Whaler, Sammie; (2018) Novel therapeutic strategies in NBIA: A gene therapy approach for PLA2G6-associated neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Infantile neuroaxonal dystrophy (INAD) is a debilitating, intractable and ultimately lethal neurodegenerative disorder. It is caused by mutations in the PLA2G6 gene which encodes for phospholipase A2. INAD patients present neurodegeneration-associated symptoms between six months and three years of age. Severe spasticity, progressive cognitive decline, and visual impairment typically result in death during the first decade (Morgan et al, 2006). There is no disease-modifying treatment available and palliative care focuses on quality of life. Therefore, there is an overwhelming need to develop novel therapies to treat INAD patients. To create a landscape of the behavioural and pathological deficits, we aim to first conduct an in-depth characterization of the PLA2G6 mouse model developed by Wada et al (2009). Additionally, we aim to develop an AAV-mediated gene therapy approach for the treatment of INAD and conduct a pre-clinical study in the pla2g6-inad mouse model. The objective is to be able to prevent or ameliorate both the central and peripheral nervous system phenotype and improve the lifespan and/or quality of life of the animal. Recombinant adeno-associated virus serotype 9 vector (AAV9) will be used to deliver the therapeutic human PLA2G6 gene to the neonatal pla2g6-inad mouse. The strong neuron specific synapsin-I promoter will drive the human PLA2G6 gene. The efficacy of different administration routes including intracerebroventricular (ICV), intravenous (IV) and a combination of intracerebroventricular (ICV)/ intravenous (IV) and intracerbroventricular (ICV)/intraperioteneal (IP) will be investigated in the pla2g6-inad mouse model. AAV9-hSyn1-hPLA2G6 gene therapy treated pla2g6-inad mice showed an increased lifespan with the largest improvements observed in the animal cohort that received a combined administration of AAV9-hPLA2G6. The significant increase in lifespan supplemented with significant improvements in behavioural tests validates the potential beneficial use of gene therapy for infantile neuroaxonal dystrophy (INAD).

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