Dual kinase inhibition provides early clues to restoration of neuroimmune homeostasis in an AAV-haSyn model of Parkinsons disease
Background Previous studies of drugs targeting mixed linage kinase type 3 (MLK3) and/or leucine rich repeat kinase type 2 (LRRK2) in sporadic Parkinsons disease (PD) have failed to meet clinical endpoints despite multiple lines of evidence implicating these kinases in pathogenesis. This has reduced enthusiasm for MLK3 and LRRK2 as druggable targets. Largely overlooked is the evidence that these…
In a recent study, researchers investigated the potential of dual kinase inhibition in restoring neuroimmune homeostasis in an AAV-haSyn model of Parkinson's disease (PD). Previous attempts to target the kinase type 3 (MLK3) and leucine rich repeat kinase type 2 (LRRK2) separately in sporadic PD without success led the team to consider the combination of these two targets as a viable therapeutic approach.
A pilot study using a mouse model, Sprague Dawley rats, was conducted to evaluate the effects of a multi-kinase inhibitor, URMC-099, on early, pre-symptomatic PD. After a two-week recovery period, the rats received either a daily intraperitoneal injection of URMC-099 or a vehicle control until terminal endpoint. The researchers assessed the impact of the treatment by measuring lateralized motor impairment through the cylinder test and analyzing neuropathology in the substantia nigra (SN) and striatum via immunohistochemical examination.
Additionally, an in vitro microglial PD model was used to further understand the mechanism behind the therapeutic activity of URMC-099.
The results showed that unilateral injection of low-dose AAV-haSyn successfully induced a lateralized model of early and progressive PD in the rats. The daily administration of URMC-099 effectively mitigated the development of PD pathology and progression in the early manifestation phenotype. The therapeutic activity was attributed to the targeted inhibition of MLK3 and LRRK2, which was further supported by reduced levels of gliosis in astrocytes and microglia in the SN.
Single-microglia segmentation analysis revealed that URMC-099 treatment preserved the dynamic effector state switching in microglia, enhancing autophagic flux and reducing the overall burden of pathologic aSyn. A complementary in vitro microglia model also corroborated the retention of a homeostatic-like effector state with URMC-099 treatment, which was unique to dual inhibition of MLK3 and LRRK2.
In conclusion, the study demonstrates that unilateral injection of low-dose AAV-haSyn can induce a lateralized model of early, progressive PD. Dual inhibition of MLK3 and LRRK2 with daily URMC-099 therapy significantly lessens the manifestation of PD pathology and progression in an early manifest phenotype. The findings propose a novel therapeutic modality that could benefit a broad population of etiologic PD patients.
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