Periodic Reporting for period 3 - NECTAR (NEutron Capture-enhanced Treatment of neurotoxic Amyloid aggRegates)
Okres sprawozdawczy: 2023-04-01 do 2025-09-30
Neutron Capture Therapy (NCT) is a radiotherapy used for cancer. Its effectiveness relies on the localised energy deposition due to the charged high LET secondaries set in motion by some neutron capture reactions. The two most used ones are boron-10, B10, and gadolinium-157, Gd157, capture reactions. The range in tissue of the secondaries spans from few tens of nm (comparable to the DNA strand) up to less than 10 μm, that is the mean diameter of cells. The reactions probability is maximised at neutron low energy when modest side effects on normal tissues are expected. NCT cell-level selectivity is due to the exploitation of the described physical properties together with the use of B10 or Gd157 enriched molecules, which are loaded only or preferentially by the neoplastic tissue.
Starting from the experience in oncology, NECTAR wants to evaluate and prove the feasibility, safety and effectiveness of the physical principles of NCT in the treatment of a completely different disease: Alzheimer’s disease (AD).
AD is the most common form of dementia (50-60% of all cases) and it destroys nerve cells limiting or abolishing higher functions. In the most advanced stages, patients will be unable to care for themselves and need constant help with their daily life.
Currently over 55 million people worldwide live with dementia. The number is expected to rise up to 139 million by 2050. Statistics say a new case of dementia arise somewhere in the world every 3 seconds. If we consider dementia as a country it would be the 14th largest economy worldwide, with a US$ 1.3 trillion current cost.
Pathogenesis and mechanisms involved in AD are still under investigation. Despite the huge amount of studies, there is currently no definitive and rehab cure. In summer 2021, a new approved FDA drug, the monoclonal antibody Aducanumab was approved for AD treatment in humans with a specific action against the beta amyloid (Aβ) protein. Anyway, the very same approval was not released by EMA due to controversy in the outcomes of the trials. In the following years, several new monoclonal antibodies have been approved or are presently under scrutiny: Lecanemab for early AD (FDA approved since 223, EMA approved since 2025), Donanemab (presently under evaluation by FDA as well as by EMA).
Aβ is a protein normally produced by neurons, In AD this protein assumes an insoluble form leading to its abnormal aggregation and accumulation in the extracellular compartment. In this forms, Aβ is toxic for neurons and in the “amyloid cascade” hypothesis its accumulation is identified as on eof the most important triggering events of the disorder. It was demonstrated that one of the very first aggregation stages, the oligomeric phase, is the most toxic for neurons. In addition, other processes are ongoing in AD, such as accumulation of iper phosphorylated tau protein and inflammation. In this context, several doubts and criticisms hover around the named monoclonal antibodies, because their action is known to address mainly senile plaques (the last stage of Aβ aggregation). Thus these drugs may be ineffective against the oligomers or they may not stop the decline process connected with the tau protein. In this scenario, the investigation of new therapeutic options, in particular those proposing a completely different principle of action, deserve attention and NECTAR sets exactly at this point.
NECTAR can’t simply take the molecules and the irradiation protocols used in the NCT of cancer because in that case the treatment faces an acute disease by an acute procedure. In AD, the treatment must address a chronic disease spreading in the whole brain, known to be radio sensitive. Only NCT basic physical principles can be translated to AD. Indeed a completely new class of neutron capture agents must be developed, in particular able to cross an almost intact blood-brain barrier. Considering the radio-sensitivity of brain, it is absolutely impossible to translate the acute irradiation protocols of NCT of cancer into an AD therapy and indeed NECTAR must identify a completely new treatment based on low doses and low dose rates.
In this frame, NECTAR objectives are:
(1) to study and prove the effectiveness of the highly localised energy deposition induced by the neutron capture reactions on B10 and Gd157 to depolymerise the Aβ aggregates or to modify their structures in such a way that their toxicity is reduced or silenced;
(2) to evaluate the stimulation on the glia cell compartment by the penetrating photons emitted by the exploited capture reactions, in particular to assess if the radio-activated glia can promote the clearance of the Aβ aggregates.
If these hypothesis will be confirmed, NECTAR will test: (1) the safety of the brain pan-irradiation by low energy neutrons in presence and absence of the neutron capture agent, and (2) the effectiveness of the irradiation in slowing down the neuron degeneration and possibly the restoration of mental functions in particular connected with memory and mobility using normal and transgenic animal models.
NECTAR pursues also a technological goal, that is the identification, development and characterisation of the optimised neutron beam to perform the brain irradiation. In particular, NECTAR addresses the development and prototyping of innovative neutron spectrometers and micro- and nano-dosimeters to quantify the physical quantities of relevance down to Aβ dimension aggregates.
Starting from the experience in oncology, NECTAR wants to evaluate and prove the feasibility, safety and effectiveness of the physical principles of NCT in the treatment of a completely different disease: Alzheimer’s disease (AD).
AD is the most common form of dementia (50-60% of all cases) and it destroys nerve cells limiting or abolishing higher functions. In the most advanced stages, patients will be unable to care for themselves and need constant help with their daily life.
