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

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Shyng , C , Nelvagal , H R , Dearborn , J T , Tyynela , J , Schmidt , R E , Sands , M S & Cooper , J D 2017 , ' Synergistic effects of treating the spinal cord and brain in CLN1 disease ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 114 , no. 29 , pp. E5920-E5929 . https://doi.org/10.1073/pnas.1701832114

Title: Synergistic effects of treating the spinal cord and brain in CLN1 disease
Author: Shyng, Charles; Nelvagal, Hemanth R.; Dearborn, Joshua T.; Tyynela, Jaana; Schmidt, Robert E.; Sands, Mark S.; Cooper, Jonathan D.
Contributor organization: Department of Biochemistry and Developmental Biology
Medicum
University of Helsinki
Date: 2017-07-18
Language: eng
Number of pages: 10
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
DOI: https://doi.org/10.1073/pnas.1701832114
URI: http://hdl.handle.net/10138/305656
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.
Subject: infantile Batten disease
adeno-associated virus
spinal cord
brain
combination therapy
NEURONAL CEROID-LIPOFUSCINOSIS
PALMITOYL-PROTEIN THIOESTERASE
ENZYME REPLACEMENT THERAPY
CENTRAL-NERVOUS-SYSTEM
DIRECTED GENE-THERAPY
MUCOPOLYSACCHARIDOSIS TYPE-VII
PRECLINICAL MOUSE MODEL
MURINE MODEL
LYSOSOMAL STORAGE
BATTEN-DISEASE
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: other
Usage restriction: openAccess
Self-archived version: publishedVersion


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