Effect of transthyretin gene therapy in the 5XFAD mouse model of Alzheimer’s disease: Nonhuman/Target identification and validation studies: Other

Background Epidemiological studies and work in transgenic animals suggest that transthyretin (TTR) levels in plasma and/or CSF may modulate Alzheimer’s disease (AD) presentation and/or progression. AD patients exhibit lower levels of TTR in CSF compared to age‐matched healthy individuals. Similarly, genetic reduction of TTR in mouse models of AD is associated with earlier onset and more severe phenotypes. The current study was designed to determine the potential of somatic AAV mediated TTR expression to modulate disease presentation in AD. Method We designed an AAV9 vector to express TTR specifically in liver and choroid plexus using a TTR promoter to drive transgene expression. Two months old male and female 5XFAD mice were injected systemically with 2E12 gc AAV9‐TTRp‐TTR T119M (n=3M+6F), or PBS as controls (n=3M+6F). At nine months of age animals were subjected to neurobehavioral tests to assess cognitive function, and 3D isotropic T2‐weighted MRI to evaluate differences in brain volume. Result Cognitive function was assessed through measure of working and spatial memory using forced and spontaneous alternation tasks in the Y‐maze, and novel object recognition tests. All treated animals showed increased recognition index of novel objects, increased % of alternation, and % time in novel arm, compared to controls. General locomotion and anxiety were evaluated using the open field test, where AAV treated females presented higher locomotor activity and decreased anxiety levels. Interestingly, MRI revealed increased CSF volume in all treated animals compared to controls, with females showing larger differences. Conclusion Our initial results show that systemic delivery of an AAV9 vector that expresses TTR in appropriate tissues improves overall cognitive function, locomotor activity and anxiety symptoms in 5XFAD mice; Interestingly more noticeably in females. The unexpected increase in CSF volume may be related to increased TTR production by the choroid plexus of AAV treated animals, and additional experiments are ongoing to determine the cause of this outcome. Biochemical and histological studies of the brain are currently ongoing to assess the disease status in all experimental groups. This new AAV vector is an outstanding platform for therapeutic development and addresses biologically relevant questions about the role of TTR in AD.