Clinical stage Alzheimer’s therapy, NNI‐362 promotes TH+ neurons associated with a reversal of motor deficits in AAV‐alpha synuclein model, leaving alpha synuclein unchanged

Abstract

AbstractBackgroundNNI‐362 is a novel small molecule identified by phenotypic screening to discover compounds that promote new neurons from human neural progenitor cells and have neuroprotective capacity. A placebo‐controlled, double‐blind Phase 1a trial examined the safety and tolerability of NNI‐362, as well as a pharmacodynamic outcome ‐ the level of plasma p‐tau181, a blood‐based biomarker specific to Alzheimer’s disease (AD) pathology. Results in animal models of other age‐related disorders suggest NNI‐362 has the potential to halt or reverse AD and PD clinically.MethodAn AAV‐alpha synuclein rat model of Parkinson’s disease (PD) (MOTAC, France) was used to examine the effects of NNI‐362 treatment. This model results in anosmia and motor phenotypes, loss of TH+ neurons, and diminished adult‐born neurons triggered by alpha‐synuclein expression in the SNpc. NNI‐362 and placebo were formulated as a lipid suspension and administered orally once daily for up to 6 weeks post‐stabilization of AAV‐synuclein expression. At 8 weeks, brains were removed, and the SNpc sectioned and stained for TH+ neurons, alpha‐synuclein, and BrdU+ adult‐born neurons. Results were compared to AAV‐GFP‐injected, vehicle‐treated rats ‐ in groups of M or F and treatment or placebo (n = 14/group, 7F/7M).ResultBrain permeable therapy NNI‐362 did not alter alpha‐synuclein levels, but promoted BrdU+ neurons in the substantia nigra. Thus, generating and protecting TH+ neurons was associated with reversing motor deficits in females. No motor deficits and no BrdU+ neuron deficits were observed in AAV alpha‐synuclein treated males (twice run model), as such no amelioration by NNI‐362 treatment.ConclusionOral NNI‐362 may be a cause‐agnostic therapeutic ‐ promoting region‐specific new neurons, TH+ neuronal protection, and behavioral improvement when induced by dopaminergic deficit, including neurogenesis deficit. After AAV‐alpha‐synuclein induction of 2 weeks, and then followed by chronic NNI‐362 treatment, both behavior and neuron numbers were no different than AAV‐GFP control levels in this clinically‐relevant experimental model of PD.