The
neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different
ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include
seizures, progressive neurological decline, deterioration of motor and language skills, and
dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive
retinal degeneration is another major hallmark of NCLs. To date, there is no curative
therapy for the treatment of
retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive
retinal degeneration and the decline in
retinal function are discussed. Different approaches, including experimental
enzyme replacement therapy, gene therapy, cell-based
therapy, and
immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene
therapies in NCL animal models with soluble lysosomal
enzyme deficiencies and transmembrane
protein deficiencies have shown the strong potential of gene-based approaches to treat
retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of CLN3 and CLN6 to bipolar cells has been shown to attenuate the
retinal dysfunction. Therapeutic benefits of ocular
enzyme replacement therapies were evaluated in CLN2 and CLN10 animal models. Since brain-targeted gene or
enzyme replacement therapies will most likely not attenuate
retinal neurodegeneration, there is an unmet need for treatment options additionally targeting the retina in patients with NCL. The long-term benefits of these therapeutic interventions aimed at attenuating
retinal degeneration and vision loss in patients with NCL remain to be investigated in future clinical studies.