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

批准号：
7244947
负责人：
Michael J. Passineau
金额：
$ 9.09万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244947
关键词：
Address Alpha-galactosidase Biochemical Biodistribution Bioreactors Blood Blood Vessels Catabolism Class Clinical Trials Code Condition Defect Disease Dose Emerging Technologies Endocrine Engineering Enzymes Evaluation Fabry Disease Face Failure Family member Funding Galactosidase Gene Transduction Agent Human Immune Immune Response Genes Immune response Intervention Knockout Mice Lead Light Longevity Lysosomal Storage Diseases Measures Modeling Mus Occupations Organ Pathology Pathway interactions Patients Pharmaceutical Preparations Physiological Physiology Plasma Proteins Recombinants Research Research Personnel Saliva Salivary Salivary Glands Site Standards of Weights and Measures Symptoms System Techniques Technology Testing Therapeutic Therapeutic Studies Tissues Transgenes Translating Translations Validation Viral Vector Virus adeno-associated viral vector base concept enzyme activity enzyme replacement therapy gene therapy human disease in vivo insight interest macromolecule pre-clinical programs research study response therapeutic protein therapeutic transgene transgene expression uptake vector

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，唾液腺中存在内在内分泌途径，与经典的外分泌途径不同，在正常的生理条件下，唾液腺产生消化酶并将其分泌到唾液中。因此，这种独特的内分泌途径最近已被证明能够通过导管后施用基因治疗载体将非调节（即组成型）基因产物稳健地合成和分泌到血管空间中。法布里病是溶酶体贮积病家族的一员，这是一组单基因疾病，其特征是缺乏或缺乏参与溶酶体内大分子分解代谢的一类酶（例如法布里病中的α-半乳糖苷酶 A）。这些疾病的一个有趣特征是观察到缺乏与疾病有关的特定溶酶体酶的组织能够从血管空间摄取特定溶酶体酶。这种生理学导致了“酶替代疗法”的提议和随后的验证，其中缺失的酶是合成产生的，并静脉注射给法布里患者，从而减轻疾病症状。我们寻求将这些新兴技术结合到高度相关的小鼠敲除模型中针对法布里病的基于唾液腺的基因治疗策略中，即 B6;129-Gla(tm1/Kul/J)，一种 α-半乳糖苷酶 A (-/O)模型。我们试图检验这样的假设：将含有人 α-Gal A 序列的 AAV 载体递送至 α-Gal A 缺陷的“Fabry”小鼠的唾液腺，将导致酶的系统性替换并逆转特定的系统性生化缺陷潜在的法布里病。我们的具体目标包括：1) 将含有 α-Gal A 的载体递送至 Fabry 小鼠的唾液腺，并对酶的全身递送进行生化测试，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。这些研究将为该系统的技术参数提供重要的见解，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生物合成来解决其他系统性疾病的基础全身治疗的场所。