Evaluation of cAbl allosteric inhibitors in Gaucher-Parkinson

National Center For Advancing Translational Sciences

Investigators

Abstract

During this period, the team evaluate the allosteric cAbl inhibitor Neurotinib in several Parkinson and Gaucher disease efficacy models with encouraging results. We evaluated Neurotinib, a novel allosteric c-Abl inhibitor with preferential distribution toward CNS, in a PD murine model over-expressing hA53T α-synuclein (SNCAA53T) without and with Gba1-haploinsufficiency (Gba+/-//SNCAA53T) at 10-12 months of age. 25 Gba+/-//SNCAA53T, 17 SNCAA53T, and 14 WT/WT mice were treated with neurotinib-infused chow (67 ppm) and compared to 19 Gba+/-//SNCAA53T, 12 SNCAA53T, and four WT/WT mice receiving chow without the drug. Behavioral tests (beam walk and foot slips) were performed biweekly to assess motor dysfunction. Signs of disease, including gait abnormalities, hunching, back arching, and bladder dysfunction, were monitored at regular intervals until euthanasia was required and tissue was collected. Brain neurotinib levels in treated mice were 0.65-1.10 μmol/kg, confirming brain delivery. Treated mice lived significantly longer (p=0.0018) with almost no neurological symptoms (p=0.0013), better beam-walk performance (p<0.0001), and fewer foot slips (p<0.001) than untreated mice. Neurotinib treatment significantly decreased midbrain phosphorylated c-Abl and α-synuclein (p<0.05) and reduced microglia and astrocyte activation. Multi-omic analyses of midbrain samples will identify pathways and genes affected by c-Abl inhibition. Publication is in progress.