Prevention of Retinal Degeneration by Transgenic Autologous Stem Cells

通过转基因自体干细胞预防视网膜变性

• 批准号: 9335857
• 负责人: MARTIN L KATZ
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335857
• 关键词: Adopted; Affect; Age related macular degeneration; Autologous; Biological Models; Biological Preservation; Blindness; Blood Circulation; Bone Marrow; Bone Marrow Cells; Brain; Brain region; Canis familiaris; Cell surface; Cells; Cerebrospinal Fluid; Cessation of life; Child; Childhood; Clinical Trials; Data; Defect; Degenerative Disorder; Development; Diabetic Retinopathy; Disease; Employee Strikes; Endosomes; Enzymes; Eye; Frameshift Mutation; Genes; Human; Implant; Infusion procedures; Inherited; Italy; Jansky-Bielschowsky Disease; Lead; Life Support Care; Location; Longevity; Lysosomal Storage Diseases; Lysosomes; Mesenchymal Stem Cells; Modeling; Molecular; Monitor; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Signs; Neuronal Ceroid-Lipofuscinosis; Neurons; Organ; Outcome; Pathology; Patients; Periodicity; Prevention; Proteins; Recombinants; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Stem cells; Structure; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Transgenic Organisms; base; blind; cerebral atrophy; disease phenotype; early childhood; effective therapy; enzyme activity; enzyme replacement therapy; extracellular; gene therapy; implantation; loss of function; prevent; progressive neurodegeneration; prototype; public health relevance; tripeptidyl aminopeptidase; uptake

DESCRIPTION (provided by applicant): Late-infantile neuronal ceroid lipofuscinosis (LINCL, or CLN2) is a progressive and fatal inherited neurodegenerative disease of children that is characterized brain atrophy as well as by progressive retinal degeneration resulting in vision loss that culminates in blindness. CLN2 results from a mutation in the gene that encodes synthesis of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Using a dog model of CLN2, we have demonstrated that periodic administration of recombinant TPP1 to the cerebrospinal fluid (CSF) or a single administration of AAV2-TPP1 gene therapy to the CSF results in uptake of active TPP1 by most brain regions, greatly inhibits brain degeneration, and substantially delays progression of neurological signs of the disease. Based on our studies with the canine model, TPP1 enzyme replacement therapy to the CSF is being employed in a human clinical trial that started in September of 2013. Unfortunately, delivery of TPP1 to the CSF does not prevent retinal degeneration and the resulting loss of vision because the TPP1 does not reach the retina from the CSF. To achieve continuous delivery of TPP1 to the retina, we propose to generate autologous bone marrow- derived mesenchymal stem cells (MSCs) from dogs that are homozygous for a null TPP1 mutation. The MSCs will be transduced to express and secrete high levels of TPP1 enzyme. The transgenic cells will then be implanted into the vitreous of the eyes of the same dogs from which the MSCs were obtained, and the dogs will be monitored for survival and location of the implanted cells, retinal TPP1 levels, and for preservation of retinal structure and function. We will also investigate the alternative approach o direct administration of AAV2-TPP1 gene therapy to the vitreous to transduce retinal cells to synthesize the TPP1 protein. If these studies are successful, they will serve as the basis for treating children with CLN2 who are receiving enzyme replacement therapy via infusion of TPP1 into the CSF or CSF TPP1 gene therapy. The addition of the eye treatment to the CSF treatments has the potential for preventing blindness in children with CLN2 who are benefiting from the brain treatments. In addition, these studies will establish intravitreal implantation of transgenic cells and direct gene therapy as means for treating many other retinal degenerative disorders, including inherited retinal degenerative diseases, age-related macular degeneration and diabetic retinopathy.

描述（由申请方提供）：晚期婴儿神经元蜡样质脂褐质沉积症（LINCL或CLN 2）是一种儿童进行性和致死性遗传性神经退行性疾病，其特征为脑萎缩以及进行性视网膜变性，导致视力丧失，最终导致失明。CLN 2由编码可溶性溶酶体酶三肽基肽酶-1（TPP 1）合成的基因突变引起。使用CLN 2的狗模型，我们已经证明，定期给予重组TPP 1至脑脊液（CSF）或单次给予AAV 2-TPP 1基因治疗至CSF导致活性TPP 1被大多数脑区域摄取，极大地抑制脑变性，并显著延迟疾病的神经学体征的进展。基于我们对犬模型的研究，2013年9月开始的人类临床试验中采用了CSF的TPP 1酶替代疗法。不幸的是，将TPP 1递送至CSF并不能预防视网膜变性和由此产生的视力丧失，因为TPP 1不会从CSF到达视网膜。为了实现TPP 1向视网膜的连续递送，我们提出从对于无效TPP 1突变纯合的狗产生自体骨髓源性间充质干细胞（MSC）。MSC将被转导以表达和分泌高水平的TPP 1酶。然后将转基因细胞植入获得MSC的相同狗的眼睛的玻璃体中，并监测狗的存活和植入细胞的位置、视网膜TPP 1水平以及视网膜结构和功能的保存。我们还将研究将AAV 2-TPP 1基因治疗直接施用到玻璃体到视网膜细胞以合成TPP 1蛋白的替代方法。如果这些研究成功，它们将作为治疗通过将TPP 1输注到CSF或CSF TPP 1基因治疗接受酶替代疗法的CLN 2儿童的基础。在CSF治疗中添加眼部治疗有可能预防受益于脑治疗的CLN 2儿童失明。此外，这些研究将建立转基因细胞的玻璃体内植入和直接基因治疗作为治疗许多其他视网膜变性疾病的手段，包括遗传性视网膜变性疾病、年龄相关性黄斑变性和糖尿病视网膜病变。