Disease-Modifying Treatment in Progressive Multiple Sclerosis

Ciotti, John R.; Cross, Anne H.

doi:10.1007/s11940-018-0496-3

Cited by 70 publications

(55 citation statements)

References 80 publications

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“…Current FDA and EMA-approved disease-modifying therapies, which target inhibition of peripheral immune attack on the CNS in MS, are increasingly effective at reducing episodes of inflammatory demyelination and neurological disability (Mahad et al, 2015, Weideman et al, 2017). However, the neurodegenerative process, particularly for patients with progressive MS, has proven significantly more challenging to decelerate (Ciotti and Cross, 2018). Similar to other neurodegenerative diseases, there is no clear mechanistic understanding of why some patients develop profound degeneration and disability.…”

Section: Introductionmentioning

confidence: 99%

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

Werneburg

Jung

Kunjamma

et al. 2019

Preprint

104

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Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on axon loss in MS, far less is known about synaptic changes. Here, in striking similarity to other neurodegenerative diseases, we identify in postmortem human MS tissue and in nonhuman primate and mouse MS models profound synapse loss and microglial synaptic engulfment. These events can occur independently of local demyelination, neuronal degeneration, and peripheral immune cell infiltration, but coincide with gliosis and increased localization of complement component C3, but not C1q, at synapses. Finally, we use AAV9 to overexpress the complement inhibitor Crry at activated C3-bound synapses in mice and demonstrate robust protection of synapses and visual function. These results mechanistically dissect synapse loss as an early pathology in MS. We further provide a novel gene therapy approach to prevent synapse loss by microglia, which may be broadly applicable to other neurodegenerative diseases.1 1 induced in these mice ( Fig. 6C). Mice were then analyzed at the onset of moderate clinical scores (average: AAV-Crry: 1.4±0.3; AAV-EGFP 1.5±0.3), which were typically observed around day 11 post-immunization (AAV-Crry: 11.2±0.6; AAV-EGFP: 11.4±0.4) ( Fig. 7A). Using confocal imaging, we first determined the degree of EGFP colocalization with VGluT2 + -retinogeniculate terminals in the LGN and found ~45% of VGluT2 + -retinogeniculate terminals in the LGN colocalized with EGFP after injection of both AAVs (Fig. 6D). We then immunostained for Crry protein and identified that Crry was highly enriched in presynaptic bouton structures in EGFPlabeled retinogeniculate arbors vs. other fine processes (i.e. axons) within the LGN of AAV-Crry injected mice (Fig. 6E). Previous work has demonstrated that these boutons represent VGluT2 +presynaptic terminals along retinogeniculate arbors (Hong et al., 2014), precisely where we originally identified enrichment of C3 (Fig. 5). These data demonstrate successful CR2-mediated Crry targeting to retinogeniculate synapses tagged by activated C3. In contrast, AAV-EGFP injected mice showed only diffuse Crry immunoreactivity with no concentration on or around retinogeniculate synapses in the LGN following EAE. Regardless of AAV treatment, mice showed comparable development of EAE clinical scores, infiltration of peripheral immune cells, and micro-and astrogliosis (Fig. 7A-D). These data suggest that retinogeniculate overexpression of Crry did not have global, systemic effects, which is important when considering the beneficial and detrimental effects of inflammation in the development of new therapeutic strategies. Crry-mediated inhibition of activated C3 at retinogeniculate synapses blocks microglial synapse engulfment, rescues synapse loss, and restores visual functionFollowing validation that Crry is successfully expressed using our AAV9 strategy and localizes to retinogeniculate presynaptic terminals, we asked if Crry overexpression reduced deposition of C3 following EAE....

