Anti-miR-155 LNA Oligonucleotide Shifts Microglia to Homeostatic State in LPS-Challenged and 3xTg-AD Mice

In_Vivo Score: 0.774 Price: $0.50 neurodegeneration C57BL/6J LPS model (chronic i.p. 0.5 mg/kg weekly x 8 wk) and 12-month 3xTg-AD mice (n=10/group x 4 groups) Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting MIR155 in C57BL/6J LPS model (chronic i.p. 0.5 mg/kg weekly x 8 wk) and 12-month 3xTg-AD mice (n=10/group x 4 groups). Primary outcome: miR-155 level in cortical microglia reduced >=60%; IL-6/TNF-alpha in CSF reduced >=40%

Description

Test whether intrathecal delivery of a locked-nucleic-acid anti-miR-155 (LNA-155) reduces the IFN-gamma/miR-155 feed-forward amplification, shifts microglia to homeostatic state, and improves memory in LPS-induced neuroinflammation model and aged 3xTg-AD mice.

TARGET GENE

MIR155

MODEL SYSTEM

C57BL/6J LPS model (chronic i.p. 0.5 mg/kg weekly x 8 wk) and 12-month 3xTg-AD mice (n=10/group x 4 groups)

ESTIMATED COST

$58,000

TIMELINE

14 months

PATHWAY

miR-155 -> SHIP1 suppression -> PI3K/NF-kB -> IFN-gamma production feedback loop

SOURCE

task:a989715e-c687-4558-91ca-74fce1474bd2

PRIMARY OUTCOME

miR-155 level in cortical microglia reduced >=60%; IL-6/TNF-alpha in CSF reduced >=40%

Scoring Dimensions

Protocol

Synthesise LNA-155 (5-T+G+T+A+G+C+A+T+T+A+A-3) or scramble-LNA. 2. Intrathecal implant osmotic pump (2 ug/day, 28-day release) at LPS day 14 or 3xTg-AD 12 months. 3. Endpoints at day 42 / 14 months: - miRNA-seq on FACS-sorted CD11b+ microglia (miR-155 readout) - Multiplex cytokine (CSF: IL-6, TNF-alpha, IFN-gamma, IL-10) - Microglia morphology (Iba1 IHC, ramification index) - Fear conditioning, Y-maze. 4. Primary: miR-155 by qRT-PCR; secondary: cytokine panel, Y-maze alternation.

Expected Outcomes

LNA-155 will reduce microglial miR-155 >=60%, suppress IFN-gamma/IL-6 in CSF >=40%, increase SHIP1 protein >=2x, and restore Y-maze alternation to >=60% (vs ~45% LPS-vehicle).

Success Criteria

Primary: miR-155 qPCR >=60% reduction in microglia (p<0.01). Secondary: Y-maze spontaneous alternation >=60% for LNA-155 group.

Related Hypotheses (1)

miR-155/Interferon-gamma Feedback Loop as a Reversible Molecular Switch for Protective Microglial St0.843

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