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Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):E5920-E5929. doi: 10.1073/pnas.1701832114. Epub 2017 Jul 3.

Synergistic effects of treating the spinal cord and brain in CLN1 disease.

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
2
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 9RX, United Kingdom.
3
Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, University of California, Los Angeles, Torrance, CA 90502.
4
Institute of Biomedicine/Biochemistry, University of Helsinki, 00014 Helsinki, Finland.
5
Division of Neuropathology, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110.
6
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; msands@dom.wustl.edu jonathan.cooper@labiomed.org.
7
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
8
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 9RX, United Kingdom; msands@dom.wustl.edu jonathan.cooper@labiomed.org.
9
Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1-/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1-/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1-/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.

KEYWORDS:

adeno-associated virus; brain; combination therapy; infantile Batten disease; spinal cord

PMID:
28673981
PMCID:
PMC5530669
DOI:
10.1073/pnas.1701832114
[Indexed for MEDLINE]
Free PMC Article

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