Hasegawa Akihiro, Nakamura-Takahashi Aki, Kasahara Masataka, Saso Nana, Narisawa Sonoko, Millán José Luis, Samura Osamu, Sago Haruhiko, Okamoto Aikou, Umezawa Akihiro
Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, Japan.
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
Regen Ther. 2021 Jul 5;18:168-175. doi: 10.1016/j.reth.2021.06.002. eCollection 2021 Dec.
Hypophosphatasia (HPP) is a congenital skeletal disease. Impairment of bone mineralization and seizures are due to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP). Enzyme replacement therapy (ERT) is available as a highly successful treatment for pediatric-onset HPP. However, the potential for prenatal ERT has not been fully investigated to date. In this study, we assessed outcomes and maternal safety using a combinational approach with prenatal and postnatal administration of recombinant TNAP in mice as a model of infantile HPP. For the prenatal ERT, we administered subcutaneous injections of recombinant TNAP to pregnant mice from embryonic day 11.5-14.5 until delivery, and then sequentially to pups from birth to day 18. For the postnatal ERT, we injected pups from birth until day 18. Prenatal ERT did not cause any ectopic mineralization in heterozygous maternal mice. Both prenatal and postnatal ERT preserved growth, survival rate and improved bone calcification in mice. However, the effects of additional prenatal treatment to newborn mice appeared to be minimal, and the difference between prenatal and postnatal ERT was subtle. Further improvement of the prenatal ERT schedule and long-term observation will be required. The present paper sets a standard for such future studies.
低磷酸酯酶症（HPP）是一种先天性骨骼疾病。骨矿化受损和癫痫发作是由于组织非特异性碱性磷酸酶（TNAP）缺乏所致。酶替代疗法（ERT）是治疗儿童期HPP的一种非常成功的方法。然而，产前ERT的潜力迄今为止尚未得到充分研究。在本研究中，我们以婴儿型HPP小鼠模型为研究对象，采用产前和产后联合给予重组TNAP的方法，评估了治疗效果和母体安全性。对于产前ERT，我们从胚胎第11.5天至14.5天对怀孕小鼠皮下注射重组TNAP直至分娩，然后从出生至第18天依次对幼崽进行注射。对于产后ERT，我们从出生至第18天对幼崽进行注射。产前ERT在杂合子母体小鼠中未引起任何异位矿化。产前和产后ERT均能维持小鼠的生长、存活率并改善骨钙化。然而，对新生小鼠额外进行产前治疗的效果似乎微乎其微，产前和产后ERT之间的差异也很细微。需要进一步优化产前ERT方案并进行长期观察。本文为此类未来研究设定了标准。
