title: Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease.
abstract: Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cabrera-Salazar
authors.forename: Eric M
authors.initials: EM
authors.lastname: Roskelley
authors.forename: Jie
authors.initials: J
authors.lastname: Bu
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Hodges
authors.forename: Nelson
authors.initials: N
authors.lastname: Yew
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: Istvan
authors.initials: I
authors.lastname: Sohar
authors.forename: David E
authors.initials: DE
authors.lastname: Sleat
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Scheule
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Peter
authors.initials: P
authors.lastname: Lobel
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
mesh_terms: D000626:Aminopeptidases; D000818:Animals; D001921:Brain / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009472:Neuronal Ceroid-Lipofuscinoses / Q000503:physiopathology / Q000628:therapy*; D057057:Serine Proteases; D016019:Survival Analysis; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D010450:Endopeptidases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human