Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes

通过生物激活 MR 对比探针实时跟踪基因治疗

• 批准号: 10248547
• 负责人: MIGUEL S ESTEVES
• 金额: $ 64.5万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248547
• 关键词: Affect; Aftercare; Alpha-glucosidase; Animal Model; Architecture; Beta-glucuronidase; Biodistribution; Biological Markers; Brain; Candidate Disease Gene; Capsid; Cells; Chemicals; Childhood; Cleaved cell; Clinical; Contrast Media; Data; Dependovirus; Detection; Development; Diagnostic radiologic examination; Disease; Disease Progression; Dose; Enzymes; Evolution; Felis catus; G(M2) Ganglioside; GLB1 gene; Galactosamine; Galactose; Galanin; Ganglioside GM1; Gangliosidoses GM2; Gangliosidosis GM1; Gene Expression; Gene Transfer; Genes; Genotype; Glycogen storage disease type II; Gold; Hemophilia A; Histologic; Human; Incidence; Infant; Injections; Intravenous; Investigational Drugs; Ionizing radiation; Ions; Libraries; Lipids; Liver; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Magnetism; Measures; Mediating; Medicine; Methods; Modality; Modification; Mucopolysaccharidoses; Mucopolysaccharidosis VII; Mus; Mutation; Neuraxis; Organ; Oxidation-Reduction; Patients; Peripheral Nervous System; Phenotype; Preclinical Testing; Prevalence; Procedures; Production; Prognosis; Property; Protein Deficiency; Proteins; Rattus; Recycling; Research Personnel; Safety; Sandhoff Disease; Series; Slice; Spinal Muscular Atrophy; Structure; Survival Rate; Techniques; Technology; Testing; Thalamic structure; Three-Dimensional Imaging; Time; Tissues; Toxic effect; Translating; Translations; Treatment Efficacy; Waste Products; Water; base; beta-n-acetylhexosaminidase; chemical synthesis; clinical development; contrast enhanced; design; disease-causing mutation; experimental study; gene therapy; gene therapy clinical trial; imaging agent; in vivo; mouse model; nervous system disorder; prevent; scale up; sugar; targeted treatment; therapeutic enzyme; therapeutic protein; translation to humans

Abstract: Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes With mean survival rate of 5 years (and most cases are fatal) lysomal storage diseases (LSD) are among the most dismal of prognosis in all of medicine. LSD's represent a large number of monogenetic diseases and while rare the prevalence is to hemophilia. As monogenetic diseases with clearly defined genotype-phenotype relations, lysosomal storage diseases are excellent candidates for gene therapy. The transformative results documented in an adeno-associated virus (AAV) gene therapy clinical trial in infants affected by spinal muscular atrophy demonstrated unequivocally the potential of in vivo gene transfer to treat monogenic neurological disorder. However, to date, there is a lack of non-invasive ways to determine biodistribution or activity levels of these AAV therapies in patients. This is a significant hinderance, leaving investigators guessing which organs or structures are effectively treated and, due to the lag time associated with clinical disease progression, this limitation ultimately impacts the evolution of treatment modalities. In order to overcome these limitations, we propose the development of a new magnetic resonance imaging (MRI)-based technology to track enzymatic activity in any organ, peripheral nervous system (PNS), or central nervous system (CNS) over time and thus have the potential to be applicable to any LSD caused by an enzymatic deficiency. Magnetic resonance imaging is an ideal technique for the study of neurological disorders. This technique is has become a gold standard in diagnostic radiology as a result of the absence of ionizing radiation and is capable of true 3D imaging and has been in use for several decades . Detailed structural information can be obtained in minutes, and single slices in seconds. However, the need to differentiate regions of tissues or organs that are magnetically similar but histologically distinct has been a major impetus for the development of contrast enhancement agents. Greater than 40% of all MR procedures employ contrast agents with more than 450,000 million doses to date have been administered to patients and Gd(III) based contrast agents are among the safest clinical probes in use. We pioneered the development of bio-responsive (i.e., conditionally activated) MR contrast agents and since that time a library of this class of probes has expanded from enzyme activated agents to pH sensitive, the detection of ions such as Zn(II) and Ca(II), and redox activated. Here, we describe the development of a platform where the substrate (that prevents access of water to a Gd(III) ion) is removed by an enzyme which can be substituted to accommodate a number of gene therapy targets.

摘要：生物活化的MR对比探针对基因治疗的实时跟踪 平均生存率为5年（大多数是致命的）裂解储存疾病（LSD） 所有医学中最令人沮丧的预后。 LSD代表大量的单基因疾病和 虽然罕见的患病率是血友病。由于具有明确定义的基因型 - 表型的单基因疾病 关系，溶酶体储存疾病是基因治疗的极好候选者。变革性结果 记录在受脊柱影响的婴儿的腺相关病毒（AAV）基因疗法临床试验中 肌肉萎缩明确表现出体内基因转移的潜力 神经系统障碍。 但是，迄今为止，缺乏确定生物分布或活动水平的非侵入性方法 患者的AAV疗法。这是一个很大的障碍，使调查人员猜测哪些器官或 结构有效治疗，并且由于与临床疾病进展相关的滞后时间， 限制最终会影响治疗方式的演变。 为了克服这些局限性，我们提出了新的磁共振成像的发展 （MRI）基于任何器官，周围神经系统（PNS）或中央的酶活性的基于基于（MRI）的技术 随着时间的流逝，神经系统（CNS），因此有可能适用于由 酶促缺乏。磁共振成像是研究神经系统的理想技术 疾病。由于缺乏，该技术已成为诊断放射学的黄金标准 电离辐射，并且能够进行真实的3D成像，并且已经使用了几十年。详细的 可以在几分钟内获得结构信息，并在几秒钟内获得单个切片。但是，需要 在磁性相似但组织学上不同的组织或器官的区分区域一直是一个 发展对比度增强剂的主要动力。大于所有MR程序的40％ 迄今为止，雇用迄今已超过4.亿剂量的对比剂已向患者服用 基于GD（III）的对比剂是最安全的临床探针之一。 我们开创了生物响应（即有条件激活的）MR造影剂和 从那时起 Zn（II）和Ca（ii）等离子的检测以及氧化还原激活。在这里，我们描述了 底物（防止水进入GD（iii）离子）的平台，该酶被酶去除 可以取代以适应许多基因治疗靶标。