Skip to main content

The layers of the retina – the part of the eye that is damaged by Batten disease – are affected differently and show distinct progression between natural sheep models of CLN5 and CLN6 disease, a study has found.

Notably, all retinal layers were affected in sheep with CLN6 disease. However, only the outer layers of the retina showed degeneration, and at an earlier time, in the sheep model of CLN5 disease.

Additionally, several characteristics of these Batten types were found to be similar to those previously reported for patients. This further supports the use of these sheep models not only to better understand disease progression, but also to assess the effectiveness of potential therapies, the researchers noted.

The results of the study suggest that different therapeutic approaches targeting the eyes are needed to treat retinal lesions in Batten – and those focused on CLN5 disease will likely need to be administered at an earlier stage to produce the best results.

The study, “Natural history of retinal degeneration in ovine models of neuronal ceroid lipofuscinoses CLN5 and CLN6was published in the journal Scientific reports.

recommended reading

Batten disease, also known as neuronal ceroid lipofuscinoses (NCL), is caused by mutations in at least 13 different genes. These mutations lead to the toxic buildup of waste molecules inside lysosomes – the recycling compartments of cells – primarily in brain cells, leading to nerve cell damage and death.

The result is progressive cognitive and motor decline, seizures and loss of vision, all due to damage to both the retina and the region of the brain that processes visual information.

The retina, a thin layer of nerve cells lining the back of the eye, detects light through its photoreceptors. It then sends vision signals to the brain via the optic nerve, which is the only connection between the eye and the brain.

“Many studies of retinal tissue from NCL patients or models have been performed in end-stage disease, therefore, a detailed analysis of the onset and progression of retinal dystrophy in NCL is still lacking,” they wrote. writes the researchers.

To solve this problem, two scientists from the School of Agriculture and Life Sciences at Lincoln University, New Zealand, analyzed the eyes of natural sheep models of two types of Batten – CLN5 and CLN6 diseases – at different stages of the disease.

CLN5 disease is caused by mutations in the CLN5 gene, while CLN6 disease is linked to mutations in the CLN6 embarrassed.

Vision problems often develop early to mid-disease in classic CLN5 and CLN6 patients. Retinal responses to light are lost between 7 and 10 years in CLN5 disease, while vision loss occurs between 3 and 7 years in CLN6 disease.

These sheep models have been widely used to study all aspects of Batten disease, including retinal damage. Indeed, the animals “reproduce the main symptomatic and neurological profiles of NCL, including progressive loss of vision,” the researchers wrote.

Now the team assessed total retinal thickness, individual retinal layer thickness, astrogliosis and lysosomal storage load in the eyes of the affected sheep. Astrogliosis refers to a process in which the number of astrocytes – star-shaped cells, supporting neurons – in the brain increases dramatically due to the loss of nearby neurons.

Sheep were examined at 3 months of age, before the onset of symptoms, then at 6 months (early symptoms), 12 months (established disease) and 18 months (terminal disease).

The data was also compared with that of healthy sheep at the same ages, which were used as controls.

Results showed that at 3 months of age, both models had thicker central retinas than controls, and CLN6 sheep also had thicker peripheral retinas.

This may be related to “early compensatory mechanisms or inflammatory edema [swelling] in the retina of affected animals,” the researchers wrote, adding that this “needs further investigation.”

At later stages of the disease, retinal differences from controls varied between the two models of Batten disease. In both models, however, significant retinal thinning was evident in end-stage disease.

Notably, this progressive reduction in thickness was observed on all retinal layers from 12 months in the CLN6 model. Conversely, in sheep with CLN5 disease, this narrowing was specific to the outer layers of the retina, with significant thinning being detected as early as 6 months of age in the layer containing the photoreceptor cell bodies.

recommended reading
biomarkers and tests

Both models also showed abnormally shaped astrocytes. Astrogliosis was detected throughout the retina from 6 months in both Batten models, contrasting with the layer-restricted astrogliosis seen in controls.

“Early and progressive increases [astrogliosis] …has also been observed in the retina of several mouse models of NCL,” the researchers wrote.

Additionally, toxic waste accumulation in lysosomes was detected primarily in retinal ganglion cell bodies (RGCs) in both sheep models, which is consistent with previous reports of retinal damage in patients with the disease. of Batten. RGCs are the bridging neurons that connect the retinal input to the brain’s visual processing centers.

Notably, this lysosomal storage accumulation was detected earlier in CLN6 sheep than in those with CLN5 – at 6 months versus 18 months.

These results generally match those previously reported for people with CLN5 or CLN6 disease, the team noted.

The data “highlighted the differential vulnerability of retinal layers and the temporal course of retinal atrophy in two distinct models of NCL disease,” the researchers wrote. These results will help determine “potential targets of ocular therapies and the optimal timing of these therapies for protection against retinal dysfunction and degeneration in NCL,” they added.

While all patients with these types of Batten would benefit the most from an “earlier the better” approach, the best outcomes in CLN5 disease can only be achieved with a very early approach, the Institute said. crew. The scientists noted that retinal thinning was detected before the onset of symptoms in the CLN5 animal model.

Additionally, since retinal shrinkage is detected in both the outer and inner layers in the CLN6 sheep model of disease, a therapeutic approach involving injections into both regions may lead to better outcomes.

Additionally, these data – along with the fact that sheep eyes are similar in size and retinal structure to human eyes – “further validate the use of sheep to study the retinal component of NCL and the potential [eye-targeting] therapies,” the researchers wrote.

Notably, the researchers are also using these models to test multiple doses and delivery routes of combined gene therapy directed at the brain and eyes.