research & development
Role of Microglia in Neuroinflammation and Neurodegenerative Diseases
The activation of immune cells, known as microglia, in the central nervous system (CNS) promotes an inflammatory response that serves as a hallmark for a range of neurologic disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis, neuropathic pain, multiple sclerosis, and Parkinson’s Disease. Microglia play a critical role in CNS immune responsiveness. There are two states of microglia, an “M1” phenotype that is predominantly neurotoxic and a neuroprotective “M2” phenotype. The role of microglia is particularly evident in AD, where M2 microglia help in clearing Aβ, while M1 microglia contribute to neuroinflammation and synaptic damage. In AD and other neurodegenerative disorders, the M1 phenotype is increased. As microglia transition from the M2 to M1 state, cannabinoid type 2 (CB2) receptor expression is induced. Activation of this receptor by NTRX-07, a novel CB2 agonist, promotes the transition from the M1, pro-inflammatory phenotype to the neuroprotective, M2 phenotype and results in reducing neuronal damage, increasing Aβ clearance and inhibiting neuroinflammation.
NTRX-07 as a Treatment for Alzheimer’s Disease (AD)
NTRX-07 represents a novel strategy for the treatment of AD. By targeting CB2 receptors, NTRX-07 has been shown to modulate microglial activation which in turn may lead to enhanced phagocytosis of Aβ in animals models of AD. Reductions in inflammation and Aβ, particularly soluble Aβ oligomers, can lead to improvements in cognitive functions as shown by improved long-term potentiation (LTP), a key assessment of neuronal function, which in turn led to improvements in memory-based behavioral testing. Somewhat unexpected but a potentially very important result of NTRX-07 treatment was the induction of Sox2, which could lead to recruitment of stem cells, neurogenesis and/or synaptic plasticity, any of which could offer hope to not simply slow progression of the disease, but also to promote recovery.
NTRX-07 and Pain
NTRX-07 has been demonstrated in three different animal models of neuropathic pain to significantly reduce pain. In a model of Complex Regional Pain Syndrome, NTRX-07 not only significantly reduced pain as measured, but also prevented the reactive hyperemia observed following reperfusion. In a second model of neuropathic pain resulting from nerve injury, NTRX-07 returned pain threshold to normal levels in a dose dependent manner. The final model NTRX-07 was tested in was a chemotherapy induced peripheral neuropathy model. Many types of chemotherapy, for example paclitaxel used to treat breast cancer, also cause neuropathic pain syndromes. It can be mild to moderate, but persist long after the treatment is done. If severe, it can limit the total dose of chemotherapy given, affecting the treatment course. In this model of chemotherapy induced pain, not only did NTRX-07 eliminate paclitaxel-induced neuropathic pain, but these effects were shown to be mediated through the CB2 receptor, since CB2 knock-out mice were not affected by NTRX-07 treatment.
Clinical Development of NTRX-07
A Phase 1a single ascending dose clinical trial in healthy individuals was recently completed that demonstrated blood exposure of NTRX-07 at levels better than expected and at concentrations predicted to be efficacious based on preclinical animal models with only non-dose limiting side effects observed at the two highest doses tested.
The Company has recently completed administration of NTRX-07 for 7 days to healthy, older adults in its Phase 1b multiple ascending dose clinical trial with no evidence of dose-limiting toxicity at the highest dose tested. A single cohort of AD subjects will be evaluated at this dose for safety in early 2023.
NeuroTherapia anticipates beginning studies of longer-term (28 day) administration of NTRX-07 in AD patients in late 2023. The trial is designed to not only demonstrate safety, but also provide evidence of bioactivity. Please visit this site later in 2023 for updates on this trial.