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：通过生物激活 MR 对比探针实时跟踪基因治疗 溶酶体贮积病 (LSD) 的平均生存率为 5 年（大多数病例是致命的） 所有医学中最悲观的预后。 LSD 代表了大量的单基因疾病 血友病的患病率虽然罕见。作为具有明确基因型-表型的单基因疾病 关系，溶酶体贮积病是基因治疗的绝佳候选者。变革性的结果 腺相关病毒 (AAV) 基因治疗临床试验记录了受脊髓影响的婴儿 肌肉萎缩症明确证明了体内基因转移治疗单基因肌萎缩症的潜力 神经系统疾病。 然而，迄今为止，缺乏非侵入性方法来确定这些物质的生物分布或活性水平。 患者的 AAV 疗法。这是一个重大障碍，让调查人员猜测哪些器官或 结构得到有效治疗，并且由于与临床疾病进展相关的滞后时间，这 限制最终会影响治疗方式的演变。 为了克服这些限制，我们建议开发一种新的磁共振成像 基于 MRI 的技术可追踪任何器官、周围神经系统 (PNS) 或中枢的酶活性 神经系统（CNS）随着时间的推移，因此有可能适用于任何由某种药物引起的LSD 酶缺乏。磁共振成像是研究神经系统疾病的理想技术 失调。由于缺乏 电离辐射，能够进行真正的 3D 成像，并且已经使用了几十年。详细的 结构信息可以在几分钟内获得，单个切片可以在几秒钟内获得。然而，需要 区分磁性相似但组织学不同的组织或器官区域一直是 对比增强剂的发展的主要推动力。超过 40% 的 MR 手术 迄今为止，已向患者注射了超过 4500 亿剂造影剂， 基于 Gd(III) 的造影剂是目前使用的最安全的临床探针之一。 我们率先开发了生物响应（即有条件激活）MR 造影剂和 从那时起，此类探针的库已从酶激活剂扩展到 pH 敏感剂， 检测 Zn(II) 和 Ca(II) 等离子，并激活氧化还原。在这里，我们描述了一个 平台上的底物（防止水接触 Gd(III) 离子）被酶去除， 可以被替换以适应许多基因治疗靶点。