Our Science:

Approach & Innovation

Therapeutic Challenge

Neurodegenerative Disease Etiology:  The genesis and progression of NDs are understood to be multifactorial, involving a complex interplay of risk factors, including ageing, genetic predisposition and environment (e.g., lifestyle stressors, head injury, etc.), among others. Relentless loss of neurons and neuronal network disintegration are central to the progressive decline of brain function in NDs.  Two molecular mechanisms recognized to be key drivers of neuronal cell death in NDs are: oxidative stress, stemming from excessive production of reactive oxygen species (ROS), and glutamate-induced excitotoxicity.

Neuropath’s TRH-based approach is targeted to combat this multifactorial disease scenario. It is designed to selectively activate receptors in the brain for the neuropeptide TRH to evoke TRH’s multiple, naturally occurring neurotherapeutic actions to improve cognitive and motor function and slow disease progression in patients with NDs.

TRH-Based Approach:

Features and Advantages

  1. “Switches on” naturally occurring neurotherapeutic system in the brain that modulates multiple pathogenic processes in NDs.

  2. Multifactorial monotherapy with potential to deliver both symptomatic relief and disease modification in NDs.

  3. Multi-indication therapeutic opportunity, including AD, ALS/MND and TBI.

  4. Strong biological rationale leverages extensive academic and pharma knowledge base for TRH.

A neuropeptide-based approach directed toward activation of the TRH central signalling system is distinct from others currently prominent in the ND drug development arena (such as those targeting risk genes and misfolded proteins), and it aligns with increasing calls in the field for multifactorial drugs to address the multiplicity of pathological mechanisms underlying NDs.

Our TRH-based strategy holds many parallels with that of the currently much-publicized class of drugs targeting receptors of the neuropeptide GLP-1. The remarkable success of GLP-1-based drugs is not only revolutionizing the treatment of obesity and potentially other therapeutic indications, but also highlighting the multi-indication clinical potential of neuropeptide signalling systems generally.

Innovation

The innovative design and mechanism of action of Neuropath’s TRH-based compounds is founded on breakthrough neuroscience that selectively harnesses TRH’s recognized central neurotherapeutic effects – a target with substantial history of pharma and academic interest and R&D.

Discovered by Dr Julie A. Kelly, Neuropath’s Founder and CEO, through her Wellcome Trust-funded academic research at TCD, these compounds overcome pharmacological constraints – namely, enzymic degradation by TRH-degrading ectoenzyme (TRH-DE) and endocrine side effects – that have limited the clinical use of TRH.

As shown below, our TRH-based compounds are uniquely dual acting – they deliver potent inhibition of TRH-DE in combination with selective high affinity for TRH receptors in the brain.  Moreover, these compounds do not bind to pituitary TRH receptors that mediate TRH’s endocrine effects.

Takeaway: Neuropath’s TRH-based compounds provide an attractive opportunity to deliver the multifactorial neurotherapeutic effects of TRH without inducing endocrine side effects.

The lead compound is demonstrated in preclinical proof-of-concept studies to significantly:

  • Reduce glutamate-induced excitotoxicity;

  • Decrease excessive ROS, thereby lessening oxidative stress;

  • Protect brain and spinal cord neurons from cell death;

  • Attenuate motor impairment relevant to ALS; and

  • Reverse memory and learning deficits and network disruption, applicable to mitigation of cognitive dysfunction in ND patients.