Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis.
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.
Sleat
David E
DE
Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA. sleat@cabm.rutgers.edu
El-Banna
Mukarram
M
Sohar
Istvan
I
Kim
Kwi-Hye
KH
Dobrenis
Kostantin
K
Walkley
Steven U
SU
Lobel
Peter
P
D000626:Aminopeptidases; D000818:Animals; D001921:Brain / Q000201:enzymology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods* / Q000401:mortality; D008099:Liver / Q000201:enzymology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D057057:Serine Proteases; D013045:Species Specificity; D000091346:Tripeptidyl-Peptidase 1
C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D010450:Endopeptidases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C103607:mitochondrial ATPase subunit c; D025261:Mitochondrial Proton-Translocating ATPases