Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Dolan Sondhi, Daniel A. Peterson, Andrew M. Edelstein, Katrina del Fierro, Neil R. Hackett, Ronald Crystal

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild-type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day-treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk-treated mice, 168 days for 7 wk-treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.

Original languageEnglish
Pages (from-to)18-27
Number of pages10
JournalExperimental Neurology
Volume213
Issue number1
DOIs
Publication statusPublished - 1 Sep 2008
Externally publishedYes

Fingerprint

Neuronal Ceroid-Lipofuscinoses
Genes
Knockout Mice
Protein Deficiency
Dependovirus
Essential Genes
Brain
Therapeutics
Genetic Therapy
Complementary DNA
Mutation

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. / Sondhi, Dolan; Peterson, Daniel A.; Edelstein, Andrew M.; del Fierro, Katrina; Hackett, Neil R.; Crystal, Ronald.

In: Experimental Neurology, Vol. 213, No. 1, 01.09.2008, p. 18-27.

Research output: Contribution to journalArticle

Sondhi, Dolan ; Peterson, Daniel A. ; Edelstein, Andrew M. ; del Fierro, Katrina ; Hackett, Neil R. ; Crystal, Ronald. / Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. In: Experimental Neurology. 2008 ; Vol. 213, No. 1. pp. 18-27.
@article{4eb7d587e5ce4aaaa39c3eccf91dee24,
title = "Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis",
abstract = "Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild-type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day-treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk-treated mice, 168 days for 7 wk-treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.",
author = "Dolan Sondhi and Peterson, {Daniel A.} and Edelstein, {Andrew M.} and {del Fierro}, Katrina and Hackett, {Neil R.} and Ronald Crystal",
year = "2008",
month = "9",
day = "1",
doi = "10.1016/j.expneurol.2008.04.022",
language = "English",
volume = "213",
pages = "18--27",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

AU - Sondhi, Dolan

AU - Peterson, Daniel A.

AU - Edelstein, Andrew M.

AU - del Fierro, Katrina

AU - Hackett, Neil R.

AU - Crystal, Ronald

PY - 2008/9/1

Y1 - 2008/9/1

N2 - Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild-type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day-treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk-treated mice, 168 days for 7 wk-treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.

AB - Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild-type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day-treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk-treated mice, 168 days for 7 wk-treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.

UR - http://www.scopus.com/inward/record.url?scp=49349114075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49349114075&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2008.04.022

DO - 10.1016/j.expneurol.2008.04.022

M3 - Article

VL - 213

SP - 18

EP - 27

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -