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Case study

Modulation of CSF1R: a promising strategy to control neuroinflammation

Lead PI: Dr Diego Gomez-Nicola, University of Southampton, UK

Start of grant
Dr Gómez-Nicola publishes first proof of the efficacy of inhibiting CSF1R in AD models
Dr Gómez-Nicola and collaborators find a selective inhibitor of CSF1R which reduces microglial proliferation and leads to reduce neurodegeneration.

ARUK invests £150,000 in a trial that uses the compound to find biomarkers that show CSF1R inhibition
Data on CSF1R modulation via IL-34 inhibition is published
CSF1R_timeline

2015

Dementia Consortium funds project

2016

Dr Gómez-Nicola publishes first proof of the efficacy of inhibiting CSF1R in AD models

2019

Dr Gómez-Nicola and collaborators find a selective inhibitor of CSF1R which reduces microglial proliferation and leads to reduce neurodegeneration

ARUK invests £150,000 in a trial that uses the compound to find biomarkers that show CSF1R inhibition

2020

Data on CSF1R modulation via IL-34 inhibition is published

In previous mouse studies, blocking CSF1R was found to reduce the inflammatory response to brain protein aggregates such as beta amyloid. This led to reduced neuronal death and improved symptoms in other neurodegenerative diseases where inflammation plays a key role.  Blocking CSF1R may dampen the chronically activated microglial-dependent immune response and thus reduce disease progression. This project aims to develop and optimise inhibitors of the interaction between CSF1R and IL34, which are key proteins involved in the proliferation of microglia, the primary immune cells in the brain. In addition, the researchers also aim to generate target validation data for the inhibition of IL34-CSF1R binding, and analyse its effects on the control of in vitro microglial proliferation versus survival.

Diego Gomez-Nicola

University of Southampton, UK

“Positive aspect was working with ARUK and contract partners. It was a productive collaboration. “

“Very good to have pharma partners & ARUK involved in projects along with academic collaborators, as they bring advice and a focused perspective.”

“Our results provided heavy validation of a significant target for Dementia, as well as overarching valuable information about the biology of key mechanisms controlling neuroinflammation.”

 

Outcomes

1

IL-34 was validated as a target for controlling microglial proliferation and the findings were related to potential development of drugs using antibodies or SMIs. The specific pocket of IL34-CSFR1 was characterised.

2

A series of assays were validated relating to the target IL-34 to test activation of CSFR1 as a research tool with confirmed activity in microglial cells suitable for in vivo use.

Publication

Obst J, Simon E, Martin-Estebane M, Pipi E, Barkwill L, Buchanan F, Prescott AR, Fox S, Brownlees J, Perry VH, Dementia Consortium Project Partners, Gomez-Nicola D*. Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in a model of chronic neurodegeneration. 2020. Front Immunol. Oct 8;11:579000. doi: 10.3389/fimmu.2020.579000.