PMID- 36040802
OWN - NLM
STAT- MEDLINE
DCOM- 20221018
LR  - 20230324
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 132
IP  - 20
DP  - 2022 Oct 17
TI  - Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and 
      sheep.
LID - 10.1172/JCI163107 [doi]
LID - e163107
AB  - CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or 
      infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder 
      resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme 
      palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven 
      challenging because of the aggressive disease course and the need to treat 
      widespread areas of the brain and spinal cord. Indeed, gene therapy has proven 
      less effective for CLN1 disease than for other similar lysosomal enzyme 
      deficiencies. We therefore tested the efficacy of enzyme replacement therapy 
      (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to 
      PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially 
      scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 
      delivery was the most effective route of administration, resulting in 
      therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had 
      improved motor function, reduced disease-associated pathology, and diminished 
      neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 
      distribution and positive treatment effects measured by quantitative structural 
      MRI and neuropathology. This study demonstrates the feasibility and therapeutic 
      efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward 
      clinical testing of ERT in children with CLN1 disease and highlight the 
      importance of a cross-species approach to developing a successful treatment 
      strategy.
FAU - Nelvagal, Hemanth R
AU  - Nelvagal HR
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Eaton, Samantha L
AU  - Eaton SL
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Wang, Sophie H
AU  - Wang SH
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Eultgen, Elizabeth M
AU  - Eultgen EM
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Takahashi, Keigo
AU  - Takahashi K
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Le, Steven Q
AU  - Le SQ
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Nesbitt, Rachel
AU  - Nesbitt R
AD  - Department of Medicine, Washington University in St. Louis, School of Medicine, 
      St .Louis, Missouri, USA.
FAU - Dearborn, Joshua T
AU  - Dearborn JT
AD  - Department of Medicine, Washington University in St. Louis, School of Medicine, 
      St .Louis, Missouri, USA.
FAU - Siano, Nicholas
AU  - Siano N
AD  - Discovery Science Division, Amicus Therapeutics Inc., Philadelphia, Pennsylvania, 
      USA.
FAU - Puhl, Ana C
AU  - Puhl AC
AD  - Collaborations Pharmaceuticals Inc., Lab 3510, Raleigh, North Carolina, USA.
FAU - Dickson, Patricia I
AU  - Dickson PI
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
AD  - Department of Genetics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Thompson, Gerard
AU  - Thompson G
AD  - Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's 
      Building, Edinburgh, Scotland, United Kingdom.
AD  - Department of Clinical Neurosciences, NHS Lothian, Edinburgh, Scotland, United 
      Kingdom.
FAU - Murdoch, Fraser
AU  - Murdoch F
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Brennan, Paul M
AU  - Brennan PM
AD  - Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's 
      Building, Edinburgh, Scotland, United Kingdom.
AD  - Department of Clinical Neurosciences, NHS Lothian, Edinburgh, Scotland, United 
      Kingdom.
FAU - Gray, Mark
AU  - Gray M
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Greenhalgh, Stephen N
AU  - Greenhalgh SN
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Tennant, Peter
AU  - Tennant P
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Gregson, Rachael
AU  - Gregson R
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Clutton, Eddie
AU  - Clutton E
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Nixon, James
AU  - Nixon J
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Proudfoot, Chris
AU  - Proudfoot C
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
AD  - The Large Animal Research and Imaging Facility (LARIF), Royal (Dick) School of 
      Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, 
      Scotland, United Kingdom.
FAU - Guido, Stefano
AU  - Guido S
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Lillico, Simon G
AU  - Lillico SG
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Whitelaw, C Bruce A
AU  - Whitelaw CBA
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Lu, Jui-Yun
AU  - Lu JY
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Hofmann, Sandra L
AU  - Hofmann SL
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Ekins, Sean
AU  - Ekins S
AD  - Collaborations Pharmaceuticals Inc., Lab 3510, Raleigh, North Carolina, USA.
FAU - Sands, Mark S
AU  - Sands MS
AD  - Department of Medicine, Washington University in St. Louis, School of Medicine, 
      St .Louis, Missouri, USA.
AD  - Department of Genetics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
FAU - Wishart, Thomas M
AU  - Wishart TM
AD  - The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of 
      Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
FAU - Cooper, Jonathan D
AU  - Cooper JD
AD  - Department of Pediatrics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
AD  - Department of Genetics, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
AD  - Department of Neurology, Washington University in St. Louis, School of Medicine, 
      St. Louis, Missouri, USA.
LA  - eng
GR  - R43 NS107079/NS/NINDS NIH HHS/United States
GR  - R01 NS124655/NS/NINDS NIH HHS/United States
GR  - BB/P013732/1 ISP/BB_/Biotechnology and Biological Sciences Research 
      Council/United Kingdom
GR  - R44 NS107079/NS/NINDS NIH HHS/United States
GR  - R01 NS100779/NS/NINDS NIH HHS/United States
GR  - BB/J004316/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - R56 NS117635/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 - 20221017
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - Ceroid Lipofuscinosis, Neuronal, 1
SB  - IM
MH  - Animals
MH  - Child
MH  - Disease Models, Animal
MH  - Enzyme Replacement Therapy
MH  - Humans
MH  - Mice
MH  - Mutation
MH  - *Neuronal Ceroid-Lipofuscinoses/drug therapy/genetics
MH  - Sheep
PMC - PMC9566914
OTO - NOTNLM
OT  - Lysosomes
OT  - Monogenic diseases
OT  - Neurodegeneration
OT  - Neuroscience
OT  - Therapeutics
EDAT- 2022/08/31 06:00
MHDA- 2022/10/19 06:00
PMCR- 2022/10/17
CRDT- 2022/08/30 12:02
PHST- 2022/06/29 00:00 [received]
PHST- 2022/08/25 00:00 [accepted]
PHST- 2022/08/31 06:00 [pubmed]
PHST- 2022/10/19 06:00 [medline]
PHST- 2022/08/30 12:02 [entrez]
PHST- 2022/10/17 00:00 [pmc-release]
AID - 163107 [pii]
AID - 10.1172/JCI163107 [doi]
PST - epublish
SO  - J Clin Invest. 2022 Oct 17;132(20):e163107. doi: 10.1172/JCI163107.