Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis.

Abstract

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a hereditary neurodegenerative disease of childhood that is caused by mutations in the gene (CLN2) encoding the lysosomal protease tripeptidyl-peptidase I (TPPI). LINCL is fatal and there is no treatment of demonstrated efficacy in affected children but preclinical studies with AAV-mediated gene therapy have demonstrated promise in a mouse model. Here, we have generated mouse CLN2-mutants that express different amounts of TPPI activity to benchmark levels required for therapeutic benefits. Approximately 3% of normal TPPI activity in brain delayed disease onset and doubled lifespan to a median of approximately 9 months compared to mice expressing approximately 0.2% of normal levels. Expression of 6% of normal TPPI activity dramatically attenuated disease, with a median lifespan of approximately 20 months which approaches that of unaffected mice. While the lifespan of this hypomorph is shortened, disease is late-onset, less severe and progresses slowly compared to mice expressing lower TPPI levels. For gene therapy and other approaches that restore enzyme activity, these results suggest that 6% of normal TPPI activity throughout the CNS of affected individuals will provide a significant therapeutic benefit but higher levels will be required to cure this disease.

• Authors: David E Sleat, Mukarram El-Banna, Istvan Sohar, Kwi-Hye Kim, Kostantin Dobrenis, Steven U Walkley, Peter Lobel
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 94 Issue 2 Pg. 222-33 (Jun 2008) ISSN: 1096-7206 [Electronic] United States
• PMID: 18343701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Tpp1 protein, mouse
• Tripeptidyl-Peptidase 1
• Endopeptidases
• Serine Proteases
• Aminopeptidases
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• mitochondrial ATPase subunit c
• Mitochondrial Proton-Translocating ATPases

Topics

• Aminopeptidases
• Animals
• Brain (enzymology)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• Disease Models, Animal
• Endopeptidases (analysis, genetics, metabolism)
• Gene Targeting
• Genetic Therapy (methods, mortality)
• Liver (enzymology)
• Lysosomes (metabolism)
• Mice
• Mice, Transgenic
• Mitochondrial Proton-Translocating ATPases (metabolism)
• Neuronal Ceroid-Lipofuscinoses (enzymology, genetics, physiopathology, therapy)
• Serine Proteases
• Species Specificity
• Tripeptidyl-Peptidase 1