PMID- 22368049
OWN - NLM
STAT- MEDLINE
DCOM- 20120830
LR  - 20230607
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Print)
IS  - 0364-5134 (Linking)
VI  - 71
IP  - 6
DP  - 2012 Jun
TI  - Synergistic effects of central nervous system-directed gene therapy and bone 
      marrow transplantation in the murine model of infantile neuronal ceroid 
      lipofuscinosis.
PG  - 797-804
LID - 10.1002/ana.23545 [doi]
AB  - OBJECTIVE: Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited 
      childhood neurodegenerative disorder caused by the loss of palmitoyl protein 
      thioesterase-1 (PPT1) activity. Affected children suffer from blindness, 
      epilepsy, motor dysfunction, cognitive decline, and premature death. The 
      Ppt1(-/-) mouse shares the histological and clinical features of INCL. Previous 
      single-therapy approaches using small molecule drugs, gene therapy, or neuronal 
      stem cells resulted in partial histological correction, with minimal improvements 
      in motor function or lifespan. Here, we combined central nervous system 
      (CNS)-directed adeno-associated virus (AAV)2/5-mediated gene therapy with bone 
      marrow transplantation (BMT) in the INCL mouse. METHODS: At birth, Ppt1(-/-) and 
      wild-type mice were given either intracranial injections of AAV2/5-PPT1 or bone 
      marrow transplantation, separately as well as in combination. To assess function, 
      we measured rotorod performance monthly as well as lifespan. At terminal time 
      points, we evaluated the therapeutic effects on several INCL-specific parameters, 
      such as cortical thickness, autofluorescent accumulation, and glial activation. 
      Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment 
      in treated mice. RESULTS: AAV2/5-mediated gene therapy alone resulted in 
      significant histological correction, improved motor function, and increased 
      lifespan. Interestingly, the addition of BMT further increased the lifespan of 
      treated mice and led to dramatic, sustained improvements in motor function. These 
      data are truly striking, given that BMT alone is ineffective, yet it synergizes 
      with CNS-directed gene therapy to dramatically increase efficacy and lifespan. 
      INTERPRETATION: AAV2/5-mediated gene therapy in combination with BMT provides an 
      unprecedented increase in lifespan as well as dramatic improvement on functional 
      and histological parameters.
CI  - Copyright (c) 2012 American Neurological Association.
FAU - Macauley, Shannon L
AU  - Macauley SL
AD  - Department of Internal Medicine, Washington University School of Medicine, 660 S. 
      Euclid Ave., St Louis, MO 63110, USA.
FAU - Roberts, Marie S
AU  - Roberts MS
FAU - Wong, Andrew M
AU  - Wong AM
FAU - McSloy, Francesca
AU  - McSloy F
FAU - Reddy, Adarsh S
AU  - Reddy AS
FAU - Cooper, Jonathan D
AU  - Cooper JD
FAU - Sands, Mark S
AU  - Sands MS
LA  - eng
GR  - R01 NS043205/NS/NINDS NIH HHS/United States
GR  - NS056728/NS/NINDS NIH HHS/United States
GR  - GR079491MA/WT_/Wellcome Trust/United Kingdom
GR  - NS043105/NS/NINDS NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R44 NS043105/NS/NINDS NIH HHS/United States
GR  - R01 NS043205-09/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120224
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Animals, Newborn
MH  - Bone Marrow Transplantation/*methods
MH  - Brain/metabolism/pathology
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Female
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/administration & dosage
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Motor Activity
MH  - Neuronal Ceroid-Lipofuscinoses/pathology/physiopathology/*therapy
MH  - Rotarod Performance Test
MH  - Thiolester Hydrolases/*biosynthesis/deficiency/therapeutic use
PMC - PMC3369009
MID - NIHMS353711
EDAT- 2012/03/01 06:00
MHDA- 2012/08/31 06:00
PMCR- 2013/06/01
CRDT- 2012/02/28 06:00
PHST- 2011/11/16 00:00 [received]
PHST- 2011/12/16 00:00 [revised]
PHST- 2012/01/13 00:00 [accepted]
PHST- 2012/02/28 06:00 [entrez]
PHST- 2012/03/01 06:00 [pubmed]
PHST- 2012/08/31 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - 10.1002/ana.23545 [doi]
PST - ppublish
SO  - Ann Neurol. 2012 Jun;71(6):797-804. doi: 10.1002/ana.23545. Epub 2012 Feb 24.