Choroid Plexus-Directed Gene Therapy for Alpha-Mannosidosis

脉络丛定向基因治疗α-甘露糖苷贮积症

基本信息

批准号：
8990855
负责人：
STEPHEN GERARD KALER
金额：
$ 57.6万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-24 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990855
关键词：
Affect Alpha-mannosidase Animal Model Animals Award Biochemical Biological Markers Biological Products Blood Brain Brain Diseases Brain Pathology Cells Cerebral Ventricles Cerebrospinal Fluid Cerebrum Choroid Plexus Epithelium Clinical Clinical Management Clinical Trials Collection Complementary DNA Copper Data Dependovirus Development Disease Dose Enzymes Epithelial Cells Evaluation Exploratory/Developmental Grant for Diagnostic Cancer Imaging Extracellular Space Extramural Activities Face Felis catus Future Gene Transfer Gene therapy trial Genes Goals Grant Health Histologic Human Hybrids Immune Inborn Genetic Diseases Infusion procedures Intellectual functioning disability Intrathecal Injections Intraventricular Injections Investigational Drugs Investigational New Drug Application Ions Laboratories Lesion Link Lysosomal Storage Diseases Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Mediating Menkes Kinky Hair Syndrome Methods Modeling Mus Natural History Neurologic New Drug Approvals Outcome Measure Pathology Patient-Focused Outcomes Patients Penetration Pharmacology and Toxicology Phase Phase I Clinical Trials Pilot Projects Process Production Proteins Protocols documentation Recombinant adeno-associated virus (rAAV)Recombinants Research Design Research Personnel Resolution Safety Series Serotyping Source Spinal Tap Structure Structure of choroid plexus Subarachnoid Space Surrogate Markers Testing Therapeutic Effect Toxic effect Toxicology Translating United States National Institutes of Health Water Work adeno-associated viral vector alpha-Mannosidosis base bench to bedside biomarker identification cellular transduction cerebrospinal fluid flow cisterna magna clinical biomarkers clinical practice enzyme replacement therapy gene therapy hearing impairment human subject innovation insight interest lateral ventricle man mouse model nonhuman primate novel phase I trial pre-clinical preclinical study research study risk benefit ratio skeletal abnormality spectroscopic imaging transgene expression treatment effect vector ventricular system

项目摘要

DESCRIPTION (provided by applicant): This proposal links a series of innovative AAV gene therapy experiments in two well-established animal models of alpha-mannosidosis with preclinical toxicology studies to develop a path forward to a first-in-human clinical trial of cerebrospinal fluid (CSF)-delivered gene therapy for this illness. The Kaler lab has treated a mouse model of Menkes disease using CSF-directed AAV5 gene therapy via efficient transduction of choroid plexus epithelia. The choroid plexuses (CP) are highly vascularized structures that project into the ventricles of the brain. The polarized epithelia of the CP produce CSF and secrete a large number of proteins. Lysosomal storage diseases (LSDs) could potentially benefit from a CP-targeted approach because AAV transduction results in sustained episomal transgene expression and CP epithelia have a slow rate of turnover. The Wolfe lab has shown that AAV gene transfer into the brains of animal models of LSDs can mediate substantial but incomplete cellular correction and clinical improvement. The advantage of targeting CSF flow is that it extends throughout the ventricular system to the subarachnoid space, from which molecules ultimately reach the entire brain. Intrathecal delivery of purified recombinant lysosomal enzyme (enzyme replacement therapy, ERT) has been successful in ameliorating some brain pathology in animal models and recently in a human clinical trial. However, a major drawback to this approach is the need for repeated intrathecal injections due to short half- lives of recombinant enzymes. An alternative long-term strategy is to remodel CP epithelial cells with an AAV vector to secrete enzyme of interest. CP epithelia have an extremely slow turnover rate, thus this approach could generate a permanent source of enzyme production for secretion into the CSF and penetration to brain structures. Furthermore, intraventricular injection AAV vectors can deliver the normal gene to some of the parenchymal cells, which can then also secrete normal enzyme into extracellular spaces for delivery to other cells. A two-year NIH Bench-to-Bedside Award (R21 equivalent) supported the initial evaluation of this hypothesis in animal models of alpha-mannosidosis (AMD), a prototypical LSD. This U01 proposal expands that effort with the goal of completing the pre-clinical studies needed to submit a phase I clinical trial IND in 3-4 years. We propose to: 1) Evaluate the relative abilities of different AAV-vector serotypes to support CSF- directed AAV transduction in a mouse model of AMD and test the most promising serotypes in the much larger brain of the AMD cat, with the goal of identifying the vector that is most likely to produce the greatest benefit in human clinica trials; 2) Establish clinical and biochemical features in AMD patients for outcome measures in a future clinical trial; and 3) Perform preclinical toxicology studies in non-human primates and develop regulatory approval for a first-in-human gene therapy trial for AMD. The potential impact on clinical practice in the field of LSD is high since, if the proposed aims are successfully achieved, the largest current barriers to health for patients with AMD and other LSDs with brain disease would be circumvented.

描述（由申请人提供）：该提案将在两种成熟的 α-甘露糖苷中毒动物模型中进行的一系列创新 AAV 基因治疗实验与临床前毒理学研究联系起来，为首次人体脑脊液临床试验开辟道路Kaler 实验室使用 CSF 引导的 AAV5 基因疗法，通过脉络丛的有效转导，治疗了门克斯病小鼠模型。脉络丛 (CP) 是高度血管化的结构，投射到脑室中。 CSF 并分泌大量蛋白质，溶酶体贮积病 (LSD) 可能会受益于 CP 靶向方法，因为 AAV 转导会导致持续的附加型转基因表达，并且 CP 上皮细胞的周转率较慢。将基因转移到 LSD 动物模型的大脑中可以介导实质性但不完全的细胞校正和临床改善。纯化的重组溶酶体酶（酶替代疗法，ERT）的鞘内递送已成功地改善了动物模型中的一些脑部病理学，但最近在人类临床试验中却出现了重大进展。这种方法的一个缺点是由于重组酶的半衰期短，需要重复鞘内注射。另一种长期策略是用 AAV 载体重塑 CP 上皮细胞。 CP上皮细胞的周转率极慢，因此这种方法可以产生永久的酶生产源，用于分泌到脑脊液中并渗透到大脑结构中。此外，脑室内注射AAV载体可以将正常基因传递给某些细胞。实质细胞，然后也可以将正常的酶分泌到细胞外空间，以输送到其他细胞。两年期的 NIH Bench-to-Bedside Award（相当于 R21）支持了在动物模型中对这一假设的初步评估。 α-甘露糖苷中毒 (AMD) 是一种典型的 LSD，该 U01 提案扩大了这一努力，目标是在 3-4 年内完成提交 I 期临床试验 IND 所需的临床前研究。相对能力不同的 AAV 载体血清型，以支持 AMD 小鼠模型中的 CSF 定向 AAV 转导，并在 AMD 猫更大的大脑中测试最有希望的血清型，目的是识别最有可能产生最大效果的载体在人类临床试验中获益；2) 建立 AMD 患者的临床和生化特征，以便在未来的临床试验中进行结果测量；3) 在非人类灵长类动物中进行临床前毒理学研究并获得监管批准； AMD 的首次人体基因治疗试验对 LSD 领域的临床实践具有很大的潜在影响，因为如果成功实现拟议的目标，AMD 和其他 LSD 患者目前面临的最大健康障碍是：脑部疾病将被避免。