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

David E. Sleat, Mukarram El-Banna, Istvan Sohar, Kwi Hye Kim, Kostantin Dobrenis, Steven U. Walkley, Peter Lobel

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 ∼9 months compared to mice expressing ∼0.2% of normal levels. Expression of 6% of normal TPPI activity dramatically attenuated disease, with a median lifespan of ∼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.

Original languageEnglish (US)
Pages (from-to)222-233
Number of pages12
JournalMolecular Genetics and Metabolism
Volume94
Issue number2
DOIs
StatePublished - Jun 2008

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Gene therapy
Genetic Therapy
Nervous System Heredodegenerative Disorders
Neurodegenerative diseases
Benchmarking
Gene encoding
Enzyme activity
Brain Diseases
tripeptidyl-peptidase 1
Brain
Peptide Hydrolases
Mutation
Enzymes
Therapeutics
Genes

Keywords

  • Hypomorph
  • Lysosomal storage disease
  • Mouse model
  • Neuronal ceroid lipofuscinosis

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis. / Sleat, David E.; El-Banna, Mukarram; Sohar, Istvan; Kim, Kwi Hye; Dobrenis, Kostantin; Walkley, Steven U.; Lobel, Peter.

In: Molecular Genetics and Metabolism, Vol. 94, No. 2, 06.2008, p. 222-233.

Research output: Contribution to journalArticle

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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 ∼9 months compared to mice expressing ∼0.2{\%} of normal levels. Expression of 6{\%} of normal TPPI activity dramatically attenuated disease, with a median lifespan of ∼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.",
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