Backing for innovative treatment approach

Neuroscience firm NRG Therapeutics, which is targeting mitochondrial dysfunction, has been awarded a non-dilutive grant from Target ALS Foundation.

It is one of five recipients of the 2024 In Vivo Target Validation grants in collaboration with Biospective. The funding will be used to support its discovery programme for a treatment for Amyotrophic Lateral Sclerosis (ALS).

NRG Therapeutics is applying breakthrough science in the field of mitochondrial biology to develop first-in-class treatments for neurodegenerative diseases including ALS/MND.

It has discovered a new class of small molecule mitochondrial permeability transition pore (mPTP) inhibitors that can block mitochondrial dysfunction. Its inhibitors are designed to penetrate the brain effectively when taken orally.

Target ALS is committed to breaking down scientific research barriers to develop effective biomarkers and treatments for ALS. The In Vivo Target Validation Program aims to generate high-quality data on candidate therapeutics in animal models of ALS, provide access to in-kind funding for a resource-intensive step of drug discovery, and accelerate the progress of candidate therapeutics from preclinical testing towards clinical trials.

Mitochondria, the batteries of cells, are crucial for energy production, especially in brain cells which have high energy demands. In diseases like ALS, mitochondria become defective, leading to brain cell death and diseaseprogression.

Recent findings have shown that dysfunctional TDP43 protein – found in nearly all ALS patients – disrupts mitochondrial function and undesirably activates the immune system.

Announcing the awards, Target ALS said: “We are thrilled to announce the recipients of the Target ALS In Vivo Target Validation grants, focusing on proof-of-concept studies for promising therapeutics in a TDP-43 mouse model.

"This initiative, in collaboration with Biospective, is designed to accelerate the evaluation of potential therapeutics, bridging the gap from preclinical research to clinical trials.”

Biospective has implemented a modified, slower progressing version of the TDP-43 NLS8 (or DELTA-NLS) mouse model that was originally developed at the University of Pennsylvania (Walker et al., 2015). This model mimics disease symptoms and pathology that people living with ALS experience, including cytoplasmic TDP-43 mislocalization, neurodegeneration, and motor deficits.

Using this standardized model, the team at Biospective will conduct robust behavioral and molecular assessments of candidate therapeutics for these preclinical efficacy studies. Successful results in this mouse model will enable groups to move their therapeutic candidate toward the clinic.

NRG Therapeutics’ co-founder and CEO Dr Neil Miller said: “Preliminary experiments using a mouse model of ALS which contains the human gene for TDP-43 showed that our mPTP inihibitor candidate therapeutic reduced brain cell death. However, due to the rapid disease progression in that mouse model, a full assessment of the therapeutic potential was not possible. This project aims to evaluate NRG’s small molecule inhibitor, in a modified ALS TDP-43 mouse model that progresses more slowly. This will allow for a comprehensive assessment of the molecule’s ability to protect mitochondria, reduce brain cell death, and decrease immune system activation. Additionally, the study will measure improvements in muscle function and strength. If successful, this project will provide crucial support for advancing our mPTP inhibitor into clinical trials for ALS.”

Imaging technique uncovers protein abnormality in motor neurone disease

Pathological abnormalities associated with motor neurone disease (MND) have been identified using a new technique developed at the University of Birmingham.

The method will help scientists better understand the changes in the brain that lead to MND and could eventually yield insights that will help with the development of new treatments.

The abnormalities were identified in a collaboration between the University of Birmingham and the University of Sheffield and published today [August 8] in Nature Communications.

Lead researcher Helen Cooper, in Birmingham’s School of Biosciences, said: “This approach is the first to show that this form of SOD1 correlates with the pathology of motor neurone disease.

“It’s a very early step towards finding treatments for MND and is also an exciting new route for understanding the molecular basis of other diseases in unprecedented detail.”

Motor neurone disease, also known as amyotrophic lateral sclerosis or ALS, is a musclewasting condition caused by messages from the brain’s motor neurones not reaching the muscles, causing them to weaken.

Around 5,000 people in the UK have the disease at any one time and currently there is no cure.

At the University of Birmingham researchers have developed a technique that enables them to examine specific proteins in their native state, directly from brain and spinal cord tissue samples.

Called native ambient mass spectrometry (NAMS), the tool enables the structure of proteins to be studied in relation to their location within the tissue in greater detail than ever before.

Working with colleagues at the University of Sheffield, they were able to identify a metal deficiency in a specific protein, known as SOD1, and show that it accumulates in specific regions of the brain and spinal cord in mice with MND.

SOD1 has been implicated in motor neurone disease previously but this is the first time that detailed molecular imaging has been able to show how versions of the protein with missing metal ions accumulate in the affected mice.

Richard Mead from the Sheffield Institute for Translational Neuroscience said: “We were very excited to apply this fantastic methodology which Helen’s team have developed to gain new insights into the biology of MND and we look forward to using the technology further to explore why motor neurons die and find new interventions for those affected by MND.”

The next steps for the researchers will be to test to see if the same imbalances are present in human tissue samples, and to try to treat the imbalance in the mice using available drug compounds.

Unlocking data’s power to speed up MND research

A new initiative is aiming to accelerate motor neurone disease research by harnessing the power of health data.

The MND Research Data Catalyst is a new initiative led by HDR UK and DPUK, with the UK Dementia Research Institute (UK DRI) and in partnership with the MND research community, to accelerate the discovery of new diagnostics, treatments and support better care for MND patients.

This will be achieved by harnessing the UK’s trustworthy, large-scale health data infrastructure and fostering collaborative partnerships across the MND research landscape.

Dr Rhoswyn Walker, director of strategy at HDR UK, said: “MND research faces many complex scientific challenges and there is a huge opportunity to accelerate research into this life-shortening disease by unlocking the power of health data. We are delighted to partner with DPUK, UK DRI and the whole MND research community to build a secure data platform that accelerates trustworthy data use to save lives.”

Professor John Gallacher, director of DPUK, said: “DPUK is delighted to add to our growing MND portfolio by supporting the MND Research Data Catalyst. We expect the Catalyst will make a fundamental contribution to MND therapeutics; delivering high-quality translation science. Through our project management and SeRP-led informatics solutions, DPUK will provide the necessary infrastructure for rapid project delivery and data access.”

The catalyst is supported by £2 million in funding from the Department of Health and Social Care (DHSC), delivered through the National Institute of Health and Care Research (NIHR). This is part of wider support to grow MND research by the UK government in partnership with charities and organisations including the NIHR, UK Research and Innovation, MND Association, My Name’5 Doddie Foundation, MND Scotland, and LifeArc.

Professor Mike Lewis, NIHR scientific director for innovation, said: “We are pleased to support our partners in the MND Research Data Catalyst. It represents an important next step in our ability to safely and securely open up data in this area to researchers from diverse disciplines, who can hopefully uncover new ways of understanding and treating this debilitating disease and improving the lives of everyone affected by it.”

Professor Siddharthan Chandran, director of the UK DRI, said: “Joining forces with HDR UK, DPUK, and the MND research community to deliver the MND Research Data Catalyst will help drive real change for those affected by this devastating disease. The UK DRI, a hub of mechanistic science powered by molecular data, leads the largest UK clinical trial, MND-SMART, and we are pleased to support this new initiative that will significantly boost UK science in this critical area.”

The MND Research Data Catalyst will be underpinned by the principle of “user-centred design”. Solutions will be co-created with the UK-wide MND research community to ensure that they deliver against an unmet need and enable novel, high-impact research outcomes.