Salivary gland-based gene therapy for lysosomal storage diseases

基于唾液腺的溶酶体贮积病基因治疗

基本信息

项目摘要

DESCRIPTION (provided by applicant): Recent studies have demonstrated that an intrinsic endocrine pathway is present in salivary glands, distinct from the classical exocrine pathway whereby digestive enzymes are produced and secreted into the saliva by the salivary glands under normal physiological conditions. As such, this distinct endocrine pathway has recently been shown to be capable of robust synthesis and secretion of non-regulated (i.e. constitutive) gene products into the vascular space as a result of retroductal administration of a gene therapy vector. Fabry disease is a member of the family of lysosomal storage diseases, a group of monogenic disorders characterized by deficiency or lack of a class of enzymes (e.g. alpha-Galactosidase A in Fabry disease) involved in intra-lysosomal catabolism of macromolecules. An interesting feature of these diseases is the observation that tissues lacking the specific lysosomal enzyme implicated in the disease are capable of uptake of the specific lysosomal enzyme from the vascular space. This physiology has led to the proposal and subsequent validation of "Enzyme Replacement Therapy" wherein the missing enzyme is produced syntheically and infused intravenously to Fabry patients, resulting in a mitigation of disease symptoms. We seek to combine these emergent technologies into a salivary gland-based gene therapy strategy for Fabry disease in highly relevant mouse knockout model, namely B6;129-Gla(tm1/Kul/J), an alpha- Galactosidase A (-/O) model. We seek to test the hypothesis that an AAV vector containing the sequence for human alpha-Gal A delivered to the salivary glands in alpha-Gal A deficient "Fabry" mice will result in systemic replacement of the enzyme and reversal of the specific systemic biochemical defect underlying Fabry disease. Our specific aims involve: 1) delivery of an alpha-Gal A containing vector to the salivary glands of Fabry mice and biochemical testing of systemic delivery of the enzyme, 2) careful examination of the organ biodistribution of the enzyme, and 3) optimization of dosing and immune physiology to achieve long-term expression of the enzyme. These studies will produce important insights into the technical paramaters of this system, including: longevity of transgene expression, host immune response, and mitigation of Fabry-associated pathology, and form the basis whereby other systemic disorders could be addressed using salivary glands as the biosynthetic site for systemic therapeutics.
描述(由申请人提供):最近的研究表明,唾液腺中存在一种内在内分泌途径,与经典的外分泌途径不同,在正常生理条件下,唾液腺通过外分泌途径产生消化酶并分泌到唾液中。因此,这种独特的内分泌途径最近已显示出由于基因治疗载体的导管后施用,能够稳健地合成和分泌非调节的(即组成型)基因产物进入血管空间。法布里病是溶酶体贮积病家族的成员,溶酶体贮积病是一组单基因疾病,其特征在于参与大分子的溶酶体内催化的一类酶(例如法布里病中的α-半乳糖苷酶A)的缺乏或缺乏。这些疾病的一个有趣的特征是观察到缺乏与疾病有关的特异性溶酶体酶的组织能够从血管空间摄取特异性溶酶体酶。这种生理学导致了“酶替代疗法”的提出和随后的验证,其中合成产生缺失的酶并静脉内输注给法布里病患者,从而减轻疾病症状。我们试图将这些新兴技术联合收割机结合到高度相关的小鼠敲除模型中,即B6;129-Gla(tm 1/Kul/J),一种α-半乳糖苷酶A(-/O)模型,用于法布里病的基于唾液腺的基因治疗策略中。我们试图检验这样的假设:将含有人α-Gal A序列的AAV载体递送到α-Gal A缺陷型“法布里病”小鼠的唾液腺中,将导致酶的系统性替代和法布里病潜在的特定系统性生化缺陷的逆转。我们的具体目标包括:1)将含有α-Gal A的载体递送至法布里病小鼠的唾液腺并对酶的全身递送进行生物化学测试,2)仔细检查酶的器官生物分布,以及3)优化剂量和免疫生理学以实现酶的长期表达。这些研究将对该系统的技术参数产生重要的见解,包括:转基因表达的寿命,宿主免疫反应和法布里相关病理的缓解,并形成使用唾液腺作为全身治疗的生物合成位点来解决其他全身性疾病的基础。

项目成果

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Michael J. Passineau其他文献

Michael J. Passineau的其他文献

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{{ truncateString('Michael J. Passineau', 18)}}的其他基金

Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8390748
  • 财政年份:
    2012
  • 资助金额:
    $ 9.09万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8514570
  • 财政年份:
    2012
  • 资助金额:
    $ 9.09万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8668774
  • 财政年份:
    2012
  • 资助金额:
    $ 9.09万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8878038
  • 财政年份:
    2012
  • 资助金额:
    $ 9.09万
  • 项目类别:
Ultrasound-Assisted Gene Transfer of Anti-Biofilm Peptides to the Salivary Gland
超声辅助将抗生物膜肽基因转移至唾液腺
  • 批准号:
    8225139
  • 财政年份:
    2011
  • 资助金额:
    $ 9.09万
  • 项目类别:
Ultrasound-Assisted Gene Transfer of Anti-Biofilm Peptides to the Salivary Gland
超声辅助将抗生物膜肽基因转移至唾液腺
  • 批准号:
    8041732
  • 财政年份:
    2011
  • 资助金额:
    $ 9.09万
  • 项目类别:
Salivary Gland-Based Gene Therapy for Lysosomal Storage Diseases
基于唾液腺的溶酶体贮积病基因治疗
  • 批准号:
    7814758
  • 财政年份:
    2009
  • 资助金额:
    $ 9.09万
  • 项目类别:
Salivary Gland-Based Gene Therapy for Lysosomal Storage Diseases
基于唾液腺的溶酶体贮积病基因治疗
  • 批准号:
    7848134
  • 财政年份:
    2008
  • 资助金额:
    $ 9.09万
  • 项目类别:
Salivary Gland-Based Gene Therapy for Lysosomal Storage Diseases
基于唾液腺的溶酶体贮积病基因治疗
  • 批准号:
    7623847
  • 财政年份:
    2008
  • 资助金额:
    $ 9.09万
  • 项目类别:
Salivary Gland-Based Gene Therapy for Lysosomal Storage Diseases
基于唾液腺的溶酶体贮积病基因治疗
  • 批准号:
    7616605
  • 财政年份:
    2008
  • 资助金额:
    $ 9.09万
  • 项目类别:

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通过突变α-半乳糖苷酶的结构模型预测临床表型
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