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：
10707992
负责人：
Tippi Mackenzie
金额：
$ 66.63万
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/10707992
关键词：
Address Affect Antibodies Antibody Therapy Attitude Back Biochemical Birth Blood Blood Transfusion Brain Cardiac Cardiomyopathies Child Clinical Trials Collaborations Data Development Diagnosis Disease Edema Education Enrollment Ensure Enzyme Induction Enzymes Exposure to FDA approved Family Fetal safety Fetus Functional disorder Funding Future 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 Penetration 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 blood-brain barrier crossing 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.

溶酶体贮积症 (LSD) 是由关键酶和酶突变引起的严重疾病估计发病率为五千分之一到五千五百分之一的活产儿。患有 LSD 的患者严重围产期发病和死亡的风险增加，有些甚至无法存活到出生。目前的儿科患者的治疗酶替代疗法（ERT）受到三个方面的限制：器官特异性表现的逐渐发展（有时在子宫内），抗 ERT 的发展抗体，以及 ERT 无法穿过血脑屏障来解决神经系统影响。因此，有尚未满足的医疗需求是从出生前开始为 LSD 患者开发更有效的疗法。在一个在 7 型粘多糖贮积症 (MPS7) 小鼠模型中，我们表明，子宫内 ERT (IUERT) 随后是产后 ERT 提高了生存率，跨越了血脑屏障，改善了疾病并诱导了耐受性到 ERT。基于这些结果，我们获得了一项 IND 来进行首次人体、非随机、单一的研究开展 IUERT 的 1 期临床试验，并寻求资金支持该临床试验。由于每个单独的 LSD 都是罕见，但它们具有相似的病理生理学，我们纳入了八种不同的 LSD（及其特定的 ERT）根据该方案：MPS 1、2、4a、6 和 7 型、婴儿发病庞贝病 (IOPD)、神经病性戈谢病（2 型和 3 型）和沃尔曼病。我们将招募 10 对母胎进行 ERT 输注从妊娠 18 周后开始，每 2-4 周通过脐静脉注射一次。我们将评估安全性和这种产前治疗的可行性，以及 ERT 在解决胎儿表现（如果存在）方面的功效改善长期结果，包括神经和心脏功能、活动能力和生长。（目标 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整个妊娠期，以及出生前后疾病特异性溶酶体积累水平（目标 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性，因为由缺乏抗药物抗体和酶特异性调节性 T 细胞的产生决定（目标 3）。在去年，我们的团队成功治疗了一名患有 IOPD 的胎儿（其前两个兄弟姐妹患有严重的 IOPD）心肌病并遭受围产期死亡）；该患者在多次产前酶治疗后足月出生输液并具有正常的心脏功能。我们组建了一支多学科团队并与几位 LSD 生化分析专家。由于我们预计根据已知的情况来识别胎儿家族史，我们还与多个国家和国际患者倡导团体合作让患者和家属参与本试验的设计和执行。我们进行了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 期临床对于未来受 LSD 影响的妊娠进行胎儿 ERT 试验。最终，我们寻求改进选项可供患有 LSD 的家庭和患者使用。