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

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

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

“…6,7 This has revealed differences in the extent, timing, and nature of changes 41,42 despite leading to a similar pathological endpoint. The spinal cord has been identi fied as exhibiting important patho logy, including loss of neurons, activation of microglia, and buildup of lipo pigment storage in Cln1 mice, 47 with impairments of the peri pheral nervous system evi dent resembling paroxysmal sympathetic hyperactivity in juvenile CLN3 disease. 48 Pathological changes have also been described in somatic tissues, including heart (eg, repolarisation disturbances, ventricular hypertrophy, sinus node dysfunction), 17 and establishing its re lationship to events in the CNS will be important.…”

Spinal manifestations of CLN1 disease start during the early postnatal period

“…To analyse AFSM accumulation and glial activation in the grey matter (GFAP-positive astrocytes + CD68-positive microglia), markers of oligodendrocyte precursors (Olig2 and NG2) in the white matter and CGRP-positive fibres in laminae III-IV of the dorsal horn of the spinal cord, semiautomated thresholding image analysis was performed using Image-Pro Premier (Media Cybernetics) [17]. This involved collecting slide-scanned images at 109 magnification from each animal followed by demarcation of regions of interest.…”

Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

“…This lack of therapeutic efficacy may be due to other disease loci not targeted by brain-directed therapies 6 – 8 . We recently demonstrated the existence of significant pathology in the spinal cords of human CLN1 patients at autopsy and in Ppt1-deficient ( Ppt1 −/− ) mice 9 . The onset of spinal pathology in Ppt1 −/− mice preceded similar changes in the brain, and therapeutically targeting the spinal cord of Ppt1 −/− mice either alone or in combination with the brain, significantly ameliorated pathology and improved lifespan 9 .…”