Dual kinase inhibition provides early clues to restoration of neuroimmune homeostasis in an AAV-haSyn model of Parkinsons disease

Once-daily i.p. URMC-099 in a unilateral low-dose AAV-haSyn rat model attenuates nigral-striatal neuropathology and prevents lateral motor deficits.

• Why it matters: Prior MLK3 and LRRK2 drug efforts in sporadic Parkinson’s disease have missed clinical endpoints, leaving uncertainty about whether these targets can work together.
• What they did: Rats with unilateral intranigral low-dose AAV-haSyn received once-daily i.p. URMC-099 or vehicle after a 2-week recovery; motor impairment (cylinder test) and neuropathology in substantia nigra and striatum were assessed, with microglia tested in vitro using aSyn pre-formed fibrils.
• The result: URMC-099 linked dual MLK3/LRRK2 inhibition to preserved neuronal integrity, reduced astrocyte/microglial gliosis, and microglial homeostatic-like effector state switching that supports autophagic flux and lowers pathologic aSyn burden.

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