Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis
PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5months of age and death by around 8months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3mg, corresponding to 12mg/kg or 180 U/kg for a 25g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3months in mice treated from birth, and although this improvement persisted it was attenuated by 7months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed.
[Show abstract][Hide abstract] ABSTRACT: The Neuronal Ceroid Lipofuscinoses (NCLs) are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause NCL, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to NCL research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscionoses or Batten Disease.
[Show abstract][Hide abstract] ABSTRACT: The Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are a group of inherited neurodegenerative diseases. Infantile Neuronal Ceroid lipofuscinosis (INCL, Infantile Batten Disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the life span of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as Juvenile Neuronal Ceroid Lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic.
[Show abstract][Hide abstract] ABSTRACT: The infantile form of neuronal ceroid lipofuscinosis (ie, infantile Batten disease) is the most rapidly progressing type and is caused by an inherited deficiency in the lysosomal enzyme palmitoyl protein thioesterase 1. The absence of enzyme activity leads to progressive accumulation of autofluorescent material in many cell types, particularly neurons of the central nervous system. Clinical signs of infantile neuronal ceroid lipofuscinosis appear between 6 months and 1 year of age and include vision loss, cognitive decline, motor deficits, seizures, and premature death, typically by 3 to 5 years of age. There is currently no effective treatment. However, preclinical experiments in the murine model of infantile neuronal ceroid lipofuscinosis have shown that gene therapy, enzyme replacement, stem cell transplantation, and small-molecule drugs, alone or in combination, can significantly slow disease progression. A more thorough understanding of the underlying pathogenesis of infantile neuronal ceroid lipofuscinosis will identify new therapeutic targets.
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