- NRG’s second therapeutic programme to explore brain penetrant small molecule inhibitors of the mitochondrial permeability transition pore (mPTP) as treatment for MND (ALS)
- Research collaboration agreement with Australia’s WEHI to work with Associate Professor Seth Masters’ group, on back of groundbreaking research1
- NRG is industrial partner in recent AUD$1 million FightMND Grant to WEHI
NRG Therapeutics Ltd (“NRG” or “company”), an innovative neuroscience company targeting mitochondrial dysfunction, today launched its second therapeutic programme, to explore the potential of its small molecules as disease modifying drugs for the treatment of motor neuronedisease (MND). The research will be undertaken in collaboration with Australia’s WEHI as part of a FightMND-funded grant.
NRG is applying breakthrough science in the field of mitochondrial biology to develop first-in-class treatments for neurodegenerative diseases. Its lead program is currently in pre-clinical testing for Parkinson’s. Its approach is based on inhibiting the mitochondrial permeability transition pore (mPTP) in brain cells which has been shown to be neuroprotective in several preclinical models of Parkinson’s and other neurodegenerative diseases including MND (also known as amyotrophic lateral sclerosis, ALS).
NRG has entered into a Research Collaboration Agreement with WEHI to further drug discovery based on pioneering studies by Associate Professor Seth Masters at WEHI who showed that the mPTP is involved in MND1. The collaborative research is funded by a recently announced AUD$1 million grant awarded to WEHI from FightMND, under which NRG is the Industrial Partner.
Associate Professor Masters was the first to show that TDP-43, a hallmark protein of MND, enters mitochondria and triggers mitochondrial DNA (mDNA) release via the mPTP. mDNA accumulates in the cytosol, activating the cGAS/STING pathway. This pathway is associated with the hyperinflammatory responses that are a signature of MND. Treatment with a mPTP inhibitor thus has the potential to prevent cytosolic mDNA accumulation, inhibit the cGAS/STING pathway, prevent downstream neuroinflammation and disease progression in MND.
NRG has discovered the first orally bioavailable and CNS penetrant mPTP inhibitors. Classical ‘first-generation’ inhibitors of the mPTP, such as cyclosporin A, inhibit cyclophilin D (CypD), a protein that is believed to regulate the pore. However, all historical attempts to develop CypD inhibitors that can cross the blood-brain barrier have been unsuccessful.
Associate Professor Seth Masters, Laboratory Head, Inflammation Division at WEHI, said: “We have identified a novel mechanism by which neuroinflammation is triggered in TDP-43 proteinopathies. Our assessment of cells lines, a mutant TDP-43 model, and human ALS-affected spinal cord samples provides support for a model where TDP-43 liberates mDNA into the cytoplasm via the mPTP to activate cGAS/STING signaling. We look forward to exploring with NRG whether targeting this pathway via mPTP inhibition can improve the symptoms of neuronal decline in patients with disease involving TDP-43 proteinopathy.”
NRG Therapeutics’ co-founder and CEO Dr Neil Miller said: “We have made significant progress with our chemistry, identifying novel mPTP inhibitors. Two of these chemical series are now in lead optimization and have the potential to be developed as breakthrough therapies for MND as well as Parkinson’s. We are excited by the opportunity to work with Seth and his team to further validate the target and develop biomarkers in MND. WEHI is a world-class medical research institute with deep expertise in immunology and a strong track record in translational research, and we look forward to working synergistically with an organization committed to making an impact for patients and the community. We thank FightMND for their grant support for the initial research and hope it will lead to a bigger collaboration with WEHI, subject to the progress of our initial studies and our series A financing.”
NRG is seeking to secure a Series A funding to advance its assets into the clinic, with the aim of completing IND-enabling studies for its lead asset by the end of 2024.