Leber's Hereditary Optic Neuropathy: Gene Therapy Clinical Trial

莱伯遗传性视神经病：基因治疗临床试验

基本信息

批准号：
8828695
负责人：
John Guy
金额：
$ 205.04万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828695
关键词：
ATP Synthesis Pathway Acute Adverse reactions Affect Amino Acids Animal Model Apoptosis Arginine Axon Bilateral Biodistribution Blindness Categories Cells Cessation of life Child Chronic Clinical Trials Codon Nucleotides Color Complex Contralateral Cultured Cells DNA Data Disease Dose Elderly Enrollment Eye Gene therapy trial Genes Genetic Code Goals Health Heart Histidine Homologous Gene Human Individual Injection of therapeutic agent Lead Leber&apos s Hereditary Optic Neuropathy Letters Maximum Tolerated Dose Mediating Mitochondria Mitochondrial DNA Mitochondrial Diseases Monitor Mus Mutate Mutation NADH dehydrogenase (ubiquinone)Natural History Neuro-Ocular System Nuclear Optic Atrophy Optic Disk Optic Nerve Pathogenesis Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenylalanine Primates Proteins Rare Diseases Rattus Reactive Oxygen Species Reading Frames Recovery Relative (related person)Research Personnel Respiratory physiology Retinal Ganglion Cells Rodent Rodent Model Safety Series Swelling Technology Testing Toxic effect Translational Research Tyrosine United States National Institutes of Health Virus Vision Visual Acuity Visual Fields Visual system structure Work blind cohort effective therapy emerging adult experience gene therapy clinical trial human disease intravitreal injection mouse model multidisciplinary mutant next generation nonhuman primate novel open label phase 2 study prevent programs research clinical testing retinal neuron safety testing targeted sequencing vector

项目摘要

DESCRIPTION (provided by applicant): Over the past decade, we have made major strides towards determining the pathogenesis and testing a treatment for Leber's Hereditary Optic Neuropathy (LHON). We successfully expressed the wild-type human NADH ubiquinone oxidoreductase subunit 4 (ND4) of complex I in the nuclear genetic code. The protein was imported into the mitochondria by agency of a mitochondrial targeting sequence. The gene was packaged into next generation tyrosine to phenylalanine modified self-complementary adenoassociated virus (AAV) then injected into rodent eyes. FLAG-tagged wild-type human ND4 was detected quickly in most inner retinal neurons by 1 day post injection and it integrated into Complex I. Furthermore, in rodent eyes also injected with a mutant Gl 1778A ND4 homologue responsible for most cases of LHON, wild-type ND4 restored defective ATP synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells and prevented demise of axons in the optic nerve that persisted long-term. The self-complementary wild-type ND4 injected at the relevant titer into the ex vivo human eye expressed in most retinal ganglion cells, suggesting that it will do so in our LHON patients. Primates vitreally injected with untagge ND4 had no adverse reactions, suggesting that this vector should be a safe and effective platform for clinical testing in LHON. Our goal in this application is to test the safety of AAV-mediated delivery of the human ND4 gene in a Phase I clinical trial of patients with mutated G11778A mtDNA and then move to a Phase II study to prove efficacy in the later years of this program. Phase I will consist of an open-label, unilateral, single-dose intravitreal injection of AAV-ND4 per patient in the worse eye in a dose-escalation study investigating the safety of three vector doses (5x10e9 vg, 2.46x10e10 vg and 1xlOel1 vg) in a small number of patients with molecularly confirmed Gl 1778A-mutated mitochondrial DNA who have chronic bilateral, severe visual loss for more than 1 year (Aim 1) or acute bilateral several visual loss for less tha 1 year (Aim 2), and then, lastly, in the eye with better vision but that we know is predestined to lose significant vision within 6 months from the onset of visual loss in the first eye (Aim 3).

描述（由申请人提供）：在过去的十年中，我们在确定发病机理并测试Leber遗传性视神经病变（LHON）方面取得了长足的进步。我们在核遗传密码中成功地表达了复合物I的野生型人NADH泛氨基氧化还原酶亚基4（ND4）。通过线粒体靶向序列的代理将蛋白质进口到线粒体中。该基因被包装到下一代酪氨酸中，以苯丙氨酸改性的自相依赖性腺关系病毒（AAV），然后注射到啮齿动物的眼睛中。 FLAG-tagged wild-type human ND4 was detected quickly in most inner retinal neurons by 1 day post injection and it integrated into Complex I. Furthermore, in rodent eyes also injected with a mutant Gl 1778A ND4 homologue responsible for most cases of LHON, wild-type ND4 restored defective ATP synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells and prevented demise of长期持续存在的视神经中的轴突。在大多数视网膜神经节细胞中表达的相关滴度以相关滴度注射的自我平衡野生型ND4，这表明它将在我们的LHON患者中这样做。玻璃体注射的灵长类动物没有不良反应，这表明该载体应该是LHON临床测试的安全有效平台。我们在此应用中的目标是测试AAV介导的人ND4基因在突变的G11778A mtDNA患者的I期临床试验中的安全性，然后进行II期研究以证明该计划后期的功效。第一阶段将包括一项开放标签，单方面的，单剂量的单剂量玻璃体玻璃体内注射AAV-ND4在较差的眼睛中，在一项剂量降低研究中，研究了三个矢量剂量的安全性（5x10E9 VG，2.46x10e10e10 vg和1xloel1 vg）在一小部分中有粒状gl的患者中，少数是gl的glirial who drimial who who who who who who who who who who who who who who who wo双边，严重的视觉损失超过1年（AIM 1）或急性双侧视觉损失，较少1年（AIM 2），最后，以更好的视力为单位，但我们知道，从视觉损失开始后6个月内，我们知道在第一只眼睛的视觉丧失开始后6个月内失去了重要视力（AIM 3）。