PMID- 25982063 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20211203 IS - 1096-7206 (Electronic) IS - 1096-7192 (Linking) VI - 116 IP - 1-2 DP - 2015 Sep-Oct TI - Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. PG - 98-105 LID - S1096-7192(15)30012-3 [pii] LID - 10.1016/j.ymgme.2015.05.005 [doi] AB - The neuronal ceroid lipofuscinoses (NCLs) are a group of related hereditary lysosomal storage disorders characterized by progressive loss of neurons in the central nervous system resulting in dementia, loss of motor skills, seizures and blindness. A characteristic intralysosomal accumulation of autofluorescent storage material occurs in the brain and other tissues. Three major forms and nearly a dozen minor forms of NCL are recognized. Infantile-onset NCL (CLN1 disease) is caused by severe deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1) and no therapy beyond supportive care is available. Homozygous Ppt1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death around 8 months. Direct delivery of lysosomal enzymes to the cerebrospinal fluid is an approach that has gained traction in small and large animal models of several other neuropathic lysosomal storage diseases, and has advanced to clinical trials. In the current study, Ppt1 knockout mice were treated with purified recombinant human PPT1 enzyme delivered to the lumbar intrathecal space on each of three consecutive days at 6 weeks of age. Untreated PPT1 knockout mice and wild-type mice served as additional controls. Four enzyme concentration levels (0, 2.6, 5.3 and 10.6 mg/ml of specific activity 20 U/mg) were administered in a volume of 80 mul infused over 8 min. Each group consisted of 16-20 mice. The treatment was well tolerated. Disease-specific survival was 233, 267, 272, and 284days for each of the four treatment groups, respectively, and the effect of treatment was highly significant (p<0.0001). The timing of motor deterioration was also delayed. Neuropathology was improved as evidenced by decreased autofluorescent storage material in the spinal cord and a decrease in CD68 staining in the cortex and spinal cord. The improvements in motor function and survival are similar to results reported for preclinical studies involving other lysosomal storage disorders, such as CLN2/TPP1 deficiency, for which intraventricular ERT is being offered in clinical trials. If ERT delivery to the CSF proves to be efficacious in these disorders, PPT1 deficiency may also be amenable to this approach. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Lu, Jui-Yun AU - Lu JY AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. FAU - Nelvagal, Hemanth R AU - Nelvagal HR AD - Pediatric Storage Disorders Laboratory, Department of Basic and Clinical Neuroscience, King's Health Partners Centre for Neurodegeneration, James Black Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK. FAU - Wang, Lingling AU - Wang L AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. FAU - Birnbaum, Shari G AU - Birnbaum SG AD - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. FAU - Cooper, Jonathan D AU - Cooper JD AD - Pediatric Storage Disorders Laboratory, Department of Basic and Clinical Neuroscience, King's Health Partners Centre for Neurodegeneration, James Black Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK. FAU - Hofmann, Sandra L AU - Hofmann SL AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. Electronic address: sandra.hofmann@utsouthwestern.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150512 PL - United States TA - Mol Genet Metab JT - Molecular genetics and metabolism JID - 9805456 RN - 0 (Membrane Proteins) RN - 0 (Recombinant Proteins) RN - 0 (Tpp1 protein, mouse) RN - 0 (Tripeptidyl-Peptidase 1) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (PPT1 protein, human) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) RN - EC 3.4.14.9 (TPP1 protein, human) SB - IM MH - Animals MH - Brain/drug effects/immunology/pathology MH - *Disease Models, Animal MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - *Enzyme Replacement Therapy MH - Humans MH - Injections, Spinal MH - Membrane Proteins/pharmacology/*therapeutic use MH - Mice, Inbred C57BL MH - Mice, Knockout MH - *Motion MH - Neuronal Ceroid-Lipofuscinoses/*drug therapy MH - Recombinant Proteins/pharmacology/therapeutic use MH - Thiolester Hydrolases/genetics MH - Tripeptidyl-Peptidase 1 OTO - NOTNLM OT - Batten disease OT - Enzyme replacement therapy OT - Infantile neuronal ceroid lipofuscinosis OT - Lysosomal storage disorder OT - Palmitoyl protein thioesterase EDAT- 2015/05/20 06:00 MHDA- 2016/07/07 06:00 CRDT- 2015/05/19 06:00 PHST- 2015/04/07 00:00 [received] PHST- 2015/05/09 00:00 [revised] PHST- 2015/05/10 00:00 [accepted] PHST- 2015/05/19 06:00 [entrez] PHST- 2015/05/20 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] AID - S1096-7192(15)30012-3 [pii] AID - 10.1016/j.ymgme.2015.05.005 [doi] PST - ppublish SO - Mol Genet Metab. 2015 Sep-Oct;116(1-2):98-105. doi: 10.1016/j.ymgme.2015.05.005. Epub 2015 May 12.