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

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。由此可见,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)的情况。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, 胎儿ERT试验是为了防止未来怀孕受迷幻药影响最终,我们寻求改善选择 提供给LSD的家庭和患者。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Tippi Mackenzie其他文献

Tippi Mackenzie的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Tippi Mackenzie', 18)}}的其他基金

Developing gene therapy strategies to treat alpha thalassemia
开发治疗α地中海贫血的基因治疗策略
  • 批准号:
    10345618
  • 财政年份:
    2022
  • 资助金额:
    $ 68.19万
  • 项目类别:
Developing gene therapy strategies to treat alpha thalassemia
开发治疗α地中海贫血的基因治疗策略
  • 批准号:
    10545021
  • 财政年份:
    2022
  • 资助金额:
    $ 68.19万
  • 项目类别:
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
  • 批准号:
    10707992
  • 财政年份:
    2022
  • 资助金额:
    $ 68.19万
  • 项目类别:
Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens
自身免疫调节基因(Aire)介导的对妊娠相关自身抗原的耐受性
  • 批准号:
    10219063
  • 财政年份:
    2019
  • 资助金额:
    $ 68.19万
  • 项目类别:
Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens
自身免疫调节基因(Aire)介导的对妊娠相关自身抗原的耐受性
  • 批准号:
    10455466
  • 财政年份:
    2019
  • 资助金额:
    $ 68.19万
  • 项目类别:
Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens
自身免疫调节基因(Aire)介导的对妊娠相关自身抗原的耐受性
  • 批准号:
    10684826
  • 财政年份:
    2019
  • 资助金额:
    $ 68.19万
  • 项目类别:
T cell activation and the breakdown of maternal-fetal tolerance in preterm labor
早产中 T 细胞激活和母胎耐受性崩溃
  • 批准号:
    9079351
  • 财政年份:
    2015
  • 资助金额:
    $ 68.19万
  • 项目类别:
T cell activation and the breakdown of maternal-fetal tolerance in preterm labor
早产中 T 细胞激活和母胎耐受性崩溃
  • 批准号:
    9280814
  • 财政年份:
    2015
  • 资助金额:
    $ 68.19万
  • 项目类别:
Maternal and fetal immune responses to in utero HSC transplantation
母体和胎儿对宫内 HSC 移植的免疫反应
  • 批准号:
    8465803
  • 财政年份:
    2010
  • 资助金额:
    $ 68.19万
  • 项目类别:
Maternal and fetal immune responses to in utero HSC transplantation
母体和胎儿对宫内 HSC 移植的免疫反应
  • 批准号:
    7771488
  • 财政年份:
    2010
  • 资助金额:
    $ 68.19万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 68.19万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了