Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis

Autor: Daniella P. Vansteenkiste, Christopher J. Tracy, Rebecca E.H. Whiting, Baye G. Williamson, Martin L. Katz, Jacqueline W. Pearce, Cheryl A. Jensen, Leilani J. Castaner, Jeffrey N. Bryan, Joan R. Coates, Lauren Elizabeth Gillespie
Rok vydání: 2016
Předmět:
0301 basic medicine
Retinal degeneration
medicine.medical_specialty
Pathology
Genetic enhancement
medicine.medical_treatment
Dog model
Biology
Aminopeptidases
03 medical and health sciences
Cellular and Molecular Neuroscience
Dogs
Gene therapy
0302 clinical medicine
Cerebrospinal fluid
Neuronal Ceroid-Lipofuscinoses
Electroretinography
medicine
Animals
Enzyme Replacement Therapy
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Stem cell therapy
Retina
Tripeptidyl-Peptidase 1
Stem Cells
Genetic Therapy
Stem-cell therapy
Electroretinogram
medicine.disease
Sensory Systems
Surgery
Disease Models
Animal
Ophthalmology
030104 developmental biology
medicine.anatomical_structure
Retinal detachment
Intravitreal Injections
Disease Progression
030221 ophthalmology & optometry
Systemic administration
Neuronal ceroid lipofuscinosis
Serine Proteases
Stem cell
Stem Cell Transplantation
Zdroj: Experimental Eye Research. 152:77-87
ISSN: 0014-4835
DOI: 10.1016/j.exer.2016.09.003
Popis: The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.
Databáze: OpenAIRE
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