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

溶酶体储存障碍(LSD)是一种严重的疾病，由关键酶和 总体而言，估计发病率为每5000人中有1人到每5500名活产儿中有1人。患有LSD的患者在 增加严重围产期发病率和死亡率的风险，有些人甚至活不到出生。海流 儿科患者的治疗，即酶替代疗法(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无法跨越血脑屏障来解决神经影响。因此，有 一个尚未得到满足的医疗需求是为LSD患者开发更有效的治疗方法，从出生前开始。在一个 7型粘多糖病(MPS7)的小鼠模型，我们发现子宫内ERT(IUERT)其次是 出生后ERT可提高存活率，跨越血脑屏障，改善疾病，并诱导耐受 送到急诊室。基于这些结果，我们获得了一种IND，以执行人类第一次、非随机、单 IUERT的现场1期临床试验，并寻求资金支持这项临床试验。因为每个单独的LSD 罕见，但它们具有相似的病理生理，我们包括了八种不同的LSD(及其特定的ERT) 根据该方案：MPS 1、2、4a、6和7型，婴儿起病庞贝病(IOPD)，神经病理性 Gaucher(2型和3型)和Wolman病。我们将招募10对母婴进行ERT输液 妊娠18周后开始，每2-4周经脐静脉注射一次。我们将评估其安全性和 这种产前治疗的可行性，以及ERTS在解决胎儿表现方面的效果(如果存在) 并改善长期结果，包括神经和心脏功能、活动能力和生长发育。(目标1)。我们 我还将通过评估酶水平来检查IUERT的药代动力学和药效学 在整个妊娠期间，以及出生前和出生后特定于疾病的溶酶体积聚水平(目的 2)。最后，我们将评估在子宫内暴露于重组酶是否会诱导耐受，如 由缺乏抗药物抗体和产生酶特异性调节T细胞决定(AIMS 3)。在 在过去的一年里，我们团队成功地治疗了一名患有IOPD的胎儿(他的前两个兄弟姐妹患有严重的 心肌病和围产期死亡)；这名患者是在多种产前酵素过后足月出生的 输液，心脏功能正常。我们已经组建了一个多学科团队，并与 几位LSD生化分析方面的专家。因为我们预计会根据已知的 家族病史，我们也一直在与多个国家和国际患者权益倡导团体合作 让患者和家属参与这项试验的设计和执行。我们进行了一项家长调查，以 评估他们的态度，发现大多数受访者会选择注册I期临床 对受LSD影响的未来妊娠进行胎儿ERT的试验。最终，我们寻求改善各种选择 适用于患有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.