AC708 / Daiichi Sankyo - LARVOL DELTA

CSF1R INHIBITION INDUCES A SEX-SPECIFIC RESILIENT MICROGLIAL PHENOTYPE AND EXTENDS THE LIFESPAN OF TAUOPATHY MICE (ADPD 2025) - "To deplete microglia, Tg2541 or wildtype mice were dosed with PLX3397 or PLX5622 in three dosing paradigms: acute(2−4 months), chronic(2−7 months), and terminal(2 months until death). Peripheral contributions were ruled out in identical experiments with PLX73086, a non-brain-penetrant CSF1R inhibitor analog...Conclusions Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects. Therapeutic modulation of microglial activation by CSF1R inhibitors is a potential approach to treating human tauopathies."

Preclinical • MAPT • THY1

Microglia overexpressing brain-derived neurotrophic factor promote vascular repair and functional recovery in mice after spinal cord injury. (PubMed, Neural Regen Res) - "To elucidate the role of microglia in spinal cord injury, we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia...Furthermore, through using specific transgenic mouse lines, TMEM119, and the colony-stimulating factor 1 receptor inhibitor PLX73086, we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages. In conclusion, our findings suggest the critical role of microglia in the formation of protective glial scars. Depleting microglia is detrimental to recovery of spinal cord injury, whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury."

Journal • Preclinical • CNS Disorders • Inflammation • Orthopedics • BDNF

Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior. (PubMed, Glia) - "In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuronal plasticity. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression."

Journal • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

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Less is more: macrophage depletion via CSF1/CSF1R pathway improves anti-VEGF therapy after adaptive resistance (AACR 2017) - "Based on these results, efficacy of AC708 (CSF1R inhibitor to target tumor-associated macrophages) was tested in the adaptive-resistance models. The addition of CSf1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects. To confirm these findings, a clinical trial at our institution is nearing activation. The REDIRECT (RandomizEd Induction DIscontinuation TRial of EmaCTuzumab) trial will randomize patients to continue weekly paclitaxel and biweekly bevacizumab with or without a CSF1R inhibitor (emactuzumab) following an induction phase."

Biosimilar • Gynecologic Cancers • Oncology • Ovarian Cancer

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