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

基本信息

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
项目类别：
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

项目摘要

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，特别是患者衍生的IPSC进行细胞置换疗法是一种具有疾病相关基因突变的遗传纠正的有吸引力的方法。如果这种疗法是在未来的患者中追求，非常需要拥有无创细胞跟踪技术这可以纵向报告移植细胞的分布和存活，以便更好地理解他们的体内命运并优化个性化疗法。我们选择了肌萎缩性侧索硬化症（ALS），作为目标疾病的一个毁灭性疾病，死亡率接近100％，其中运动丧失神经元是导致肌肉麻痹的关键事件。对于家族形式的ALS，基因超氧化物中的突变歧化酶1（SOD1）是疾病发展的病因。在此提案中，我们的目标是将两种新型的实验成像方式（MPI和PSMA靶向18F-DCFPYP PET）连接使用临床新兴技术（1H MRI）回答与功效相关的几个基本问题和基因组编辑的细胞疗法的安全性。这些是互补的技术，其中MPI和PSMA- 有针对性的18F-DCFPYL PET可以报告施用细胞的全身分布，而MRI可以关于实时归巢和立即保留细胞的报告。这种三管齐下的成像方法相同细胞（用SPIO标记为MPI和MRI，PET 18F-DCFPYL）将用于跟踪患者 - 派生的天然（39B-SOD1+/AV4）和经基因组校正（39b-SOD1+/+）IPSC，具有和不分化进入运动神经元，在ALS的转基因SOD1G37R小鼠模型中。动脉内注射，新出现的细胞输送路线将用于研究实时图像引导的细胞注射的可行性，旨在获得更全球的脑细胞分布，而脊髓中的核内注射将作为A 临床上有效的输送技术，可在运动神经元受损部位局部输送细胞。如果成功，此示例成像在ALS中的基因组校正细胞的应用可能鼓励使用MPI，MRI，和/或基于PMSA的PET成像，以在其他疾病情景中询问细胞的命运。