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Section: Introductionmentioning

confidence: 99%

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

Werneburg

Jung

Kunjamma

et al. 2019

Preprint

104

View full text Add to dashboard Cite

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“…MS thus places a large economic burden on society . Current disease‐modifying treatments for MS mainly target adaptive immune processes, in turn reflected as diminished new or contrast‐enhancing lesions on magnetic resonance imaging (MRI) . Meanwhile, few therapeutic options exist for the progressive forms of MS .…”

Section: Introductionmentioning

confidence: 99%

MRI‐Based Manual versus Automated Corpus Callosum Volumetric Measurements in Multiple Sclerosis

Plattén

Martola

Fink

et al. 2019

Journal of Neuroimaging

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BACKGROUND AND PURPOSE Corpus callosum atrophy is a neurodegenerative biomarker in multiple sclerosis (MS). Manual delineations are gold standard but subjective and labor intensive. Novel automated methods are promising but require validation. We aimed to compare the robustness of manual versus automatic corpus callosum segmentations based on FreeSurfer. METHODS Nine MS patients (6 females, age 38 ± 13 years, disease duration 7.3 ± 5.2 years) were scanned twice with repositioning using 3‐dimensional T1‐weighted magnetic resonance imaging on three scanners (two 1.5 T and one 3.0 T), that is, six scans/patient, on the same day. Normalized corpus callosum areas were measured independently by a junior doctor and neuroradiologist. The cross‐sectional and longitudinal streams of FreeSurfer were used to segment the corpus callosum volume. RESULTS Manual measurements had high intrarater (junior doctor .96 and neuroradiologist .96) and interrater agreement (.94), by intraclass correlation coefficient (P < .001). The coefficient of variation was lowest for longitudinal FreeSurfer (.96% within scanners; 2.0% between scanners) compared to cross‐sectional FreeSurfer (3.7%, P = .001; 3.8%, P = .058) and the neuroradiologist (2.3%, P = .005; 2.4%, P = .33). Longitudinal FreeSurfer was also more accurate than cross‐sectional (Dice scores 83.9 ± 7.5% vs. 78.9 ± 8.4%, P < .01 relative to manual segmentations). The corpus callosum measures correlated with physical disability (longitudinal FreeSurfer r = –.36, P < .01; neuroradiologist r = –.32, P < .01) and cognitive disability (longitudinal FreeSurfer r = .68, P < .001; neuroradiologist r = .64, P < .001). CONCLUSIONS FreeSurfer's longitudinal stream provides corpus callosum measures with better repeatability than current manual methods and with similar clinical correlations. However, due to some limitations in accuracy, caution is warranted when using FreeSurfer with clinical data.

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“…Currently, there is no definitive treatment for multiple sclerosis. Most approved therapies are focused on controlling peripheral inflammation and preventing migration across the blood brain barrier thereby reducing the incidence of acute flares [13,30,39,40]. A majority of these therapies are administered orally, as an injection or through an infusion.…”

Section: Current Disease-modifying Therapiesmentioning

confidence: 99%

Enkephalin Therapy Improves Relapsing-Remitting Multiple Sclerosis

Patel¹,

Zagon²,

Thomas³

et al. 2020

An Overview and Management of Multiple Chronic Conditions

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Multiple sclerosis (MS) is accompanied by decreases in serum endogenous enkephalin/endorphins and alterations in inflammatory cytokines. This retrospective analysis of serum levels was conducted in 53 patients with established relapsing-remitting MS treated with the disease-modifying therapies (DMT) glatiramer acetate, dimethyl fumarate or with the biotherapeutic low dose naltrexone (LDN) to elevate enkephalins, an off-label alternative. Opioid growth factor (OGF), an inhibitory endogenous opioid involved in modulating cellular replication, was measured and correlated to serum β-endorphin, IL-17A and TNFα. Results revealed that MS leads to a significant reduction in OGF levels in subjects on DMTs, but patients on LDN had OGF levels comparable to non-MS controls. Individuals on DMTs had significantly elevated TNFα levels, while IL-17A levels were significantly elevated only in patients taking dimethyl fumarate. A direct correlation was established between OGF and IL17A indicating a potential interaction between the OGF-OGFr axis and pro-inflammatory T-helper cells providing insight into the disease etiology.

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Disease-Modifying Treatment in Progressive Multiple Sclerosis

Cited by 70 publications

References 80 publications

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

MRI‐Based Manual versus Automated Corpus Callosum Volumetric Measurements in Multiple Sclerosis

Enkephalin Therapy Improves Relapsing-Remitting Multiple Sclerosis

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