Gallardo Maria D, Girard Mauricio, Portiansky Enrique L, Goya Rodolfo G
School of Medicine, National University of La Plata (UNLP), La Plata, Argentina.
Image Analysis lab; School of Veterinary Sciences, National University of La Plata, La Plata, Argentina.
Aging (Albany NY). 2025 Jan 24;17(1):161-169. doi: 10.18632/aging.206191.
In middle-aged (MA) female rats, we have demonstrated that intrahypothalamic gene therapy for insulin-like growth factor-I (IGF-I) extends the regular cyclicity of the animals beyond 10 months (the age at which MA rats stop ovulating). Here, we implemented long-term OSKM gene therapy in the hypothalamus of young female rats. The main goal was to extend fertility in the treated animals. We constructed an adenovector that harbors the GFP gene as well as 4 Yamanaka genes. An adenovector that only carries the gene for GFP or DsRed was used as control. At 4 months of age 12 female rats received an intrahypothalamic injection of our OSKM vector (treated rats); 12 control rats received a vector expressing a marker gene (control rats). At 9.3 months of age control and treated rats were mated with young males. A group of 12 young intact female rats was also mated. The rate of pregnancy recorded was 83%, 8.3 and 25% for young, MA control and MA treated animals, respectively. Pup body weight (BW) at weaning was significantly higher in the MA OSKM rats than in MA controls. At the age of estropause (10 months), OSKM treated females still showed regular estrous cycles. The particular significance of the present results is that, for the first time, it is shown that long-term OSKM gene therapy in the hypothalamus is able to extend the functionality of such a complex system as the hypothalamo-pituitary-ovarian axis.
在中年（MA）雌性大鼠中，我们已经证明，下丘脑内注射胰岛素样生长因子-I（IGF-I）基因疗法可使动物的正常发情周期延长至10个月以上（MA大鼠停止排卵的年龄）。在此，我们在下丘脑对年轻雌性大鼠实施了长期的OSKM基因疗法。主要目标是延长接受治疗动物的生育能力。我们构建了一种携带绿色荧光蛋白（GFP）基因以及4个山中因子基因的腺病毒载体。仅携带GFP或红色荧光蛋白（DsRed）基因的腺病毒载体用作对照。在4月龄时，12只雌性大鼠接受下丘脑内注射我们的OSKM载体（治疗组大鼠）；12只对照大鼠接受表达标记基因的载体（对照组大鼠）。在9.3月龄时，对照组和治疗组大鼠与年轻雄性大鼠交配。一组12只年轻未处理的雌性大鼠也进行了交配。年轻、MA对照组和MA治疗组动物的妊娠率分别为83%、8.3%和25%。MA OSKM大鼠断奶时幼崽的体重显著高于MA对照组。在绝经年龄（10个月）时，接受OSKM治疗的雌性大鼠仍表现出规律的发情周期。本研究结果的特别意义在于，首次表明下丘脑内长期的OSKM基因疗法能够延长下丘脑-垂体-卵巢轴这样复杂系统的功能。
