Periodic Reporting for period 1 - NeutrAD (Targetting neutrophil-mediated neurotoxicity for the treatment of Alzheimer's Disease)
Reporting period: 2022-06-01 to 2024-05-31
Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide, and its prevalence is projected to nearly double every 20 years with tremendous social and economic impact on society. The central neuropathological characteristics of AD include neuronal death, amyloid beta (Abeta) deposition, and formation of neurofibrillary tangles. Inflammation is also a pathological hallmark of AD, and understanding the underlying mechanisms may facilitate the development of new treatments.
Our previous pioneer research has demonstrated a role for neutrophils in the induction of memory decline and neuropathological hallmarks of AD, highlighting the role of peripheral immune cells in AD. Moreover, our recent supporting data showed that neutrophils have an activated and degranulating phenotype in AD mouse models. Moreover, we obtained results showing that neutrophil granule molecules have a direct neurotoxic effect on neurons, indicating that targeting specific neutrophil pro-inflammatory and cytotoxic activities is a novel therapeutic strategy in AD. Therefore, the main aim of NeutrAD was to determine the technical and commercial feasibility of novel inhibitors targeting neutrophil granule molecules as disease-modifying drugs against AD.
Our previous pioneer research has demonstrated a role for neutrophils in the induction of memory decline and neuropathological hallmarks of AD, highlighting the role of peripheral immune cells in AD. Moreover, our recent supporting data showed that neutrophils have an activated and degranulating phenotype in AD mouse models. Moreover, we obtained results showing that neutrophil granule molecules have a direct neurotoxic effect on neurons, indicating that targeting specific neutrophil pro-inflammatory and cytotoxic activities is a novel therapeutic strategy in AD. Therefore, the main aim of NeutrAD was to determine the technical and commercial feasibility of novel inhibitors targeting neutrophil granule molecules as disease-modifying drugs against AD.
We first obtained more evidence on the role of neutrophil granule molecules in AD, and our new data revealed an increase of key granule proteins in circulating neutrophils in mice with AD-like disease and patients with AD compared to controls. We also obtained unexpected data showing that neutrophil granule molecules potentiate each other, promoting the amplification of neurotoxic inflammation. Together, these new data increase the relevance of our project and further point to neutrophil granule molecules as new therapeutic targets for AD.
To block the activity of key neutrophil granule molecules, we first produced small inhibitory molecules and drugs based on proteolysis targeting chimeras (PROTACs). These new potential drugs were first tested in functional assays in vitro for their capacity to block neutrophil-dependent neurotoxicity on neurons using advanced wide-field live imaging. The most promising drugs were next tested for their bioavailability, and lead molecules were tested in an animal model of AD, developing the neuropathological hallmarks of the disease. In this context, we identified the most effective inhibitor leading to a significant reduction of Abeta deposition and tau hyperphosphorylation, when compared to animals treated with vehicle. Also, our data showed that treatment with the same promising drug improved the performance and significantly reduced memory loss when compared to vehicle treatment. This shows that the reduction of neuropathological disease hallmarks is paralleled by improved cognitive functions in mice treated with NeutrAD drug candidate.
Collectively, NeutrAD results show the therapeutic efficacy of neutrophil granule molecule inhibition in AD mouse models and suggest that blocking neutrophil-dependent toxic mechanisms represents a novel and promising therapeutic approach in AD.
To block the activity of key neutrophil granule molecules, we first produced small inhibitory molecules and drugs based on proteolysis targeting chimeras (PROTACs). These new potential drugs were first tested in functional assays in vitro for their capacity to block neutrophil-dependent neurotoxicity on neurons using advanced wide-field live imaging. The most promising drugs were next tested for their bioavailability, and lead molecules were tested in an animal model of AD, developing the neuropathological hallmarks of the disease. In this context, we identified the most effective inhibitor leading to a significant reduction of Abeta deposition and tau hyperphosphorylation, when compared to animals treated with vehicle. Also, our data showed that treatment with the same promising drug improved the performance and significantly reduced memory loss when compared to vehicle treatment. This shows that the reduction of neuropathological disease hallmarks is paralleled by improved cognitive functions in mice treated with NeutrAD drug candidate.
Collectively, NeutrAD results show the therapeutic efficacy of neutrophil granule molecule inhibition in AD mouse models and suggest that blocking neutrophil-dependent toxic mechanisms represents a novel and promising therapeutic approach in AD.
Intense research efforts in the past decades to understand the pathogenesis of neurodegenerative diseases and design effective therapeutics have been focused mainly on neurons and other CNS resident cells. Although this “neurocentric” view has contributed to our understanding of neuronal dysfunction, death pathways, and accumulation of proteinaceous aggregates during chronic neurodegenerative processes, this approach has not resulted in disease-modifying therapeutics. This suggests that the pathogenesis of neurodegenerative disorders is more complex than previously thought, and that the lack of success of neurocentric-based therapies may be due to the participation of non-neuronal cells in the disease process. WE OVERCAME THIS CONCEPTUAL LIMITATION in NeutrAD by demonstrating that circulating leukocytes and neuroimmune interactions play a pivotal role in the induction of a process of neurotoxic inflammation promoting disease pathogenesis.
The study of neutrophil-neuron interactions has never been proposed for the study of AD and our project was based on the novel idea of the direct harmful effect of neutrophils on neuronal activity contributing to disease pathogenesis. NeutrAD presents a new approach to rescue neuronal death and cognitive deficit in AD by introducing new candidates that use a neutrophil-targeted approach.
A patent protecting NeutrAD data is currently under the submission process. Market analysis, commercial feasibility and business development were produced for NeutrAD and the hurdles of the development roadmap were also identified.
The study of neutrophil-neuron interactions has never been proposed for the study of AD and our project was based on the novel idea of the direct harmful effect of neutrophils on neuronal activity contributing to disease pathogenesis. NeutrAD presents a new approach to rescue neuronal death and cognitive deficit in AD by introducing new candidates that use a neutrophil-targeted approach.
A patent protecting NeutrAD data is currently under the submission process. Market analysis, commercial feasibility and business development were produced for NeutrAD and the hurdles of the development roadmap were also identified.