Gene Therapy for Blood Protein Deficiencies
血液蛋白缺乏症的基因治疗
基本信息
- 批准号:6687743
- 负责人:
- 金额:$ 26.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-01 至 2005-12-31
- 项目状态:已结题
- 来源:
- 关键词:Retroviridaeanimal genetic material tagantibody formationartificial immunosuppressionbiotechnologycell mediated lymphocytolysis testcoagulation factor IXcomplementary DNAcytotoxic T lymphocytedisease /disorder modeldogsenzyme linked immunosorbent assaygene expressiongene therapyhemophilia Bhemorrhagehuman genetic material tagimmunomodulatorslaboratory mouseliver cellsmature animalnewborn animalsnonhuman therapy evaluationtechnology /technique developmenttransfection /expression vector
项目摘要
Hemophilia B occurs in 1:30,000 males and is associated with a life-long bleeding diathesis. Although IV injection of Factor IX can prevent or stop bleeding, this treatment is inconvenient, expensive, and can transmit infections. Hepatic gene therapy could permanently correct the clinical manifestations of hemophilia. Retroviral vectors (RV) can result in long-term and therapeutic levels of expression of coagulation factors from the liver in rodents, and are currently being used in a clinical trial for Hemophilia A in humans. However, there are two major problems that must be solved before RV-mediated hepatic gene therapy will be used routinely: 1) identify ways to achieve a higher efficiency of stable gene transfer without major toxicity; and 2) identify methods for blocking an immune response to the therapeutic gene in the context of RV-mediated hepatic gene therapy. This project will address both of these issues. The first aim is to determine if delivery of an RV expressing the canine Factor IX (cFIX) cDNA into the liver can reduce the bleeding manifestations of Hemophilia B dogs obtained from a colony that rarely makes antibodies to the canine protein. This should allow us to quantify gene expression without the confounding issue of an immune response. Initial studies will use neonatal dogs, as their high baseline level of hepatocyte replication allows transduction of 9 percent of liver cells. Subsequent studies will use hepatocyte growth factor to induce replication in young adult dogs. Animals will be evaluated for cFIX levels, development of antibodies, bleeding, and for other adverse effects. The second aim will address the second major problem of RV-mediated hepatic gene therapy, that of immune responses to the therapeutic gene product. In this aim, we will try to block immune responses to the de novo expression of a transgene from an RV in mice by either performing neonatal gene transfer, or by injecting immunoinhibitory agents at the time of gene therapy in young adults. Although mice are optimal for initial studies due to cost considerations, approaches that function in inbred mice sometimes fail in outbred larger animals. We will therefore test any immunomodulatory approaches that function in mice for their efficacy in normal and Hemophilia B dogs in Aim III. Success in this project might lead to a safe, effective, and permanent therapy for Hemophilia B.
