UCL researchers demonstrate the therapeutic potential of gene delivery to retinal bipolar cells in restoring the photoreceptor structure and function in a mice model of neuronal ceroid lipofuscinosis, a lysosomal storage disease characterized by vision loss.
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. It represents the most common neurodegenerative disease during childhood. Mutations in at least thirteen CLN genes have been linked to various forms of NCL and specifically, deficiency in the transmembrane protein CLN6 has been linked to impaired vision.
Brain-directed therapies to deliver CLN6 gene have been tested to restore vison loss but have not proven to be effective. In the study published in Molecular Therapy, Dr Robin Ali and colleagues at the University College London investigated if ocular gene therapy could treat vision loss in NCL.
The team used adeno-associated virus (AAV) serotype 7m8 to deliver CLN6 to the photoreceptor cells of Cln6nclf mice, a mice model for NCL. Although photoreceptor degeneration was common in Cln6nclf mice, CLN6 delivery to the photoreceptors did not restore vision in these animals. Further analysis revealed that CLN6 expression was low in photoreceptors but high in adjacent bipolar cells (retinal interneurons), which are lost only in Cln6-deficient mice at late disease stages. AAV-CLN6 was then delivered to the retnal bipolar cells of Cln6nclf mice which showed that bipolar cell-specific expression of CLN6 slowed down the loss of photoreceptor cells and their function.
Findings from the study clearly shows that deficiency of the transmembrane protein CLN6 normally expressed in bipolar cells could result in photoreceptor loss and this could be restored by bipolar cell-directed delivery of CLN6 gene.
Source: Kleine Holthaus SM et al., Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells. Molecular Therapy, May 2018. DOI