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

子宫内酶替代疗法治疗溶酶体贮积病的一期研究

基本信息

批准号：
10542951
负责人：
Tippi Mackenzie
金额：
$ 68.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542951
关键词：
Address Affect Antibodies Antibody Therapy Attitude Back Biochemical Birth Blood Blood - brain barrier anatomy Blood Transfusion Brain Cardiac Cardiomyopathies Child Clinical Trials Data Development Diagnosis Disease Edema Education Enrollment Ensure Enzymes Exposure to FDA approved Family Fetal safety Fetus Functional disorder Funding Future GAG Gene Generations Genetic Genotype Glycogen storage disease type II Glycosaminoglycans Goals Growth Hydrops Fetalis Immune Immune response Incidence Individual Infrastructure Infusion procedures Injections International Investigational Drugs Live Birth Lysosomal Storage Diseases Measures Medical Microglia Mucopolysaccharidoses Mucopolysaccharidosis VII Mus Mutation Nervous System Physiology Nervous System Trauma Neurocognitive Deficit Neurologic Effect New Drug Approvals Organ Outcome Parents Pathology Patient Participation Patients Perinatal Perinatal mortality demographics Pharmaceutical Preparations Phase I Clinical Trials Phenotype Pregnancy Pregnant Women Progressive Disease Proteins Protocols documentation Publishing Recombinants Recording of previous events Regulatory T-Lymphocyte Respondent Risk Safety Severities Siblings Site Surveys Techniques Testing Time Umbilical vein Wolman Disease base blood-brain barrier penetration design disease prognosis effective therapy enzyme replacement therapy exome sequencing experience fetal first-in-human genetic testing heart function immunoreaction improved improved outcome in utero infancy maternal safety mouse model multidisciplinary multiorgan damage organ growth patient advocacy group pediatric patients perinatal morbidity pharmacokinetics and pharmacodynamics phase 1 study postnatal prenatal prenatal exposure prenatal therapy prevent programs safety and feasibility skeletal dysplasia specific biomarkers success treatment center trial design ultrasound

项目摘要

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.

溶酶体储存障碍（LSD）是严重疾病，是由关键酶突变和估计有5,000至1分的5,500例活生子的发病率是1分之一。 LSD的患者处于严重的围产期发病率和死亡率的风险增加，有些甚至无法生存。电流小儿患者，酶替代疗法（ERT）的治疗受三个方面的限制：器官特异性表现的渐进发展（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系统作用。因此，有从出生前开始，未满足的医疗需要为LSD患者开发更有效的疗法。在粘多糖化的小鼠模型7型（MPS7），我们在子宫（IUERT）中表明产后ERT改善生存率，越过血脑屏障，改善疾病并诱发了耐受性到ert。基于这些结果，我们获得了一个IND来执行第一个人类，非随机，单个 IUERT的现场1阶段临床试验并寻求资金支持该临床试验。由于每个LSD都是很少见，但它们具有相似的病理生理学，我们包括八种不同的LSD（及其特定的ERT）根据此协议：MPS类型1、2、4A，6和7，婴儿发作疾病（IOPD），神经性疾病 Gaucher（2型和3型）和沃尔曼病。我们将注册10个母亲 - 供应ERT 从妊娠18周开始，每2-4周通过脐静脉每2-4周开始。我们将评估安全性和这种产前疗法的可行性，以及ERT在解决胎儿表现方面的功效（如果存在）并改善包括神经和心脏功能，活动性和生长在内的长期结局。（目标1）。我们还将通过评估酶槽水平来检查IUERT的药代动力学和药效学整个妊娠以及出生前后疾病特异性溶酶体积累的水平（AIM 2）。最后，我们将评估子宫内是否暴露于重组酶会诱导耐受性，因为通过缺乏抗药物抗体和酶特异性调节性T细胞的产生（目标3）确定。在过去一年，我们的团队成功地用IOPD对待了胎儿（前两个兄弟姐妹很严重心肌病并遭受围产期灭亡）；该患者在多个产前酶后期出生输注且具有正常的心脏功能。我们已经组建了一个多学科团队，并与关于LSD的生化分析的几位专家。因为我们预计会根据已知的家族史，我们还与多个国家和国际患者倡导小组合作在此试验的设计和执行中包括患者和家人。我们对父母进行了调查评估他们的态度，发现大多数受访者将选择参加I期临床胎儿ERT试验未来妊娠受LSD影响。最终，我们试图改善选择权可用于LSD的家庭和患者。