Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

“…Consequently, mice show a reduced lifespan, with most dying between 3 and 6 months of age. As observed in the previous mouse model (Sleat et al, 2004) To date there is evidence of NCL in over 20 canine breeds and mixedbreed dogs (Katz, Rustad et al, 2017). The canine Tpp1 gene sequence (GenBank AF114167) includes all 13 exons that are present in the human TPP1 gene, and exonic sequences are highly conserved between both species (Drögemüller, Wöhlke, & Distl, 2005).…”

“…To date there is evidence of NCL in over 20 canine breeds and mixed‐breed dogs (Katz, Rustad et al, ). The canine Tpp1 gene sequence (GenBank AF114167) includes all 13 exons that are present in the human TPP1 gene, and exonic sequences are highly conserved between both species (Drögemüller, Wöhlke, & Distl, ).…”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…Since the clinical signs of NCLs mimic other lysosomal storage diseases, definitive diagnosis is based on presence of a mutation in one of the established NCL genes (116). Fortunately, dogs suspected of suffering from NCL can be tested easily for any of the known mutations from a blood sample or cheek swab (117). Like humans, dogs show differences in disease onset, lesion distribution, and chemical storage material.…”

Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies

“…Numerous LSDs have also been diagnosed in dog breeds, of which mucopolysaccharidoses (MPS) and neuronal ceroid lipofuscinoses (NCLs) are the most interesting models for preclinical studies. Causative mutations have been identified for eight NCLs (Katz et al 2017) and five MPS (Switonski 2014) diseases.…”