Science

Activation of glial cells in neural tissue plays a critical role in pathogenesis of neurodegenerative diseases.

To date, there are no disease-modifying therapies that reverse, stop or slow the relentless neurodegeneration in Parkinson’s (PD), Alzheimer’s (AD) and other neurodegenerative diseases. The existing treatments only provide temporary symptomatic improvements, their effectiveness diminishes over time and they don’t halt disease progression.

Numerous attempts to develop disease modifying therapies have failed partly due to poorly understood mechanisms of neurodegeneration. Understanding why and how susceptible neuronal cells in the brain die in PD and AD is the critical step toward preventing the death of these cells and developing new disease-modifying therapies capable of curing or slowing the disease.

The scientific foundation of Neuraly’s approach to treating neurodegenerative diseases was laid by the groundbreaking research of a team of world class neuroscientists led by Neuraly co-founder Dr. Ted Dawson at Johns Hopkins University School of Medicine. Their findings clearly demonstrate the critical role of the glial compartment of neural tissue in the pathogenesis of neurodegenerative diseases such as PD and AD. In the healthy brain, glial cells support the normal functioning of neurons; however, in pathologically activated states, these cells turn neurotoxic. The process starts with activation of microglial cells by protein aggregates (fibrils). Activated microglial cells cause direct neurotoxic effects on neuronal cells in the affected areas and induce differentiation of astroglia into neurotoxic A1 astrocytes, further exacerbating neurotoxic effects of glial activation.

We hypothesized that inhibition of pathological glial activation could prevent neuronal cell death and lead to highly efficient treatments for Parkinson’s and other neurodegenerative diseases:
In the recent paper published in Nature Medicine (https://doi.org/10.1038/s41591-018-0051-5), we demonstrate unprecedented efficacy of our lead product, NLY01, in slowing down or stopping the course of disease in highly relevant complementary animal models of PD. The study also reveals a detailed cellular mechanism of action for NLY01. By inhibiting glial activation and subsequent pro-inflammatory cytokine products, NLY01 prevents neuronal cell death and protects against the motor function decline apparent in the absence of treatment.

NLY01 blocks neurotoxic microglia-astrocyte formation in PD and AD

• Activated microglia and A1 astrocytes are the upstream targets in PD and AD

• NLY01 binds its receptor (GLP-1R) in activated microglia and effectively shuts down microglial activation

• In turn, NLY01 prevents A1 astrocyte formation and subsequent neuronal death -> Halt or Slow Down the progression of PD/AD