Non-Invasive Tracking of Genome-Corrected iPS cells in ALS

对 ALS 中基因组校正的 iPS 细胞进行无创追踪

• 批准号: 10472760
• 负责人: Jeff W. Bulte
• 金额: $ 48.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472760
• 关键词: ALS patients; Amyotrophic Lateral Sclerosis; Antigen Targeting; Biodistribution; Cell Proliferation; Cell Therapy; Cell Transplantation; Cells; Cerebrum; Clinic; Clinical; DNA Sequence Alteration; Detection; Development; Disease; Disease Progression; Evaluation; Event; FOLH1 gene; Feasibility Studies; Future; Gene Mutation; Genes; Genetic Diseases; Genome; Glutamatergic Agents; Homing; Human; Image; Imaging Device; Imaging Techniques; Immune; In Vitro; Injections; Intra-Arterial Injections; Knockout Mice; Label; Longevity; Magnetic Resonance Imaging; Magnetism; Modality; Molecular; Motor; Motor Neurons; Mus; Muscle; Mutate; Mutation; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Onset of illness; Organism; Outcome; Paralysed; Patients; Pharmaceutical Preparations; Phase; Point Mutation; Positron-Emission Tomography; Property; Proteins; Protocols documentation; Reporting; Resources; Riluzole; Route; Safety; Site; Spinal Cord; Stem cell transplant; System; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Undifferentiated; United States Food and Drug Administration; amyotrophic lateral sclerosis therapy; base; cell replacement therapy; cellular transduction; clinical application; enzyme activity; experience; gene correction; genetic approach; genome editing; image guided; imaging approach; imaging modality; improved; in vivo; induced pluripotent stem cell; knock-down; mortality; motor impairment; mouse model; mutant; non-invasive imaging; novel; particle; personalized medicine; pre-clinical; pyrrolidin-3-yl-methanesulfonic acid; real-time images; regenerative approach; safety study; stem cell therapy; stem cells; superoxide dismutase 1; tumor; zinc finger nuclease

The use of gene-edited stem cells and in particular patient-derived iPSCs for cell replacement therapy is an appealing approach for genetic correction of a disease-associated gene mutation. If such therapies are pursued in future patients, it would be highly desirable to have non-invasive cell tracking techniques available that can report longitudinally on the distribution and survival of transplanted cells, in order to better understand their fate in vivo and to optimize personalized therapies. We have chosen amyotrophic lateral sclerosis (ALS), a devastating disease with near 100% mortality as an example of a target disease, in which loss of motor neurons is a key event leading to muscle paralysis. For familial forms of ALS, mutations in the gene superoxide dismutase 1 (SOD1) are known to be a causative factor for disease development. In this proposal, we aim to apply two novel experimental imaging modalities (MPI and PSMA-targeted 18F-DCFPyL PET) in conjunction with a clinically emerging technique (1H MRI) to answer several basic questions associated with the efficacy and safety of genome-edited cell therapy. These are complementary techniques, where MPI and PSMA- targeted 18F-DCFPyL PET can report on the whole-body distribution of administered cells, whereas MRI can report on real-time homing and immediate retention of cells. This three-pronged approach of imaging the same cell (labeled with SPIO for MPI and MRI, and 18F-DCFPyL for PET) will be applied for tracking of patient- derived native (39b-SOD1+/AV4) and genome-corrected (39b-SOD1+/+) iPSCs, with and without differentiation into motor neurons, in a transgenic SOD1G37R mouse model of ALS. Intra-arterial injection, an emerging cell delivery route, will be used to study the feasibility of real-time image-guided cell injections aimed at obtaining a more global cerebral cell distribution, while intraparenchymal injection in the spinal cord will be applied as a clinically effective delivery technique to deliver cells locally at the site of impaired motor neurons. If successful, this example imaging application of genome-corrected cells in ALS may encourage the use of MPI, MRI, and/or PMSA-based PET imaging to interrogate the fate of cells in other disease scenarios in vivo.

使用基因编辑的干细胞，特别是患者来源的ipscs进行细胞替代治疗是一种 一种疾病相关基因突变的基因矫正方法。如果这样的疗法是 在未来的患者中，非常希望有可用的非侵入性细胞跟踪技术 可以纵向报告移植细胞的分布和存活情况，以便更好地了解 他们在体内的命运，并优化个性化治疗。我们选择了肌萎缩侧索硬化症(ALS)， 一种具有近100%死亡率的破坏性疾病，作为目标疾病的例子，其中运动丧失 神经元是导致肌肉瘫痪的关键事件。对于家族性肌萎缩侧索硬化症，超氧化物基因突变 歧化酶1(SOD1)被认为是疾病发展的一个致病因素。在这项建议中，我们的目标是 联合应用两种新的实验成像方式(MPI和PSMA靶向18F-DCFPyL PET) 使用临床新兴技术(1H MRI)回答与疗效相关的几个基本问题 以及基因组编辑细胞疗法的安全性。这些是互补的技术，其中MPI和PSMA- 靶向18F-DCFPyL PET可以报告给药细胞的全身分布，而MRI可以 关于细胞的实时定位和即时保留的报告。这种三管齐下的方法成像相同的 细胞(MPI和MRI用SPIO标记，PET用18F-DCFPyL标记)将用于跟踪患者- 衍生的原生(39b-SOD1+/AV4)和基因组校正(39b-SOD1+/+)IPSCs，有分化和无分化 在ALS转基因SOD1G37R小鼠模型中，转化为运动神经元。动脉内注射--一种新兴细胞 传递路线，将用于研究实时图像引导细胞注射的可行性，目的是获得 更多的全球脑细胞分布，而脊髓实质内注射将作为 临床上有效的输送技术，将细胞局部输送到受损运动神经元的部位。如果成功， 基因组校正细胞在ALS中的这一示例成像应用可以鼓励使用MPI，MRI， 和/或基于PMSA的PET成像，以询问体内其他疾病场景中细胞的命运。