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Natural canine models of several types of neuronal ceroid lipofuscinosis (NCL), also known as Batten’s disease, may aid in the development of new effective therapies for these conditions, according to a review study.

The study, “Canine neuronal lipofuscinosis ceroids: promising models for preclinical testing of therapeutic interventions, ”Was published in the journal Neurobiology of the disease.

NCLs are the most common group of pediatric neurodegenerative disorders characterized by progressive intellectual and motor deterioration, seizures, and vision loss.

They are caused by mutations in at least 13 different genes, which lead to the toxic build-up of waste molecules, including lipofuscin, inside lysosomes – the cell compartment responsible for breaking down waste products – mainly in brain cells, leading to nerve cell damage and death.

Since the symptoms of some forms of CNL overlap, genetic testing is the only way to determine with absolute certainty a patient’s form.

NCL-like disorders also occur naturally in other mammals, including dogs, cats, horses, cattle, mice, and monkeys. Studies on these animals can help identify new disease-causing mutations or test experimental therapies for further evaluation in clinical trials in human patients.

Researchers have now reviewed what is known about NCL in dogs and ongoing efforts to develop or test treatments for human NCL using natural canine models of these diseases.

So far, 12 mutations in eight genes equivalent to known human genes linked to NCL have been identified in more than 20 canine breeds and mixed breed dogs.

According to the researchers, a diagnosis of NCL should be considered for any dog ​​that exhibits several signs of the disease, including anxiety, development of aggressive and compulsive behaviors, loss of responsiveness to previously learned commands, dyscoordination of movements, tremors, convulsions and blurred vision. – which gradually worsen over time.

The presence of lipofuscin accumulation in nerve cell tissues also supports a diagnosis of NCL, but definitive diagnosis and classification of NCL requires genetic testing.

The absence of mutations known to cause NCL in dogs does not rule out NCL as a cause of dog symptoms, as the animal may carry a causative mutation of NCL that has not yet been identified.

“If the mutation occurs in another gene, it will be necessary to determine whether the disease should be classified as a new form of NCL or whether it should be placed in another established group of inherited lysosomal storage disorders,” the researchers wrote.

To date, researchers have evaluated potential therapeutic approaches in dogs with CLN8 disease or CLN2 disease – a late childhood form of Batten disease.

The positive results of enzyme replacement therapy for CLN2 disease in miniature long-haired dachshunds have actually led to the development of a clinical trial (NCT02963350) evaluating this therapy – Brineura (cerliponase alfa), developed by BioMarin Pharmaceuticals – in children with CLN2 disease. Brineura was then approved in 2017.

Previous studies have also evaluated the potential therapeutic benefits of gene therapy – the introduction of the healthy version of a gene known to be associated with CLN2 disease when mutated – and of stem cell therapy in this model. canine disease CLN2.

Since canine NCLs are relatively rare and genetic testing allows breeders to identify dogs with mutations in NCL-related genes to avoid breeding them, establishing canine disease patterns and preserving their semen may be required for future therapeutic studies.

The team also noted that “continued research on other canine NCLs, with further characterization and understanding of disease processes, will likely lead to the development of successful therapeutic interventions for other forms of NCL, to the both for human patients and animals with these diseases. ”

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