Guinea pigs as a model of in utero stem cell therapy for spina bifida

摘要 脊柱裂（SB）是美国儿童终身瘫痪的最常见原因。 States. SB是由在第四周的神经管不完全闭合引起的。 怀孕暴露的脊髓承受着子宫内的化学和机械创伤， 使儿童终身瘫痪，大小便失禁，肌肉骨骼 畸形和认知障碍。这些残疾需要广泛的医疗护理， 持续的身体和认知康复，使SB成为最昂贵的童年之一 疾病最近的研究--包括我们自己的研究--表明， 干细胞或其他技术有可能改善出生时患有 这种毁灭性的疾病。当医学和科学界从未像现在这样 定位为SB开发新的突破性疗法，该领域缺乏 合适的动物模型。为了准确地模拟SB，动物必须具有长的妊娠期，耐受性， 胎儿的手术操作，并在出生时充分发育，以允许 运动功能的评估。SB的常用动物模型包括大鼠、兔、 和绵羊。到目前为止，小动物模型在很大程度上不适合开发 新疗法;由于其体积小，妊娠期短，对胎儿进行手术操作 不能在足够早的胎龄进行以准确地模拟人SB。 此外，无法从这些模型中收集功能性运动数据，因为大鼠 兔子出生时也不能走动。虽然大型动物模型的妊娠时间较长， 更适合胎儿操作，出生后不久就可以走动， 昂贵得令人望而却步且劳动密集。为了统计一个绵羊研究的单臂 将花费超过10万美元，可能需要一个外科医生和兽医团队整整一年的时间， 完成. 我们建议开发一个高通量，成本效益的小动物模型的SB使用 豚鼠豚鼠有一个自然的历史，使该物种独特地适合SB， 子宫治疗研究。豚鼠在所有常用的小型哺乳动物中妊娠期最长 动物模型，是大鼠的三倍，是兔子的两倍。此外，几内亚 猪代表唯一常用的能够进行免疫的小动物模型， 出生时独立喂养。我们建议使用豚鼠来开发一种可重复的小型 SB的动物模型，这将使研究人员能够快速，经济地评估 子宫内新疗法的有效性。

Abstract Spina bifida (SB) is the most common cause of lifelong childhood paralysis in the United States. SB results from the incomplete closure of the neural tube during the fourth week of gestation. The exposed spinal cord sustains intrauterine chemical and mechanical trauma, leaving children with lifelong paralysis, bowel and bladder incontinence, musculoskeletal deformities, and cognitive disabilities. These disabilities require extensive medical care and ongoing physical and cognitive rehabilitation, making SB one of the most costly childhood diseases. Recent studies – including our own – have suggested that fetal interventions with stem cells or other techniques have the potential to improve the prognosis of children born with this devastating disease. While the medical and scientific community has never been better positioned to develop new groundbreaking therapies for SB, the field suffers from a lack of suitable animal models. To accurately model SB, animals must have a long gestation, tolerate surgical manipulation of the fetus, and be sufficiently developed at birth to allow for the assessment of locomotor function. Commonly used animal models of SB include rats, rabbits, and sheep. To date, small animal models have been largely unsuitable for the development of new therapies; due to their small size and short gestation surgical manipulation of the fetus cannot be performed at an early enough gestational age to accurately model human SB. Furthermore, functional locomotor data cannot be collected from these models as neither rats nor rabbits are ambulatory at birth. While large animal models have longer gestational times, are more suited for fetal manipulation, and are ambulatory shortly after birth, they are prohibitively expensive and labor intensive. To statistically power a single arm of a sheep study will cost well over $100,000 and can take a team of surgeons and veterinarians an entire year to complete. We propose to develop a high-throughput, cost effective small animal model of SB using guinea pigs. Guinea pigs have a natural history that makes the species uniquely suited for SB in utero treatment research. Guinea pigs have the longest gestation of any commonly used small animal models, three times as long as rats and twice as long as rabbits. Additionally, guinea pigs represent the only commonly used small animal model capable of ambulation and independent feeding at birth. We propose to use guinea pigs to develop a reproducible small animal model of SB that will allow investigators to quickly and economically assess the effectiveness of new in utero therapies.