An Anti-Neuroinflammatory That Targets Dysregulated Glia Enhances the Efficacy of CNS-Directed Gene Therapy in Murine Infantile Neuronal Ceroid Lipofuscinosis

Macauley, Shannon L.; Wong, Andrew; Shyng, Charles; Augner, David P.; Dearborn, Joshua T.; Pearse, Yewande; Roberts, Marie S.; Fowler, Stephen C.; Cooper, Jonathan D.; Watterson, Daniel; Sands, Mark S.

doi:10.1523/jneurosci.2518-14.2014

Cited by 60 publications

(87 citation statements)

References 25 publications

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“…Our data support the notion that HGF may exert neuroprotective effects via direct interaction with neurons and glia (61). Data from phase I and II studies for diabetic peripheral neuropathy demonstrated that pCK-HGF-X7 was safe and produces a remarkably high pain-reducing effect (22).…”

Section: Discussionsupporting

confidence: 90%

Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model

Nho

Lee

et al. 2018

FASEB j.

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Hepatocyte growth factor (HGF) is a multifunctional protein that contains angiogenic and neurotrophic properties. In the current study, we investigated the analgesic effects of HGF by using a plasmid DNA that was designed to express 2 isoforms of human HGF—pCK-HGF-X7 (or VM202)—in a chronic constriction injury (CCI) –induced mouse neuropathic pain model. Intramuscular injection of pCK-HGF-X7 into proximal thigh muscle induced the expression of HGF in the muscle, sciatic nerve, and dorsal root ganglia (DRG). This gene transfer procedure significantly attenuated mechanical allodynia and thermal hyperalgesia after CCI. Injury-induced expression of activating transcription factor 3, calcium channel subunit α2δ1, and CSF1 in the ipsilateral DRG neurons was markedly down-regulated in the pCK-HGF-X7–treated group, which suggested that HGF might exert its analgesic effects by inhibiting pain-mediating genes in the sensory neurons. In addition, suppressed CSF1 expression in DRG neurons by pCK-HGF-X7 treatment was accompanied by a noticeable suppression of the nerve injury–induced glial cell activation in the spinal cord dorsal horn. Taken together, our data show that pCK-HGF-X7 attenuates nerve injury–induced neuropathic pain by inhibiting pain-related factors in DRG neurons and subsequent spinal cord glial activation, which suggests its therapeutic efficacy in the treatment of neuropathic pain.—Nho, B., Lee, J., Lee, J., Ko, K. R., Lee, S. J., Kim, S. Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model.

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Section: Discussionsupporting

confidence: 90%

Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model

Nho

Lee

et al. 2018

FASEB j.

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“…Consistent with previous studies, intracranial injection of an AAV2/9-hPPT1 vector resulted in a significantly increased life span, a preservation of motor function that we have shown previously to correlate with improved cerebellar pathology, and decreased pathology in the forebrain (12,(24)(25)(26)(27). However, there was almost no improvement in spinal cord pathology following braindirected gene therapy in Ppt1 −/− mice.…”

Section: Discussionsupporting

confidence: 90%

“…Based on a previous study that showed that intrathecal delivery of recombinant PPT1 enzyme could minimally improve the disease phenotype of Ppt1 −/− mice (31), we delivered AAV2/9-hPPT1 intrathecally to target the spinal cord. We also combined this approach with braindirected gene therapy (12,(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we tested whether intrathecal (IT) injections of an AAV2/9-hPPT1 vector, either alone or in combination with intracranial (IC) injections (12,(24)(25)(26)(27), would have any beneficial effect on disease progression and brain and spinal cord pathology.…”

Section: Significancementioning

confidence: 99%

“…Various experimental therapies have been tested to treat forebrain pathology in Ppt1 −/− mice, including antioxidants (19,20), enzyme replacement therapy (ERT) (21,22), human neuronal stem cells (23), and forebrain-directed gene therapy (12,(24)(25)(26)(27). Of these, adeno-associated virus (AAV) vector-mediated gene transfer has been the most promising (3,28).…”

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confidence: 99%

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

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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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

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Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

Meiman

Kick

Jensen

et al. 2022

Developmental Neurobiology

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Golden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane-like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.

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An Anti-Neuroinflammatory That Targets Dysregulated Glia Enhances the Efficacy of CNS-Directed Gene Therapy in Murine Infantile Neuronal Ceroid Lipofuscinosis

Cited by 60 publications

References 25 publications

Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model

Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model

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

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

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