PMID- 22310926
OWN - NLM
STAT- MEDLINE
DCOM- 20130404
LR  - 20230701
IS  - 1573-2665 (Electronic)
IS  - 0141-8955 (Print)
IS  - 0141-8955 (Linking)
VI  - 35
IP  - 5
DP  - 2012 Sep
TI  - Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a 
      treatment for infantile neuronal ceroid lipofuscinosis.
PG  - 847-57
LID - 10.1007/s10545-011-9446-x [doi]
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a profoundly neurodegenerative 
      disease of children caused by a deficiency in the lysosomal enzyme palmitoyl 
      protein thioesterase-1 (PPT1). There is currently no effective therapy for this 
      invariably fatal disease. To date, preclinical experiments using single 
      treatments have resulted in incremental clinical improvements. Therefore, we 
      determined the efficacy of CNS-directed AAV2/5-mediated gene therapy alone and in 
      combination with the systemic delivery of the lysosomotropic PPT1 mimetic 
      phosphocysteamine. Since CNS-directed gene therapy provides relatively high 
      levels of PPT1 activity to specific regions of the brain, we hypothesized that 
      phosphocysteamine would complement that activity in regions expressing 
      subtherapeutic levels of the enzyme. Results indicate that CNS-directed gene 
      therapy alone provided the greatest improvements in biochemical and histological 
      measures as well as motor function and life span. Phosphocysteamine alone 
      resulted in only minor improvements in motor function and no increase in 
      lifespan. Interestingly, phosphocysteamine did not increase the biochemical and 
      histological response when combined with AAV2/5-mediated gene therapy, but it did 
      result in an additional improvement in motor function. These data suggest that a 
      CNS-directed gene therapy approach provides significant clinical benefit, and the 
      addition of the small molecule PPT1 mimetic can further increase that response.
FAU - Roberts, Marie S
AU  - Roberts MS
AD  - Department of Internal Medicine, Washington University School of Medicine, Campus 
      Box 8007, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
FAU - Macauley, Shannon L
AU  - Macauley SL
FAU - Wong, Andrew M
AU  - Wong AM
FAU - Yilmas, Denis
AU  - Yilmas D
FAU - Hohm, Sarah
AU  - Hohm S
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
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120207
PL  - United States
TA  - J Inherit Metab Dis
JT  - Journal of inherited metabolic disease
JID - 7910918
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
RN  - YC9U0409D3 (Cystaphos)
SB  - IM
MH  - Animals
MH  - Biomimetic Materials/pharmacology
MH  - Brain/metabolism/pathology
MH  - Central Nervous System/pathology
MH  - Cystaphos/metabolism
MH  - Female
MH  - Genetic Therapy/methods
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Motor Activity/genetics
MH  - Neurodegenerative Diseases/*genetics/metabolism/pathology/*therapy
MH  - Neuronal Ceroid-Lipofuscinoses/*genetics/metabolism/pathology/*therapy
MH  - Thiolester Hydrolases/*genetics
PMC - PMC4108163
MID - NIHMS609910
EDAT- 2012/02/09 06:00
MHDA- 2013/04/05 06:00
PMCR- 2014/07/23
CRDT- 2012/02/08 06:00
PHST- 2011/08/16 00:00 [received]
PHST- 2011/12/27 00:00 [accepted]
PHST- 2011/12/21 00:00 [revised]
PHST- 2012/02/08 06:00 [entrez]
PHST- 2012/02/09 06:00 [pubmed]
PHST- 2013/04/05 06:00 [medline]
PHST- 2014/07/23 00:00 [pmc-release]
AID - 10.1007/s10545-011-9446-x [doi]
PST - ppublish
SO  - J Inherit Metab Dis. 2012 Sep;35(5):847-57. doi: 10.1007/s10545-011-9446-x. Epub 
      2012 Feb 7.