Huang Wei, Mohammed Tawfiq, Zou Xunchang, Krishnan Anya A, Mo Xiaokui, Xiao Min, Cao Lei
Department of Cancer Biology & Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Mol Ther Methods Clin Dev. 2025 May 30;33(3):101500. doi: 10.1016/j.omtm.2025.101500. eCollection 2025 Sep 11.
Congenital leptin deficiency is a monogenic disease originated from adipose tissue, causing hyperphagia, severe obesity, and hyperinsulinemia. Moreover, most forms of lipodystrophy syndromes exhibit leptin deficiency. Leptin replacement therapy with leptin protein analog requires frequent injection for life and is extremely expensive. We previously reported that a single intraperitoneal injection of an adipose-targeting Rec2-leptin adeno-associated virus (AAV) vector normalized metabolic syndromes in the leptin deficient mice. Here, we conducted a dose-deescalating study with four doses (2E10, 1E10, 5E9, and 1E9 viral genome per mouse) in mice and extended monitoring to 27 weeks post dosing. Rec2-leptin at all doses normalized excessive weight gain, hyperphagia, obesity, low core temperature, glucose intolerance, and hyperinsulinemia in the mice. Transgene expression was restricted in the targeting visceral adipose tissues and sustained throughout the 27-weeks study. Rec2-leptin at the lowest dose 1E9 viral genome (vg)/mouse restored the circulating leptin level to 18% of the normal level of wild-type (WT) mice. Rec2-leptin at all doses reversed liver steatosis and pancreatic islet hyperplasia. Behavioral assessment, serum chemistry, and histopathology noted no significant adverse effects attributed to Rec2-leptin. This study demonstrates that Rec2-leptin is safe and highly efficacious, supporting further development for genetic or acquired leptin deficiency.
先天性瘦素缺乏是一种起源于脂肪组织的单基因疾病，可导致食欲亢进、严重肥胖和高胰岛素血症。此外，大多数形式的脂肪营养不良综合征都表现出瘦素缺乏。使用瘦素蛋白类似物进行瘦素替代疗法需要终身频繁注射，而且极其昂贵。我们之前报道过，单次腹腔注射靶向脂肪的Rec2-瘦素腺相关病毒（AAV）载体可使瘦素缺乏小鼠的代谢综合征恢复正常。在此，我们在小鼠中进行了一项剂量递减研究，设置了四个剂量（每只小鼠2×10¹⁰、1×10¹⁰、5×10⁹和1×10⁹病毒基因组），并将监测期延长至给药后27周。所有剂量的Rec2-瘦素都使小鼠的体重过度增加、食欲亢进、肥胖、低体温、葡萄糖不耐受和高胰岛素血症恢复正常。转基因表达局限于靶向的内脏脂肪组织，并且在整个27周的研究中持续存在。最低剂量为每只小鼠1×10⁹病毒基因组（vg）的Rec2-瘦素将循环瘦素水平恢复到野生型（WT）小鼠正常水平的18%。所有剂量的Rec2-瘦素都逆转了肝脏脂肪变性和胰岛增生。行为评估、血清化学和组织病理学检查均未发现Rec2-瘦素引起的明显不良反应。这项研究表明，Rec2-瘦素安全且高效，支持其在遗传性或获得性瘦素缺乏症方面的进一步研发。
