋白和成纤维细胞生长因子21（fibroblast growth factor 21, FGF21）的半衰期显著增加了它们在血液循环中的浓度。此外，AAV递送FGF21 延长其半衰期使2 型糖尿病动物模型中肝损伤和血糖显著降低，并改善了葡萄糖耐量和胰岛素敏感性。这些结果证明了延长药物半衰期的基因治疗在应对人类疾病中的治疗潜力。

Prolonged half-life of protein-based therapeutics can improve drug efficacy. However, the impact of drug half-life on gene therapy, which inherently provides long-lasting production of the desired therapeutic protein, remains unclear. In this study, several proteins with extended half-lives were engineered by fusion with the soluble monomeric immunoglobulin G 1 (IgG1) fragment crystallizable (sFc) or Fc region of IgG in adeno-associated virus (AAV)-delivered gene therapy. It was demonstrated that extending the half-life of a small-sized bifunctional protein and fibroblast growth factor 21 (FGF21) significantly increased their concentrations in the bloodstream circulation. Moreover, the half-life extension of AAV-delivered FGF21 resulted in a remarkable reduction in liver injury and blood glucose, and improved glucose tolerance and insulin sensitivity in type 2 diabetes mellitus animal models. These results demonstrate the therapeutic potential of gene therapy with prolonged drug half-life in the treatment of human diseases.