I think the poster is only available to those registered for the ECTRIMS meeting. I've been attending yesterday and today. I can't cut and paste the figures so I'll annotate.
Bryostatin-1 modulates CNS innate immunity
and augments remyelination
EfratAbramson1
, Payam Gharibani1
, Jingwen Hu5
, Matthew D. Smith1
,
Soonmyung Hwang1
, Solomon H. Snyder2-4
, Peter A. Calabresi1,2, Jeffrey Huang5
,
Paul M. Kim3
, Michael D. Kornberg1
Depts. of Neurology1
, Neuroscience2
, Psychiatry3
, Pharmacology4
, Johns Hopkins University, Baltimore, MD
Dept. of Biology, Georgetown University5
Disclosures
• Johns Hopkins University holds a patent on the use of
bryostatin-1 and its derivatives in multiple sclerosis, on
which M. Kornberg, P. Kim, P. Calabresi, and S. Snyder
are listed as inventors
Background
• Chronic activation of central nervous system (CNS) innate immune cells drives
progression and prevents remyelination in multiple sclerosis (MS), yet therapies
targeting this aspect of inflammation do not exist.
• Bryostatin-1 (bryo-1), a potent protein kinase C (PKC) modulator, is a clinically
safe, brain-penetrant1 macrocyclic lactone we previously found to have antiinflammatory effects on peripheral myeloid cells at nanomolar doses, promoting
a shift to tolerogenic/regulatory phenotypes and thereby attenuating rodent
experimental autoimmune encephalomyelitis (EAE)2
.
• Previous work also demonstrated that bryo-1 acts directly on OPCs to promote
differentiation in the presence of inhibitory myelin debris3
.
• Bryo-1 therefore has the potential to promote remyelination/repair through
both direct effects on OPCs and modulation of the CNS innate immune
environment
1. Sun MK, Alkon DL. CNS Drug Rev (2006) 12:1-8
2. Kornberg MD, et al. Proc Natl Acad Sci U.S.A. (2018) 115:2186-2191
3. Gonzalez GA, et al. Sci Rep (2016) 6:31599
They then go over background from the PNAS paper with pics and words:
Our previous work demonstrated that bryo-1 (30 mg/kg i.p. given 3 days per week) attenuates
MOG35-55 EAE whether treatment is initiated (green arrow) early or late in the disease course. This
effect is mediated by modulation of innate myeloid cells rather than lymphocytes. Because bryo-1 is
brain-penetrant, we hypothesize that it modulates innate immunity within the CNS, which is
critically related to neurodegeneration and remyelination in MS
The objectives of the new work:
Objectives
• Determine the effects of bryo-1 on phenotypes of CNS-resident
macrophages/microglia and astrocytes in vitro and in vivo
• Evaluate the impact of systemic treatment with bryo-1 on
remyelination in animal models
They then show in mixed cultures that bryostatin-1 downregulated key inflammatory pathways and prevents A1 astrocyte polarization (these are the reactive astrocytes that are upregulated in chronic neurodegenerative disease including AD and progressive MS).
They then show Bryo-1 augments transcriptional programs in microglia associated with debris clearance and remyelination/repair --- basically bryo-1 augmnents the anti-inflammatory action of IL-4 which is associated with phagocytosis and myelin repair.
Recall in the PNAS paper, bryo-1 attenuated EAE in mice, and improved recovery after EAE has occurred (Fig 2C of the PNAS paper). This is further evaluated in late chronic EAE (establish disease at day 0, give bryo-1 at day 28 and do flow cytometry of cells in the brain at day 42). At day 42, 20% of macrophage//microglia have the regenerative M2 phenotype (CD206+ CD45hi CD11b+) vs. only 10% without bryo.
Finally, (preliminary work) using the lysolecithin demyelination model and evaluating the spinal cord 12-15 days later they show that bryo-1 promotes remyelination:
(A) Schematic of experimental
paradigm. (B) At 12 days post-lesion
(dpl), bryo-1 augments the number
of Olig2+ cells within the lesioned
site. (C) At 15 dpl, a pilot study (n=2
mice per group) suggests that bryo1 increases the number of both
total (Olig2+) and mature
(Olig2+/CC1+) oligodendrocytelineage cells. (D) Representative
image demonstrating the increase
in Olig2+ and Olig2+/CC1+ cells
within the lesioned site at 15 dpl. *
p < 0.05 by two-tailed student’s ttest
