Experimental Therapeutic Approaches for the Treatment of Retinal Pathology in Neuronal Ceroid Lipofuscinoses

Abstract

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.

Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8mnd mice

“…Prior investigations have highlighted glial dysfunction in NCL murine models coinciding with subsequent neuronal damage of the visual cortex and retina, resulting in deterioration of visual perception and retinal function [48][49][50]. Moreover, attenuation of inflammatory microglia via therapeutic agents in Batten disease animal models improved visual acuity, reduced retinal thinning, and improved retinal ganglion cell survival [49,[51][52][53]. Sex comparisons of microglia contribution to pathology and response to therapy in vision related systems may better elucidate this process.…”

Characterization of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances

“…Studies using animal and cell model systems of CLN3 disease have shed light on a wide range of roles that CLN3 protein may participate in, including: intracellular trafficking [3][4][5][6] , autophagy [7][8][9] , Ca 2+ levels 10 , lysosomal egress 11 , and lysosomal pH 12 . However, the exact pathway(s) that CLN3 is involved in are still debatable, which may contribute to the lack of treatments for this disease despite of current development of potential interventions such as gene therapy 13,14 . Clinically, the most common (in 80% of patients) and often an early symptom is functional vision loss, the onset of which occurs around 5-6 years of age 15 .…”

“…Our characterization of sleep in a mouse model of CLN3 disease contributes to a better understanding of the sleep disturbances commonly reported for CLN3 disease and other NCLs, which will facilitate the development of new disease treatment and management strategies. therapy 13,14 . Clinically, the most common (in 80% of patients) and often an early symptom is functional vision loss, the onset of which occurs around 5-6 years of age 15 .…”

Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics

“…Currently, there are no available treatments to alleviate clinical symptoms for the majority of Batten disease. 8 , 9 In the case of CLN2 Batten disease, research studies have shown that a recombinant human tripeptidyl peptidase-1 (TPP1) can be delivered into the cerebrospinal fluid every two weeks. 10 , 11 , 12 , 13 While positive results have been seen with this form of enzyme replacement therapy, it has a high incremental cost-utility ratio and the frequent delivery causes distress for paediatric patients.…”