Biopharmaceutical innovation and world class R&D
NSB (ASX:NSB) is a drug development company focused on developing peptide-based pharmaceutical drugs for the treatment of neurodegenerative conditions with high unmet medical need.
The NSB product portfolio includes several therapeutic peptides that are modeled on the domains of a naturally occurring protein called Metallothionein-II (MT-II).
EmtinB is the lead candidate that has shown to closely mimic the neuroprotective and neuroregenerative ability of MT-II.
Unique Mechanism of Action
The mechanism of action of EmtinB occurs via binding to surface-based cell receptors belonging to the LDLR family, which activate intracellular signaling pathways that “turn on” survival processes of neurons and modulate neuroinflammation.
EmtinB is currently being developed as a treatment for neurodegenerative dementia and Alzheimer’s disease, and degenerative conditions of the optic nerve.
Phase I clinical studies commencing 2021
NeuroScientific Biopharmaceuticals is committed to a research and development program that is methodically planned, efficiently executed and risk aware.
How it Works
Science driven medical innovation
The Neuroscientific Biopharmaceuticals product portfolio includes several therapeutic peptides that are modeled on the domains of a naturally occurring protein called Metallothionein-II (MT-II).
The main cell type expressing Metallothionein-II in the central nervous system (CNS) is the astrocyte. Expression is significantly increased in reactive astrocytes post injury. Neuronal expression of MT-II is low, whereas resting microglia and oligodendrocytes are essentially devoid of MT-II.
While initially, MT-II was believed to have purely intracellular functions, it was also demonstrated to be an important extracellular agent in the brain. Cell surface receptors for MT-II, low-density lipoprotein receptor-related protein 1 (LRP1) and megalin (LRP2), have recently been identified and shown to be expressed by neuronal cells.
Thus, MT-II can act directly on injured neurons, i.e. outside the context of astrocytic cytoplasm. Numerous studies have shown that “exogenous” MT-II strongly promotes regenerative neurite growth of cortical, dopaminergic, and hippocampal neurons and retinal ganglion cells suggesting that there is a robust and generic neuronal response to extracellular MT-II.
Data suggests that astrocytes respond to neural trauma by up-regulating MT-II expression with the MT-II being subsequently secreted, allowing direct interaction with neurons. Extracellular MT-II thus promotes axon regeneration, a response mediated by neuronal uptake of MT-II via the LRP1 receptor.
Extracellular function does not preclude the intracellular roles of MT-II, such as free radical scavenging and metal binding, and it is likely that there is a complex combination of intra- and extracellular roles of MT-II following brain injury.
In addition, MT-II have shown an indirect neuroprotective action via modulation of the immune system (i.e. MT-II alters the response of microglia to TNFα). MTII was shown to reduce cytokine-stimulated activation of microglia, which would ordinarily impair neurite outgrowth.
Multiple indications, infinite possibilities
MT-II may be a promising therapeutic target for treatment of CNS disorders. However, therapeutic use of MT-II may be hampered by the batch-to-batch variability characteristic of recombinant proteins and decreased passage through the blood–brain barrier (BBB), because MT-II tend to form polymers in solution.
Neuroscientific Biopharmaceuticals is developing EmtinB, which is modeled after the beta-domain of MT-II (see figure below) and mimics the biological effects of MTI/II in various animal models as well as in vitro studies. EmtinB is manufactured as tetrameric dendrimer, in which four monomer peptides (14aa monomers) are linked via a Lysine backbone. Since monomer peptides usually demonstrate a short half-life due to rapid proteolytic breakdown, the dendrimer structure increases the stability of EmtinB in biological environments.
Neuroscientific have successfully demonstrated that EmtinB passes the blood–brain barrier and is detectable in plasma for up to 24 hours.
Similar to MT-II, the mechanism of action of EmtinB involves:
Axonal regeneration – EmtinB acts via binding to surface-based cell receptors belonging to the LDLR family (LRP1 and LRP2), which activate intracellular signaling pathways (activation of ERK, Akt, and CREB) that “turn on” survival promoting processes of neurons. Activation of ERK and Akt is transient. It is therefore noteworthy that EmtinB stimulation also leads to activation of the transcription factor CREB, which modulates gene transcription leading to more long-lasting responses such as neurite outgrowth, neuronal survival and memory formation.
Modulation of microglia induced neuroinflammation (i.e. inhibitory effect of EmtinB on activated microglia).
EmtinB is currently being developed as treatment for neurodegenerative dementia and Alzheimer’s disease, and degenerative conditions of the optic nerve.