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Sophia Kleine Holthaus, Ulrich F O Luhmann, Alexander J Smith, Sara E Mole, Robin R Ali; Retinal phenotype in Cln6nclf mice, a mouse model of neuronal ceroid lipofuscinoses, amenable to AAV mediated gene therapy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3314.
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The neuronal ceroid lipofuscinoses (NCL) are inherited lysosomal storage disorders and represent the most common neurodegenerative disease during childhood. Probably the biggest obstacle to developing therapies for NCL is the insufficient delivery of agents to the brain. In the eye it has been shown that adeno-associated virus (AAV) mediated gene therapies successfully restore the expression of absent proteins and improve retinal morphology and function in animals. As one of the key features in NCL is vision loss, we hypothesize that an AAV mediated gene therapy could be used to preserve eyesight in NCL and may pave the way towards more widespread therapeutic treatments of the disease.
The Cln6nclf mouse is an animal model for a variant form of late infantile NCL that harbors a frame shift mutation in the Cln6 gene causing a truncated short-lived protein product. Cln6 is a transmembrane ER protein of unknown function. To determine the time window for therapeutic interventions in Cln6 deficient mice, we have investigated morphological and functional changes in the eye of the animals using scanning laser ophthalmology, optical coherence tomography, electroretinography and histological processing. Currently, we explore whether subretinally injected AAV vectors carrying Cln6 are therapeutic in Cln6 deficient mice.
Our data shows that histological and functional alterations occur in Cln6nclf mice as early as 1 month of age including activated Mueller glia cells, fundus autofluorescence and diminished scotopic a-wave amplitudes at high light intensities. Over time the degeneration progresses and results in a widespread activation of macrophages, pronounced autofluorescence, thinning of the outer nuclear layer and sustainable reduction of the scotopic a-wave amplitude at 6 months. Apoptotic cells are predominantly present in the outer retina; while, changes in the b-wave amplitude are mild across different light intensities.
Based on these findings we conclude that Cln6nclf mice present with an early but slowly progressing eye phenotype. Furthermore, the decreased a-wave amplitudes indicate that Cln6 may be of particular importance for the normal functioning of photoreceptors and RPE in response to light stimuli. Consequently, an AAV based gene therapy will be developed aiming for the restoration of Cln6 in photoreceptors and/or RPE.
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