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
基本信息
- 批准号:6801420
- 负责人:
- 金额:$ 26.22万
- 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:2003-10-03 至 2007-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant):
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficient alpha-L-iduronidase (IDUA)activity. It results in bone and joint abnormalities, cardiac disease, growth retardation, and corneal clouding, and is usually associated with early death and mental retardation. We have previously demonstrated that neonatal injection of a retroviral vector expressing beta-glucuronidase (GUSB) results in efficient transduction of hepatocytes, which secrete mannose 6-phosphorylated GUSB that can be taken up by other organs. This results in improvement in many of the clinical manifestations of the related disorder, MPS VII, in both mice and dogs. There are two reasons for extending this approach to treat MPS I, which is the goal of this project. First, MPS I dogs usually make potent immune responses to IDUA, which will allow the immunological consequences of this gene therapy approach to be better understood. This will be important "to define prior to using this approach in humans with null mutations". Second, MPS I is the most common of the MPS syndromes with an incidence of 1:100,000 live births, while MPS VII is quite rare. The higher incidence of MPS I will facilitate identifying patients to treat should this approach prove to be safe and effective. This project will involve development of a retroviral vector expressing the canine IDUA cDNA. Initial studies will deliver the vector to hepatocytes of newborn mice or dogs with MPS I. Animals will be evaluated for enzyme levels in organs and blood, immunological responses to clDUA, and clinical and pathological manifestations of lysosomal storage disease. Although treatment of newborns has many advantages and may reduce immunological responses, most patients with MPS I are diagnosed well after birth. We will therefore test if this retroviral vector can be delivered to juvenile animals with MPS I, and if this is more likely to generate an immune response. If immune responses develop, immune modulators will be given at the time of gene therapy to prevent their development. Finally, one of the devastating features of severe MPS is mental retardation, and this liver-directed approach may be ineffective at treating this aspect of disease. We will therefore test if modification of the IDUA protein produced by the liver can improve delivery to the brain from the blood. This project may result in application of this approach for patients with
MPS I in the future, although clinical trials are not proposed here.
描述(由申请人提供):
粘多糖样沉积症I(MPS I)是一种由于α-L-艾杜糖醛酸酶(IDUA)活性缺陷引起的溶酶体贮积病。它导致骨和关节异常、心脏病、生长迟缓和角膜混浊,并且通常与早死和智力迟钝有关。我们先前已经证明,新生儿注射表达β-葡萄糖醛酸酶(GUSB)的逆转录病毒载体导致肝细胞的有效转导,肝细胞分泌甘露糖6-磷酸化的GUSB,可以被其他器官吸收。这导致小鼠和犬中相关疾病MPS VII的许多临床表现得到改善。将这种方法扩展到治疗MPS I有两个原因,这是本项目的目标。首先,MPS I犬通常对IDUA产生有效的免疫应答,这将使这种基因治疗方法的免疫学后果得到更好的理解。这将是重要的“在使用这种方法之前,在人类与无效突变”。其次,MPS I是最常见的MPS综合征,发病率为1:100,000活产,而MPS VII非常罕见。MPS I的发生率较高,如果该方法被证明是安全有效的,将有助于确定患者进行治疗。该项目将涉及表达犬IDUA cDNA的逆转录病毒载体的开发。最初的研究将把载体输送到患有MPS I的新生小鼠或狗的肝细胞中。将评价动物器官和血液中的酶水平、对clDUA的免疫应答以及溶酶体贮积病的临床和病理学表现。虽然新生儿治疗有许多优点,并可能减少免疫反应,但大多数MPS I患者在出生后就被诊断出来。因此,我们将测试这种逆转录病毒载体是否可以递送给患有MPS I的幼年动物,以及这是否更有可能产生免疫应答。如果免疫反应发展,免疫调节剂将在基因治疗时给予,以防止其发展。最后,严重MPS的破坏性特征之一是精神发育迟滞,这种肝脏导向的方法在治疗疾病的这一方面可能无效。 因此,我们将测试由肝脏产生的IDUA蛋白的修饰是否可以改善从血液到大脑的递送。该项目可能会导致这种方法在以下患者中的应用
MPS I在未来,虽然临床试验不建议在这里。
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)
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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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 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:
$ 26.22万 - 项目类别: