Toxicology studies for gene-modified stem cell transplantation for cystinosis

基因修饰干细胞移植治疗胱氨酸病的毒理学研究

基本信息

  • 批准号:
    8560474
  • 负责人:
  • 金额:
    $ 26.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-06 至 2015-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cystinosis is a metabolic hereditary disease characterized by intracellular accumulation of cystine. Affected individuals typically present with proximal tubulopathy before one year of age and eventually progress to end- stage renal failure. Cystine accumulation leads to multi-organ dysfunction. The drug cysteamine reduces the intracellular cystine content. However, cysteamine does not prevent the proximal tubulopathy nor the end- stage renal failure and only delay the progression of the disease. The long-term objective of this project is to develop a new treatment for cystinosis by transplantation of autologous Hematopoietic Stem and Progenitor Cells (HSPC) genetically modified ex vivo to express a functional CTNS gene. Using the mouse model for cystinosis, the Ctns-/- mice, we showed that transplantation of syngeneic Sca1+ HSPC expressing Ctns resulted in abundant bone marrow-derived cell engraftment and significant reductions of cystine content in all the tissues tested. This treatment also prevented the progression of kidney dysfunction. We obtained the same results with ex vivo transduced HSPC using our lentiviral vector construct, pCCL-CTNS, and established the first proof-of-concept in the Ctns-/- mice that this strategy could work in young patients with cystinosis before significant disease progression. After obtaining the approval from the FDA to move forward to a pre- Investigator New Drug (IND) application, we are now proposing the pharmacology/toxicology studies required to obtain an IND for a phase I a clinical trial for cystinosis. This treatment would represent a life-long theray that may prevent kidney transplantation and long-term complications associated with cystinosis. Lentiviral vectors have proven its efficacy for long-term HSPC transduction in mice but also in humans. All the pharmacology/toxicology studies will be done with a pre-clinical batch of the vector pCCL-CTNS produced under Good Manufacturing Practice. In Specific aim 1, we propose to optimize the transduction of human CD34+ cells using our vector pCCL-CTNS and to test the capacity of the transduced cells to go through lineage-committed progenitors without becoming leukemic using the Colony-Forming Units (CFU) assay. The other in vitro assay to assess genotoxicity of integrating viral vectors is the In Vitro Immortalization (IVIM) assay using murine lineage-negative bone marrow cells. Vector Copy Numbers (VCN) and Vector Integration Sites (VIS) will be determined in the final colonies and clones for both assays. In Specific aim 2, we will test the efficacy and safety of this strategy in vivo using murine Sca1+ HSPC ex vivo transduced by pCCL-CTNS and transplanted in primary and secondary recipient Ctns-/- mice. Efficacy will be measured by CTNS expression in blood and tissue samples, tissue cystine levels and renal function. Toxicity will be determined by comprehensive clinical and histological tissue analyses, by assessing VCN and VIS in myeloid and lymphoid cells and detecting potential antibody immunity to CTNS proteins. This work represents the last steps towards a phase I clinical trial for cystinosis and is also a proof of concept to treat other lysosomal storage disorders.
描述(由申请人提供):胱氨酸病是一种代谢性遗传性疾病,其特征为胱氨酸在细胞内蓄积。受影响的个人通常表现为 近端肾小管病变,并最终进展为终末期肾衰竭。胱氨酸蓄积导致多器官功能障碍。药物半胱胺降低细胞内胱氨酸含量。然而,半胱胺不能预防近端小管病变,也不能预防终末期肾衰竭,而只能延缓疾病的进展。该项目的长期目标是通过移植经遗传修饰的自体造血干细胞和祖细胞(HSPC)来开发一种新的胱氨酸病治疗方法,以表达功能性CTNS基因。使用胱氨酸病的小鼠模型,Ctns-/-小鼠,我们表明,移植表达Ctns的同基因Sca1 + HSPC导致大量的骨髓源性细胞植入和所有测试组织中胱氨酸含量的显著降低。该治疗还防止了肾功能障碍的进展。我们使用我们的慢病毒载体构建体pCCL-CTNS用离体转导的HSPC获得了相同的结果,并在Ctns-/-小鼠中建立了第一个概念验证,即该策略可以在显著疾病进展之前在患有胱氨酸病的年轻患者中起作用。在获得FDA批准后,我们将继续进行研究者新药(IND)申请,我们现在提出了获得IND所需的药理学/毒理学研究,用于胱氨酸病的I期临床试验。这种治疗将代表一种终身治疗,可以预防肾移植和与胱氨酸病相关的长期并发症。慢病毒载体已证明其在小鼠中以及在人中长期HSPC转导的功效。所有药理学/毒理学研究将使用根据药品生产质量管理规范生产的载体pCCL-CTNS的临床前批次进行。在具体目标1中,我们提出使用我们的载体pCCL-CTNS优化人CD 34+细胞的转导,并使用集落形成单位(CFU)测定来测试转导的细胞通过谱系定型祖细胞而不变成白血病的能力。评估整合病毒载体的遗传毒性的另一种体外测定法是体外永生化(IVIM)测定法,其使用 鼠谱系阴性骨髓细胞。将在两种试验的最终菌落和克隆中测定载体拷贝数(VCN)和载体整合位点(维斯)。在具体目标2中,我们将使用由pCCL-CTNS离体转导并移植到原代和二代受体Ctns-/-小鼠中的鼠Sca1 + HSPC在体内测试该策略的有效性和安全性。将通过血液和组织样本中的CTNS表达、组织胱氨酸水平和肾功能来测量疗效。将通过全面的临床和组织学组织分析,通过评估骨髓和淋巴细胞中的VCN和维斯以及检测对CTNS蛋白的潜在抗体免疫来确定毒性。这项工作代表了胱氨酸病I期临床试验的最后一步,也是治疗其他溶酶体贮积症的概念证明。

