top of page

OUR LEAD ASSET

NT-101 shown preclinically to be safe and reduce gliosis in TBI-induced mice (similar to sham mice)

The company’s principal strategic focus is developing our lead candidate (NT-101) which is a solution of our proprietary streptolysin O preparation.  

 

Streptolysin O (SLO) is a 60 kDa exotoxin from Group A beta-hemolytic streptococci. While historically used as a permeabilizing agent in diagnostic tests, we have formulated NanoSLO, a 55 kDa recombinant form of SLO as a therapeutic agent.

 

NT-101 has been developed for the treatment of chronic Traumatic Brain Injury, a condition which can be described as concussions that have not completely healed.

 

NT-101 has been shown preclinically to be safe and to reduce gliosis in TBI-induced mice

 

​

Traumatic Brain Injury

Traumatic injury to the brain elicits physical damage to the vascular networks and neural circuit architecture alike. Gliosis is a reactive cellular process that occurs after injury. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system. Although glial scarring limits axonal regeneration, its evolutionary role in containing damage and preserving tissue integrity may reflect a protective trade-off. (Rolls 2009)..
​

As part of scar formation in the brain, astrocytes contribute to scar formation through hypertrophy and deposition of extracellular matrix proteins, forming a physical and biochemical barrier to axon extension. (Cregg 2014). Coupled with many neuro-development inhibitor molecules that are secreted by the cells within the glial scar, physical and functional recovery from chronic injury is inhibited. Consequently, we believe that the recovery can be attributed to one or more of the following hypothesized mechanisms of action:

​

  • Reductions in neuroinflammation being achieved through down-regulation of pro-inflammatory genes and up-regulation of anti-inflammatory genes (Teng-Chao 2021, Mamber 2011)

  • Reversal of gliosis associated with post-concussive syndrome.

  • Reduced scarring in damaged areas of the cerebrovascular system potentially leading to improved brain hemodynamics.

  • Lowered fibrin levels lessening the physical interference of scar tissue with normal transmission of brain signals and restoring the extracellular matrix (Mamber 2004).

  • Inhibition of microglial infiltration of the wound area decreasing inflammation and gliosis (Beech Tree Labs / Harvard Medical School).

  • Induction of neuron remyelination; observations of remyelination in peripheral nerves (B.E.T.) may be broadened to encompass all neurons.

  • Stimulation of dendritic cells may influence macrophage polarization, potentially promoting resolution of inflammation.  They may also signal macrophages to shift from their active state (which can be destructive if uncontrolled) to a resting phase which facilitates healing (Sanders, Mitchell – personal communication).

Genomic Profiling

Gene expression studies have been completed on NanoSLO, starting with early efforts with qPCR and more recently with NanoString. These studies suggest that in 48 hours of exposure to NanoSLO, statistically significant changes in the gene expression occur  (Alira 2022).  The biochemical pathways primarily involved include cytokine signaling, integrated stress response, autophagy and growth factor signaling.  They also discovered that PLA2G4A, a gene involved in inflammatory lipid signaling and associated with cognitive impairment, and CD209, a dendritic cell receptor implicated in immune modulation, were downregulated

 

To put it another way, NanoSLO suppresses certain inflammatory genes of dendritic cells, which contributes a crucial component in modulating the detrimental conditions associated with cTBI. In addition, genes associated with selected growth factors were up-regulated.  During TBI-induced blood brain barrier disruption, dendritic cells may infiltrate the CNS and influence local immune response
 

AdobeStock_526688666.jpeg

The Role of Microglia 

Increased Density associated with TBI 

Preclinical Efficacy

NanoSLO Reduces Inflammatory Microglia

Effects of NaSLO were studied in mice models for acute TBI (concussion).  The concussed mice were treated with subcutaneous administration of NanoSLO or a vehicle control.  Sham-concussed mice (no treatment) served as normal positive control.  The subcutaneous dosing route was used due to the difficulty of administering a dose to a mouse sublingually. 

 

As shown in the graph the microglia of the NanoSLO-treated mice had post-concussion levels of the non-concussed mice, and the microglia of the untreated post-concussion mice we markedly elevated.

It has been shown that mild repetitive head impacts affect microglia density. Adult male rats subjective to sham or two mild head impacts were compared. Significant increase in microgliosis was demonstrated in rats with head impact versus sham control (Cai, 2021)
BrainComms
SLO Mouse Study

Preclinical Safety 

The safety of NT-101 has been evaluated preclinically in:
​
  • (2) single dose acute toxicity studies (rat and dog)
  • (2) 7-day repeat dose studies (rat)
  • (2) 28-day repeat dose studies (rat and sheep)
  • NanoSLO was shown to be safe, well-tolerated with no toxicity observed in all species in both single and multiple dose studies.
 

The No Observed Adverse Effect Level (NOAEL) in rat was demonstrated to be 13.8 ng/kg/day (equivalent to about 2.2 ng/kg/day in humans) and 2.5 ng/kg/day in sheep (equivalent to about 2.5 ng/kg/day in humans)

 

These levels are more than 20 times the anticipated dose in humans.

bottom of page