Tolerance Induction by Neonatal Gene Delivery

通过新生儿基因传递诱导耐受

基本信息

批准号：
7224956
负责人：
KARIN L GAENSLER
金额：
$ 30.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-15 至 2011-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7224956
关键词：
Adoptive Transfer Adult Affect Animals Antigen Presentation Antigen-Presenting Cells Antigens Biodistribution Bioluminescence Cell Maturation Cells Development Disease Disease susceptibility Exhibits Factor IX Funding Gene Delivery Gene Expression Gene Transfer Genes Goals Growth Hemophilia A Hemophilia B Hemorrhage Hereditary Disease Heterophile Antigens Histocompatibility Antigens Class II Human Human Development Immune Immune response Immune system Immunity Immunologic Monitoring Injection of therapeutic agent Intervention Invasive Life Liver Luc Gene Luciferases Mediating Modeling Morbidity - disease rate Mus Muscle Nature Neonatal Pattern Peptides Perinatal Polymerase Chain Reaction Population Pre-Clinical Model Pregnancy Proteins Reporter Reporter Genes Research Personnel Route Serotyping T-Cell Development T-Lymphocyte Testing Time Tissues Transgenes Week adeno-associated viral vector base critical developmental period gene therapy gene transfer vector in utero in vivo mortality neonate nonhuman primate postnatal prevent programs promoter research study response therapeutic gene therapeutic protein tissue tropism transduction efficiency transgene expression uptake vector viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): Development of inhibitory immune responses to vector and transgene products continues to be a major impediment to long-term correction of genetic disorders. To circumvent this problem, we propose to deliver and express genes early in the maturation of the immune system, with the goal of achieving tolerance to therapeutic gene products and gene delivery vectors. This would also enable pre-emptive treatment of genetic Disorders with perinatal morbidity and mortality. In this context, one of the important differences in ontogeny between mouse and human immune systems is that T cell maturation primarily occurs early during the postnatal period in the mouse, but during mid-gestation in human development. Thus, the'immunological maturity of postnatal mice within the first 3 weeks of life represents a more relevant preclinical model to test strategies for perinatal gene delivery and induction of immunotolerance in humans. Therefore, the overall goal of this revised proposal is to develop strategies for induction of immunotolerance to AAV vector- mediated delivery and expression of transgenes in neonatal mice. Throughout, we will (1) compare bio- distribution, level, and duration of gene expression after primary neonatal delivery and secondary adult re- challenge with highly efficient AAV 1 and 8 serotype vectors, (2) monitor immune responses to the vectors and an intracellular reporter, luciferase, or a secreted therapeutic protein, Factor IX, and (3) define the critical period in the first 3 weeks of life when induction of tolerance is feasible. We will also examine whether differences in AAV 1 vs. 8 tissue tropism affect immune response, and whether the route of administration (IV or IP delivery) affects immune responses to human Factor IX in normal and hemophilic animals. Finally, through adoptive transfer and immunodepletion experiments, we will identify specific immune mechanisms that may influence the persistence or abrogation of gene expression following neonatal gene delivery and adult re-challenge with AAV-murine F.IX vectors in hemophilic animals. RELEVANCE. These studies will define a period in immune ontogeny when viral gene delivery vectors can be repeatedly injected and expressed without eliciting inhibitory immune responses that limit therapeutic gene expression. Furthermore, for many genetic disorders, intervention in the perinatal period to correct the disorder would limit or abrogate the development of irrevocable, often lethal consequences of the disease.

描述（由申请人提供）：抑制性免疫反应对载体和转基因产物的发展仍然是对遗传疾病长期纠正的主要障碍。为了解决这个问题，我们建议在免疫系统成熟的早期传递和表达基因，以实现对治疗基因产物和基因递送载体的耐受性。这也将使围产期发病率和死亡率的遗传疾病进行先发制人的治疗。在这种情况下，小鼠和人免疫系统之间的个体发育的重要差异之一是，T细胞成熟主要发生在小鼠产后的早期，但在人类发育的妊娠中期。因此，在生命的前三周内，产后小鼠的免疫学成熟是一种更相关的临床前模型，用于测试围产期基因递送和诱导人类免疫耐药性的策略。因此，这项修订的提案的总体目标是制定诱导AAV载体介导的介导的免疫耐受性的策略，而新生儿小鼠中转基因的表达。在整个过程中，我们将（1）比较原发性新生儿分娩后基因表达的水平，水平和持续时间，以及高效的AAV 1和8血清型向量，（2）监测对载体的免疫反应和细胞内报告剂，荧光素酶，或者是一个秘密的蛋白质，（3周）的生命（3），（3）的生命（3）定期（3）始终为（3）。宽容是可行的。我们还将检查AAV 1与8组织的差异是否会影响免疫反应，以及给药途径（IV或IP递送）是否影响正常和血友病动物中对人为IX的免疫反应。最后，通过过继转移和免疫部门实验，我们将确定可能影响新生儿基因递送后基因表达的持久性或废除基因表达的特定免疫机制，并与成年动物中的AAV-丝氨酸F.IX载体重新促进了基因表达。关联。这些研究将定义一个免疫个体发育中的时期，可以反复注射病毒基因递送载体，而不会引起抑制性免疫反应，从而限制了治疗基因表达。此外，对于许多遗传疾病，在围产期纠正疾病的干预措施将限制或消除不可撤销的，通常是致命的疾病后果。