项目成果

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Stephanie Cherqui其他文献

Stephanie Cherqui的其他文献

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{{ truncateString('Stephanie Cherqui', 18)}}的其他基金

Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia
造血干细胞基因治疗弗里德赖希共济失调
  • 批准号:
    10413884
  • 财政年份:
    2018
  • 资助金额:
    $ 26.97万
  • 项目类别:
Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia
造血干细胞基因治疗弗里德赖希共济失调
  • 批准号:
    9635234
  • 财政年份:
    2018
  • 资助金额:
    $ 26.97万
  • 项目类别:
Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia
造血干细胞基因治疗弗里德赖希共济失调
  • 批准号:
    10176616
  • 财政年份:
    2018
  • 资助金额:
    $ 26.97万
  • 项目类别:
Hematopoietic stem cell-based therapy for Friedrich Ataxia
基于造血干细胞的弗里德里希共济失调疗法
  • 批准号:
    8807433
  • 财政年份:
    2014
  • 资助金额:
    $ 26.97万
  • 项目类别:
Toxicology studies for gene-modified stem cell transplantation for cystinosis
基因修饰干细胞移植治疗胱氨酸病的毒理学研究
  • 批准号:
    8715802
  • 财政年份:
    2013
  • 资助金额:
    $ 26.97万
  • 项目类别:
Lentiviral-transduced hematopoictic stem cell transplantation for cystinosis
慢病毒转导的造血干细胞移植治疗胱氨酸病
  • 批准号:
    8024643
  • 财政年份:
    2011
  • 资助金额:
    $ 26.97万
  • 项目类别:
Lentiviral-transduced hematopoictic stem cell transplantation for cystinosis
慢病毒转导的造血干细胞移植治疗胱氨酸病
  • 批准号:
    8387022
  • 财政年份:
    2011
  • 资助金额:
    $ 26.97万
  • 项目类别:
Lentiviral-transduced hematopoictic stem cell transplantation for cystinosis
慢病毒转导的造血干细胞移植治疗胱氨酸病
  • 批准号:
    8627162
  • 财政年份:
    2011
  • 资助金额:
    $ 26.97万
  • 项目类别:
Lentiviral-transduced hematopoictic stem cell transplantation for cystinosis
慢病毒转导的造血干细胞移植治疗胱氨酸病
  • 批准号:
    9029117
  • 财政年份:
    2011
  • 资助金额:
    $ 26.97万
  • 项目类别:
Kidney-targeted gene delivery for cystinosis
胱氨酸病的肾脏靶向基因递送
  • 批准号:
    8323892
  • 财政年份:
    2011
  • 资助金额:
    $ 26.97万
  • 项目类别:

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