Phase 1 Study of In Utero Enzyme Replacement Therapy for the Treatment of Lysosomal Storage Diseases

溶酶体贮积症（LSD）是由关键酶突变引起的严重疾病， 估计发病率为1/5 000至1/5 500。患有LSD的患者在 严重的围产期发病率和死亡率的风险增加，有些甚至活不到出生。当前 用于儿科患者的治疗，酶替代疗法（ERT），受到三个方面的限制： 器官特异性表现的进行性发展（有时在子宫内），抗ERT的发展 抗体，以及ERT不能穿过血脑屏障以解决神经学效应。因此，有 未满足的医疗需求，即从出生前开始为LSD患者开发更有效的治疗方法。中 在7型粘多糖沉积症（MPS 7）小鼠模型中，我们发现子宫内ERT（IUERT）， 出生后的ERT可提高存活率，穿过血脑屏障，改善疾病，并诱导耐受性 紧急反应小组基于这些结果，我们获得了IND，以进行首次人体非随机单次给药。 研究中心开展IUERT的1期临床试验，并寻求资金支持该临床试验。因为每一种LSD 罕见，但它们具有相似的病理生理学，我们纳入了8种不同的LSD（及其特定的ERT） 根据本方案：MPS 1、2、4a、6和7型，婴儿型庞贝氏症（IOPD），神经病性 戈谢病（2型和3型）和沃尔曼病。我们将入组10对母胎对进行ERT输注 从妊娠18周后开始，每2-4周通过脐静脉注射一次。我们将评估安全性， 这种产前治疗的可行性，以及Erts在解决胎儿表现（如果存在）方面的疗效 并改善长期结果，包括神经和心脏功能、活动性和生长。(Aim 1）。我们 还将通过评估酶谷水平来检查IUERT的药代动力学和药效学 在整个妊娠期间，以及出生前后疾病特异性溶酶体积累的水平（目的 2）。最后，我们将评估子宫内暴露于重组酶是否会诱导耐受性， 通过缺乏抗药物抗体和酶特异性调节性T细胞的产生来确定（目的3）。在 在过去的一年里，我们的团队成功地治疗了一个患有IOPD的胎儿（他的两个兄弟姐妹患有严重的IOPD）。 心肌病和遭受围产期死亡）;这名患者出生在多个产前酶 输注，并具有正常的心脏功能。我们组建了一个多学科团队， 几位迷幻药生化分析专家因为我们预计根据已知的 家族史，我们也一直在与多个国家和国际患者倡导团体合作 将患者和家属纳入本试验的设计和执行。我们进行了一项家长调查， 评估他们的态度，发现大多数受访者会选择参加I期临床试验， 针对未来怀孕受LSD影响的胎儿ERT试验。最终，我们寻求改善选择 提供给LSD的家庭和患者。

Lysosomal storage disorders (LSDs) are severe diseases arising from mutations in critical enzymes and collectively have an estimated incidence of 1 in 5,000 to 1 in 5,500 live births. Patients with LSDs are at increased risk of serious perinatal morbidity and mortality, with some not even surviving to birth. The current treatment for pediatric patients, enzyme replacement therapy (ERT), is limited by three aspects: the progressive development (sometimes in utero) of organ-specific manifestations, the development of anti-ERT antibodies, and the inability of ERT to cross the blood-brain barrier to address neurologic effects. Thus, there is an unmet medical need to develop more effective therapies for patients with LSDs, starting before birth. In a mouse model of mucopolysaccharidosis type 7 (MPS7), we showed that in utero ERT (IUERT) followed by postnatal ERT improved survival, crossed the blood-brain barrier, ameliorated disease, and induced tolerance to the ERT. Based on these results, we obtained an IND to perform a first-in-human, non-randomized, single site phase 1 clinical trial of IUERT and seek funding to support this clinical trial. Since each individual LSD is rare, but they share similar pathophysiology, we have included eight different LSDs (and their specific ERT) under this protocol: MPS Types 1, 2, 4a, 6, and 7, Infantile-onset Pompe Disease (IOPD), Neuronopathic Gaucher (Types 2 and 3), and Wolman disease. We will enroll 10 maternal-fetal pairs for infusion of the ERT via the umbilical vein every 2-4 weeks, starting after 18 weeks of gestation. We will evaluate the safety and feasibility of this prenatal therapy, as well as the efficacy of ERTs in resolving fetal manifestations (if present) and improving long-term outcomes including neurologic and cardiac function, mobility, and growth. (Aim 1). We will also examine the pharmacokinetics and pharmacodynamics of IUERT by evaluating enzyme trough levels throughout gestation, as well as levels of disease-specific lysosomal accumulations before and after birth (Aim 2). Finally, we will evaluate whether in utero exposure to the recombinant enzyme will induce tolerance, as determined by lack of anti-drug antibodies and generation of enzyme-specific regulatory T cells (Aims 3). In the past year, our team has successfully treated a fetus with IOPD (whose two previous siblings had severe cardiomyopathy and suffered perinatal demise); this patient was born at term after multiple prenatal enzyme infusions and has normal cardiac function. We have assembled a multidisciplinary team and partnered with several experts on biochemical analyses for LSDs. Since we anticipate identifying fetuses based on a known family history, we have also been collaborating with multiple national and international patient advocacy groups to include patients and families in the design and execution of this trial. We conducted a parent survey to evaluate their attitudes and found that the majority of respondents would choose to enroll in a phase I clinical trial for fetal ERT for a future pregnancy affected by an LSD. Ultimately, we seek to improve the options available to families and patients with LSDs.