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: 9131739
• 负责人: MARTIN L KATZ
• 金额: $ 37.68万
• 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/9131739
• 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; Health; Human; Implant; Infusion procedures; Inherited; 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; Neuronal Ceroid-Lipofuscinosis; Neurons; Organ; Outcome; Pathology; Patients; 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; 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（由申请人提供）：晚期神经元的脂肪促脂肪促脂肪促脂肪促脂肪促脂肪促脂肪促脂肪（Lincl或CLN2）是一种进行性且致命的遗传性神经退行性疾病，它表征了脑萎缩以及通过逐步性视网膜变性以及导致视力丧失的渐进性视网膜变性，使盲目丧失了盲目性。 CLN2是由编码可溶性溶酶体三肽基肽酶-1（TPP1）合成的基因突变引起的。使用CLN2的狗模型，我们证明了对脑脊液（CSF）的重组TPP1的定期施用或单一给药对CSF的AAV2-TPP1基因疗法导致大多数大脑区域吸收活性TPP1，从而极大地抑制了大脑的脑部变性，并实质上延迟了神经学的疾病症状。根据我们对犬种模型的研究，在2013年9月开始的人类临床试验中，正在对CSF进行TPP1酶的替代治疗。不幸的是，TPP1向CSF的传递并不能阻止视网膜变性和导致视力丧失，因为TPP1无法从CSF到达视网膜。为了使TPP1连续递送到视网膜，我们建议从纯合子的狗中产生自体骨衍生的间充质干细胞（MSC）。 MSC将被转导为表达和分泌高水平的TPP1酶。然后，转基因细胞将植入获得MSC的同一只狗的眼睛的玻璃体中，并将​​监测狗的生存和位置，以确保植入的细胞的存活和位置，视网膜TPP1水平以及保存视网膜结构和功能。我们还将研究替代方法o直接施用AAV2-TPP1基因治疗玻璃体以转导视网膜细胞，以合成TPP1蛋白。如果这些研究成功，它们将作为治疗CLN2儿童通过将TPP1输注到CSF或CSF TPP1基因治疗中接受酶替代疗法的基础。在CSF治疗中加入眼科处理有可能预防受益于大脑治疗的CLN2儿童的失明。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退行性疾病的手段，包括遗传性视网膜退行性疾病，与年龄相关的黄斑变性和糖尿病性视网膜病。