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Title: Exploring the potential for gene therapy in multiple forms of neuronal ceroid lipofuscinosis (Batten disease)
Author: Pearse, Yewande Elizabeth Oluwashubomi
ISNI:       0000 0004 5994 5308
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage disorders that cause profound neurodegeneration and predominantly affect children. Currently, there are no effective treatments available for any form of NCL. This thesis focuses on novel applications of gene therapy for CLN1 disease, which is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and CLN3 disease, which results from mutations in CLN3, which encodes a lysosomal transmembrane protein of unknown function. Therapy for transmembrane protein-deficient NCLs is complicated because uptake of therapeutically-delivered enzyme or “cross-correction” is not possible. Gene therapy could theoretically correct the CLN3 defect, but would require widespread transduction, and overexpression of CLN3 may have safety concerns. We used AAV2/9 vectors to deliver either mouse or human Cln3/CLN3 to the brains of wild- type and Cln3Adeficient mice, and assessed the short-and long-term response. Although a neuroinflammatory response to Cln3 over-expression was initially seen, this declined over time, and no obvious toxicity was associated with this overexpression. Compared to the brain, little is known about NCL systemic pathology, but we show that both Cln1A and Cln3Adeficient mice display functional and pathological phenotypes including heart rate abnormalities, sinoatrial node pathology, left ventricular hypertrophy and cardiac remodeling, thus providing a more complete picture of NCL pathology and where to target therapy. Although gene therapy has been partly successful for treating murine CLN1 disease, it has shown limited ability to extend lifespan. One way to enhance this efficacy would be to combine CNS gene therapy with treating systemic pathology, and we used neonatal intracranial AAV2/9Amediated gene therapy combined with enzyme replacement therapy (ERT) to treat the brain and body, respectively. While gene therapy alone significantly improved neuropathological changes, ERT conferred little additional benefit, and appeared to negate the positive effects of gene therapy.
Supervisor: Thuret, Sandrine ; Cooper, Jonathan David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available