血友病B发生在1:30,000的男性中,并与终身出血素质相关。 虽然IV注射因子IX可以预防或止血,但这种治疗不方便,昂贵,并且可能传播感染。 肝脏基因治疗可以永久纠正血友病的临床表现。 逆转录病毒载体(RV)可导致啮齿动物肝脏中凝血因子的长期和治疗水平表达,目前正用于人类血友病A的临床试验。 然而,在常规使用RV介导的肝脏基因治疗之前,必须解决两个主要问题:1)确定在没有重大毒性的情况下实现更高效率的稳定基因转移的方法;和2)确定在RV介导的肝脏基因治疗背景下阻断对治疗基因的免疫反应的方法。 本项目将解决这两个问题。第一个目的是确定将表达犬因子IX(cFIX)cDNA的RV递送到肝脏中是否可以减少从很少产生犬蛋白抗体的菌落获得的血友病B犬的出血表现。 这应该使我们能够量化基因表达,而不会出现免疫反应的混淆问题。 最初的研究将使用新生狗,因为它们的高基线肝细胞复制水平允许转导9%的肝细胞。后续研究将使用肝细胞生长因子在年轻成年犬中诱导复制。 将评价动物的cFIX水平、抗体形成、出血和其他不良反应。 第二个目标将解决RV介导的肝脏基因治疗的第二个主要问题,即对治疗性基因产物的免疫反应。 在这一目标中,我们将尝试通过进行新生儿基因转移或在年轻成人中进行基因治疗时注射免疫抑制剂来阻断小鼠中RV转基因从头表达的免疫反应。 尽管出于成本考虑,小鼠是初始研究的最佳选择,但在近交系小鼠中起作用的方法有时会在远交系较大动物中失败。因此,我们将在Aim III中检测在小鼠中起作用的任何免疫调节方法在正常和血友病B犬中的有效性。 该项目的成功可能为血友病B提供安全、有效和永久的治疗。
项目成果
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Katherine P. Ponder其他文献
859. Cats Produce a CTL Response That Reduces Expression of Human Factor IX and Human Factor VIII after Neonatal Gene Transfer and Represent an Important Model for Translation into Humans
- DOI:
10.1016/j.ymthe.2006.08.945 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Lingfei Xu;Manxue Mei;Mark E. Haskins;Patty O'Donnell;Karyn Cullen;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
73. Cats Produce a Potent CTL Response after Neonatal Gene Therapy That Can Be Blocked with CTLA4-Ig
- DOI:
10.1016/j.ymthe.2006.08.090 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Katherine P. Ponder;Baomei Wang;Ping Wang;Xiucui Ma;Ramin Herati;Bin Wang;Karyn Cullen;Patty O'Donnell;Tina M. Primeau;Mark E. Haskins - 通讯作者:
Mark E. Haskins
403. Long-Term, High alpha-L-iduronidase Expression in MPS I Dogs Following Neonatal, Intravenous, Retroviral Vector Gene Therapy
- DOI:
10.1016/j.ymthe.2006.08.466 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Anne Traas;Ping Wang;Xiucui Ma;Patricia O'Donnell;Meg Sleeper;Gus Aguirre;Mark Haskins;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
Effects of neonatal enzyme replacement therapy and simvastatin treatment on cervical spine disease in mucopolysaccharidosis type I dogs
- DOI:
10.1016/j.ymgme.2013.12.244 - 发表时间:
2014-02-01 - 期刊:
- 影响因子:
- 作者:
Lachlan J. Smith;Joseph A. Chiaro;Patricia O'Donnell;Neil R. Malhotra;Eileen M. Shore;Katherine P. Ponder;Mark E. Haskins - 通讯作者:
Mark E. Haskins
984. Liver Restricted Expression of Canine Iduronidase Does Not Prevent a CTL Response in Adult MPS I Mice after Retroviral Vector-Mediated Gene Therapy, but Transient Immunomodulation with CTLA4-Ig Combined with Anti-CD4 or Anti- CD40 Ligand Does
- DOI:
10.1016/j.ymthe.2006.08.1077 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Xiucui Ma;Ramin Herati;Yuli Liu;Anne K. Hennig;Attila Kovacs;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
Katherine P. Ponder的其他文献
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{{ truncateString('Katherine P. Ponder', 18)}}的其他基金
PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII
粘多糖贮积症 I 和 VII 疾病的发病机制
- 批准号:
7923965 - 财政年份:2009
- 资助金额:
$ 26.68万 - 项目类别:
PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII
粘多糖贮积症 I 和 VII 疾病的发病机制
- 批准号:
7729874 - 财政年份:2009
- 资助金额:
$ 26.68万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
8245107 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
Retroviral Vector-mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
6801420 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7752811 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7581492 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
Retroviral Vector-mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
6813222 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7623653 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
8462966 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别:
Retroviral Vector-Mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
7446367 - 财政年份:2003
- 资助金额:
$ 26.68万 - 项目类别: