Neuronal Ceroid Lipofuscinosis (NCL, CLN) or Batten’s disease comprises at least thirteen forms of monogenic inherited diseases, characterized by similar clinical characteristics (neurological decline, seizures, loss of vision) and deposition of lipofuscin-containing storage material in the lysosomes. While progress has been made in other lysosomal storage diseases in the development of enzyme replacement therapies, substrate-reduction therapies and chaperone therapies, only one treatment has so far been approved for CLN2. Main limitations for therapeutic progress on CLN disease has been the need to deliver the therapy to the CNS, eyes ad somatic organs, the fact that every subtype requires a separate tailored drug development approach, the ultra-rare nature and lack of newborn screening of the disease, making it difficult to enroll patients at an early disease stage, the high cost of drug development and the lack of funding to bring experimental drugs to approval.
Regulators recently established a platform approach that would allow drug developers to use one manufacturing process for several therapies. His approach is particularly applicable to viral-mediated gene therapy. We have generated a novel form of adenovirus (AAV) mediated gene therapy with re-targeted organ tropism, allowing the delivery of the virus across the blood-brain-barrier and the blood-retinal barrier for CNS and ocular delivery, respectively. This was accomplished by including an antibody against the human transferrin receptor in the capsid to allow viral delivery via receptor-mediated transcytosis. Further mutations in the viral capsid resulted in reduction of liver tropism by more than 95%. Applying this new viral gene therapy system to preclinical models of CLN1 and CLN2 disease resulted in remarkable substrate reduction in the CNS and periphery, prolongation of survival, preservation of retinal thickness, motor coordination and prevention of tremor and seizures in treated CLN1 and CLN2 mice.