Show simple item record

dc.contributor.advisorHughes, Stephanie
dc.contributor.authorMcIntyre Wilson, Madeline
dc.date.available2021-12-01T19:52:06Z
dc.date.copyright2021
dc.identifier.citationMcIntyre Wilson, M. (2021). Preclinical Assessment of Experimental Therapeutics for CLN6 Batten Disease (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/12538en
dc.identifier.urihttp://hdl.handle.net/10523/12538
dc.description.abstractNeuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of thirteen genetically heterogenous lysosomal storage diseases that, collectively, are the most common cause of fatal neurodegeneration in children. CLN6 Batten disease (CLN6 BD), also known as LakeCavanagh disease, is a late infantile onset variant of the NCLs caused by loss-of-function mutations in the CLN6 gene. Mutations in both alleles of the gene result in classic NCL symptoms – blindness, epilepsy and progressive cognitive and motor decline – as well as characteristic pathophysiological features such as premature and accelerated neuronal cell death, chronic neuroinflammation and the intracellular accumulation of autofluorescent storage material in lysosomes. As a monogenic, inherited and fatal disorder, CLN6 BD is an excellent candidate for experimental gene therapy. Several preclinical and clinical trials of gene therapy have been conducted for a range of genetic disorders, including several NCL variants, and these have shown promising results. Subsequently, a clinical phase I/II CLN6 BD trial was initiated by the Gray Foundation and Amicus Therapeutics in 2016. This trial, which is ongoing at the time of writing, has produced optimistic safety and tolerance interim data. But, past experience with clinical gene therapy trials for several other genetic and metabolic disorders suggests that any improvements will not be curative. For this reason, the Gray Foundation began to investigate complementary treatments that might augment the therapeutic efficacy of gene therapy in CLN6 BD. This project used a naturally occurring murine model of CLN6 BD (the Cln6nclf mouse) to investigate the efficacy of two small molecule (drug) therapies – gemfibrozil and cannabidiol (CBD) – alone and in combination with adenovirus associated virus (AAV2/9)- mediated gene therapy, as protection against the CLN6 behavioural phenotype. Specifically, Cln6nclf and C57Bl/6 (control) mice received a unilateral intracerebroventricular (i.c.v) injection iv of gene therapy (an AAV2/9 vector expressing hCLN6 under the control of a chicken β-actin gene promoter) or saline (1x PBS) on post-natal days 0-2. Post-weaning, mice were dosed orally (every second day) with either gemfibrozil, CBD, a combination of the two drug therapies or a vehicle solution. Behavioural testing (ataxia phenotyping and rotarod performance) was conducted at 6, 9 and 12 months of age. Testing of over 500 animals determined that the oral administration of gemfibrozil, CBD, or a combination of the two drugs did not make any consistently significant improvements to untreated or gene-therapy treated Cln6nclf mouse behaviour. The study was successful, however, in reaffirming the apparent efficacy of i.c.v gene therapy in protecting against CLN6 BD behaviour in Cln6nclf mice (of both sexes), with no significant reduction in behavioural scores, when compared to healthy controls. This study represents the first long-term, large-scale preclinical study of this particular combination of therapies for CLN6 BD. It provides a solid foundation for further work searching for a comprehensive and curative treatment regimen for CLN6 BD.en_NZ
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.language.isoenen_NZ
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectCLN6en_NZ
dc.subjectBattenen_NZ
dc.subjectCLN6 Batten Diseaseen_NZ
dc.subjectBatten Diseaseen_NZ
dc.subjectNeuronal ceroid lipofuscinosisen_NZ
dc.subjectCLN6 Neuronal ceroid lipofusincosisen_NZ
dc.subjectCLN6 BDen_NZ
dc.subjectNeurodegenerationen_NZ
dc.subjectNeurodegenerative diseaseen_NZ
dc.subjectNCLen_NZ
dc.subjectCLN6 NCLen_NZ
dc.subjectNCLsen_NZ
dc.subjectLINCLen_NZ
dc.subjectLate Onset Infantile NCLen_NZ
dc.subjectGene therapyen_NZ
dc.subjectViral-mediated gene therapyen_NZ
dc.subjectPre-clinical trialen_NZ
dc.subjectSmall molecule therapyen_NZ
dc.subjectGemfibrozilen_NZ
dc.subjectCBDen_NZ
dc.subjectCannabidiolen_NZ
dc.subjectCBD oilen_NZ
dc.subjectCombination therapyen_NZ
dc.subjectBehavioural assessmenten_NZ
dc.subjectCLN6 miceen_NZ
dc.subjectNclf miceen_NZ
dc.subjectFibrateen_NZ
dc.titlePreclinical Assessment of Experimental Therapeutics for CLN6 Batten Diseaseen_NZ
dc.typeThesis
dc.date.updated2021-11-29T04:01:19Z
dc.language.rfc3066en
thesis.degree.disciplineBiochemistry Departmenten_NZ
thesis.degree.nameMaster of Scienceen_NZ
thesis.degree.grantorUniversity of Otago
thesis.degree.levelMasters
otago.openaccessOpenen_NZ
otago.evidence.presentYes
 Find in your library

Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record