Therefore, the purpose of this study was to generate an alternative cLINCL animal model that would allow for the assessment of all therapeutic approaches including nonsense suppression therapies. antisense oligonucleotides and nonsense suppression compounds) is limited by the genotypes of available cLINCL animal models for example, the genotype of the commonly used Cln2 -/- mouse model does not permit the assessment of significantly relevant mutation-targeted therapies. However, the assessment of some therapeutic approaches (i.e. Experimental and clinical trials for cLINCL focus on gene therapy and enzyme replacement therapy. To combat this premature death, numerous therapeutic approaches have been hypothesized and assessed. Like all other NCLs, cLINCL results in premature death. This deficiency leads to a disease onset ranging from 2 to 4 years of age with initial clinical symptoms consisting of developmental delay and epilepsy. ĬLINCL, also referred to as CLN2 disease, stems from a deficiency in the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). The most common altered genes are CLN1, CLN2, and CLN3 causing classic Infantile Neuronal Ceroid Lipofuscinosis (cINCL), classic Late Infantile Neuronal Ceroid Lipofuscinosis (cLINCL), and classic Juvenile Neuronal Ceroid Lipofuscinosis (cJNCL) respectively. Generally, these NCL forms are based on disease onset and mutated gene. Currently, several mutations have been identified in more than 13 different genes all resulting in a specific form of NCL. Unfortunately, the NCLs are not limited to a single gene or genetic mutation. Given the large neurological manifestations and predominance in childhood onset, the NCLs are considered to be the most common pediatric neurodegenerative disease. Symptomatic hallmarks of the NCLs consist of but are not limited to epilepsy, tremors, retinopathy, gross and fine motor deterioration, and cognitive decline. Most commonly, NCL onset begins in childhood however in rarer occasions onset can occur in adulthood. The Neuronal Ceroid Lipofuscinoses (NCLs) are a special category of LSD and accumulate a storage material referred to as ceroid lipofuscin. All LSDs affect multiple physiological systems however, most appear to illicit a significant effect on the central nervous system (CNS). LSDs are commonly categorized according to the constituents of this accumulated material thus resulting in generalized LSD categories for example the mucopolysaccharidoses accumulate mucopolysaccharides. These deficiencies affect normal lysosomal function resulting in an accumulation of various lysosomal substrates. Collectively, these assessments indicate that the Cln2 R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.Ĭhildren across the globe are affected by any one of more than 40 different lysosomal storage disorders (LSDs) many of them resulting from deficiencies in either a lysosomal membrane protein or lysosomal enzyme. This reduction leads to the development of neurological impairment (e.g. Molecular assessment of Cln2 R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2 R208X. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. The genotype of the original mouse model of CLN2 disease, Cln2 -/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Nevertheless, preclinical and clinical trials exist for various therapies. The NCLs result in premature death due to the absence of curative therapies. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes.
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