Intra-arterial Gene Therapy for LINCL

 描述（由申请方提供）：本项目的总体目标是开发一种治疗和评价一致致死性儿科神经退行性疾病的新策略，该疾病称为晚期婴儿神经元蜡样脂褐质沉积症（LINCL），是一种Batten病。具体来说，我们将研究的价值动脉内（IA）交付的病毒载体介导的基因治疗的临床前模型LINCL，并开发成像技术，以评估疾病的严重程度，载体分布和治疗效果。目前，没有LINCL的治疗已被证明在人类中产生显着的生存或生活质量的好处，突出了开发新的治疗策略的迫切需要。LINCL是由CLN 2基因突变引起的常染色体隐性遗传神经退行性溶酶体贮积病。该基因的缺陷导致缺乏三肽基肽酶-1（TPP-I），并导致类似于脂褐质的自发荧光物质在溶酶体中积累，在10-12岁时发生广泛的进行性神经变性和死亡。一种在动物和临床研究中都显示出前景的LINCL治疗是使用腺相关病毒载体（AAV）的基因治疗。然而，目前这种疗法是通过直接输注给大脑的，这需要进行大手术。相反，我们建议开发IA注射技术，从而通过血管内导管将治疗直接输送到向受疾病折磨的组织供血的动脉。我们将解决三个具体目标：具体目标1：使用两种血清型AAV（即AAVrh.10CLN2和AAV 9 CLN 2）的动脉内递送在小鼠脑中表达CLN 2基因。动脉内和静脉内给药将与我们早期使用直接输注的研究进行比较。具体目标2：开发用于测量LINCL疾病严重程度、病毒载体递送和治疗反应的非侵入性工具。我们将开发一种多组分磁共振成像生物标志物面板来测量LINCL的严重程度，并使用一种涉及正电子发射断层扫描的新策略来评估大脑中的矢量分布。具体目的3：使用AAVrh.10CLN2或AAV 9 CLN 2的动脉内递送来阻止CLN 2-/-小鼠中的LINCL疾病进展。将进行存活研究，并使用成像、行为和组织学方法评价小鼠。如果我们成功了，这项工作将导致在人类受试者中进行临床试验。此外，我们将推进该领域的动脉内药物输送的基因工程小鼠成功的基因治疗的IA交付标准化的管理参数，以中枢神经系统。最后，该项目的许多结果，包括基因递送和成像的结果，将不是特定于LINCL，但将适用于广泛的神经系统和其他疾病。

 DESCRIPTION (provided by applicant): The overall goal of this project is to develop a new strategy for treatment and evaluation of a uniformly fatal pediatric neurodegenerative disease known as Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), which is a form of Batten disease. Specifically, we will examine the value of intra-arterial (IA) delivery of viral vector mediated gene therapy in a preclinical model of LINCL, and develop imaging techniques to assess disease severity, vector distribution, and therapeutic efficacy. At present no therapy for LINCL has been shown to yield significant survival or quality of life benefits in humans, highlighting the critical need for the development of new therapeutic strategies. LINCL is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations of the CLN2 gene. A defect in this gene results in a lack of tripeptidyl peptidase-1 (TPP-I), and a resultant accumulation of autofluorescent material resembling lipofuscin in lysosomes, with widespread progressive neurodegeneration and death occurring by the ages of 10-12 years. One treatment for LINCL that has shown promise in both animal and clinical studies is gene therapy using adeno-associated viral vectors (AAV). However, currently this therapy is administered to the brain by direct infusion, a procedure that requires major surgery. Instead, we propose to develop IA injection techniques whereby therapy is delivered through an endovascular catheter directly to the arteries that supply blood to the disease afflicted tissue. We will address three Specific Aims: Specific Aim 1: Express the CLN2 gene in the mouse brain using intra-arterial delivery of two serotypes of AAV, namely AAVrh.10CLN2 and AAV9CLN2. Intra-arterial and intravenous delivery will be compared to our earlier studies using direct infusion. Specific Aim 2: Develop non-invasive tools for measuring LINCL disease severity, viral vector delivery, and therapeutic response. We will develop a multi-component magnetic resonance imaging biomarker panel to measure LINCL severity, and use a novel strategy involving positron emission tomography to evaluate vector distribution in the brain. Specific Aim 3: Arrest LINCL disease progression in CLN2-/- mice using intra-arterial delivery of AAVrh.10CLN2 or AAV9CLN2. A survival study will be conducted and mice will be evaluated using imaging, behavioral, and histological methods. If we are successful, this work would lead to a clinical trial in human subjects. Also, we would advance the field of intra-arterial drug delivery by standardizing administration parameters in genetically engineered mice for successful IA delivery of gene therapy to the central nervous system. Finally, many of the results from this project, including those from both gene delivery and imaging, will not be specific to LINCL but will be applicable to a wide range of neurological and other disorders.