Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus Macaque-derived Adeno-associated virus vector

Dolan Sondhi, Neil R. Hackett, Daniel A. Peterson, Jamie Stratton, Michael Baad, Kelly M. Travis, James M. Wilson, Ronald Crystal

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a lysosomal storage disorder caused by mutations in the CLN2 gene and a deficiency of tripeptidyl peptidase I (TPP-I). Prior studies with adeno-associated virus (AAV) serotype 2 or 5 mediated transfer of the CLN2 complementary DNA to the central nervous system (CNS) of CLN2-/- mice cleared CNS storage granules, but provided no improvement in the phenotype or survival of this model of LINCL. In this study, AAV serotypes (AAV2, AAV5, AAV8, and AAVrh.10) were compared for the delivery of the same CLN2 expression cassette. AAVrh.10, derived from rhesus macaque, provided the highest TPP-I level and maximum spread beyond the site of injection. The AAVrh.10-based vector functioned equally well in naive rats and in rats previously immunized against human serotypes of AAV. When administered to the CNS of CLN2-/- mice, the AAVrh.10CLN2 vector provided widespread TPP-I activity comparable to that in the wild-type mice. Importantly, the AAVrh.10CLN2-treated CLN2-/- mice had significant reduction in CNS storage granules and demonstrated improvement in gait, nest-making abilities, seizures, balance beam function, and grip strength, as well as having a survival advantage.

Original languageEnglish
Pages (from-to)481-491
Number of pages11
JournalMolecular Therapy
Volume15
Issue number3
DOIs
Publication statusPublished - 1 Mar 2007
Externally publishedYes

Fingerprint

Neuronal Ceroid-Lipofuscinoses
Dependovirus
Macaca mulatta
Central Nervous System
Survival
Genes
Hand Strength
Gait
Seizures
Complementary DNA
Phenotype
Mutation
Injections
Serogroup
tripeptidyl-peptidase 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus Macaque-derived Adeno-associated virus vector. / Sondhi, Dolan; Hackett, Neil R.; Peterson, Daniel A.; Stratton, Jamie; Baad, Michael; Travis, Kelly M.; Wilson, James M.; Crystal, Ronald.

In: Molecular Therapy, Vol. 15, No. 3, 01.03.2007, p. 481-491.

Research output: Contribution to journalArticle

Sondhi, Dolan ; Hackett, Neil R. ; Peterson, Daniel A. ; Stratton, Jamie ; Baad, Michael ; Travis, Kelly M. ; Wilson, James M. ; Crystal, Ronald. / Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus Macaque-derived Adeno-associated virus vector. In: Molecular Therapy. 2007 ; Vol. 15, No. 3. pp. 481-491.
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abstract = "Late infantile neuronal ceroid lipofuscinosis (LINCL) is a lysosomal storage disorder caused by mutations in the CLN2 gene and a deficiency of tripeptidyl peptidase I (TPP-I). Prior studies with adeno-associated virus (AAV) serotype 2 or 5 mediated transfer of the CLN2 complementary DNA to the central nervous system (CNS) of CLN2-/- mice cleared CNS storage granules, but provided no improvement in the phenotype or survival of this model of LINCL. In this study, AAV serotypes (AAV2, AAV5, AAV8, and AAVrh.10) were compared for the delivery of the same CLN2 expression cassette. AAVrh.10, derived from rhesus macaque, provided the highest TPP-I level and maximum spread beyond the site of injection. The AAVrh.10-based vector functioned equally well in naive rats and in rats previously immunized against human serotypes of AAV. When administered to the CNS of CLN2-/- mice, the AAVrh.10CLN2 vector provided widespread TPP-I activity comparable to that in the wild-type mice. Importantly, the AAVrh.10CLN2-treated CLN2-/- mice had significant reduction in CNS storage granules and demonstrated improvement in gait, nest-making abilities, seizures, balance beam function, and grip strength, as well as having a survival advantage.",
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