Interactions between Batten disease proteins suggest novel strategies for the treatment of CLN6 Batten disease Stephanie M. Hughes*, Hollie E. Wicky and Hannah L. Best Neurodegenerative and Lysosomal Disease Laboratory, Department of Biochemistry, University of Otago, New Zealand *Corresponding author
Batten disease refers to a group of at least 13 genetically distinct neurodegenerative diseases of childhood, with common clinical symptoms including motor and cognitive decline, blindness and seizures. The genes mutated in Batten disease encode diverse proteins, including soluble lysosomal proteases, membrane proteins localized to the lysosome, endosome and ER, and cytosolic proteins. We have identified a novel association between two of these proteins, CLN5 - a soluble lysosomal protein and CLN6 - an ER membrane protein. While neither CLN5 nor CLN6 have well-defined functions, we found that CLN5 expression is down regulated in CLN6-/- animal models. In addition we found that in primary neural cultures from CLN6-/- animals, CLN5 could compensate for lysosomal, synaptic and autophagy defects. Being a secreted lysosomal protein and therefore a preferred target for gene therapy, we tested AAV9-CLN5 gene therapy in a mouse model of CLN6 disease. Mice were injected with AAV9-CLN5 or an AAV9-GFP control vector at 1 month of age, and monitored for behavioral improvements monthly until 12 months of age. We found an increased rate of decline in motor function, in females compared to males, with partial correction in females treated with CLN5 gene therapy. However postmortem analysis showed that CLN5 expression in CLN6 mice did not alter disease pathologies such as storage material or astrocyte activation. These results suggest an alternative strategy for gene therapy in CLN6 Batten disease however it likely, given only partial correction, that other secreted factors may also be required for therapy. In addition our data support the need for careful evaluation of both females and males in assessing disease development.
Funded by Cure Kids New Zealand.
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