Currently over 55 million people worldwide live with dementia. The number is expected to rise up to 139 million by 2050. Statistics say a new case of dementia arise somewhere in the world every 3 seconds. If we consider dementia as a country it would be the 14th largest economy worldwide, with a US$ 1.3 trillion current cost.
Pathogenesis and mechanisms involved in AD are still under investigation. Despite the huge amount of studies, there is currently no definitive and rehab cure. In summer 2021, a new approved FDA drug, the monoclonal antibody Aducanumab was approved for AD treatment in humans with a specific action against the beta amyloid (Aβ) protein. Anyway, the very same approval was not released by EMA due to controversy in the outcomes of the trials. In the following years, several new monoclonal antibodies have been approved or are presently under scrutiny: Lecanemab for early AD (FDA approved since 223, EMA approved since 2025), Donanemab (presently under evaluation by FDA as well as by EMA).
Aβ is a protein normally produced by neurons, In AD this protein assumes an insoluble form leading to its abnormal aggregation and accumulation in the extracellular compartment. In this forms, Aβ is toxic for neurons and in the “amyloid cascade” hypothesis its accumulation is identified as on eof the most important triggering events of the disorder. It was demonstrated that one of the very first aggregation stages, the oligomeric phase, is the most toxic for neurons. In addition, other processes are ongoing in AD, such as accumulation of iper phosphorylated tau protein and inflammation. In this context, several doubts and criticisms hover around the named monoclonal antibodies, because their action is known to address mainly senile plaques (the last stage of Aβ aggregation). Thus these drugs may be ineffective against the oligomers or they may not stop the decline process connected with the tau protein. In this scenario, the investigation of new therapeutic options, in particular those proposing a completely different principle of action, deserve attention and NECTAR sets exactly at this point.
NECTAR can’t simply take the molecules and the irradiation protocols used in the NCT of cancer because in that case the treatment faces an acute disease by an acute procedure. In AD, the treatment must address a chronic disease spreading in the whole brain, known to be radio sensitive. Only NCT basic physical principles can be translated to AD. Indeed a completely new class of neutron capture agents must be developed, in particular able to cross an almost intact blood-brain barrier. Considering the radio-sensitivity of brain, it is absolutely impossible to translate the acute irradiation protocols of NCT of cancer into an AD therapy and indeed NECTAR must identify a completely new treatment based on low doses and low dose rates.
In this frame, NECTAR objectives are:
(1) to study and prove the effectiveness of the highly localised energy deposition induced by the neutron capture reactions on B10 and Gd157 to depolymerise the Aβ aggregates or to modify their structures in such a way that their toxicity is reduced or silenced;
(2) to evaluate the stimulation on the glia cell compartment by the penetrating photons emitted by the exploited capture reactions, in particular to assess if the radio-activated glia can promote the clearance of the Aβ aggregates.
If these hypothesis will be confirmed, NECTAR will test: (1) the safety of the brain pan-irradiation by low energy neutrons in presence and absence of the neutron capture agent, and (2) the effectiveness of the irradiation in slowing down the neuron degeneration and possibly the restoration of mental functions in particular connected with memory and mobility using normal and transgenic animal models.
NECTAR pursues also a technological goal, that is the identification, development and characterisation of the optimised neutron beam to perform the brain irradiation. In particular, NECTAR addresses the development and prototyping of innovative neutron spectrometers and micro- and nano-dosimeters to quantify the physical quantities of relevance down to Aβ dimension aggregates.
During the last 30 months of project, the following objectives have been pursued:
- conclusion of the in vitro tests about the safety of the CENI (Capture Enhanced Neutron Irradiation) treatment in 2D models of neuronal cells and glial cells;
- conclusion of the in vivo tests about the safety and the effectiveness of the CENI treatment;
- final development of the instruments for neutron field characterization; an IT patent has been submitted in October 2024, dealing with the new dosimetry tools;
- conclusion of the Monte Carlo studies to design the neutron source to perform the CENI treatment;
- conclusion of the Monte Carlo simulations to describe the effect of the CENI in the different targets at the different scales (from Abeta aggregates up to human brain).
In addition, starting from approximately January 2024 unforeseen experiments have been realized to address the topic of how the high LET radiations of the CENI affects (1) the structure of Abeta aggregates and (2) the mechanisms by which the protein is produced at cell level. Finally, during the very last months of the project, a 3D in vitro model based on spheroids has been developed to further confirm the outcomes observed in the 2D in vitro studies.
- conclusion of the in vitro tests about the safety of the CENI (Capture Enhanced Neutron Irradiation) treatment in 2D models of neuronal cells and glial cells;
- conclusion of the in vivo tests about the safety and the effectiveness of the CENI treatment;
- final development of the instruments for neutron field characterization; an IT patent has been submitted in October 2024, dealing with the new dosimetry tools;
- conclusion of the Monte Carlo studies to design the neutron source to perform the CENI treatment;
- conclusion of the Monte Carlo simulations to describe the effect of the CENI in the different targets at the different scales (from Abeta aggregates up to human brain).
In addition, starting from approximately January 2024 unforeseen experiments have been realized to address the topic of how the high LET radiations of the CENI affects (1) the structure of Abeta aggregates and (2) the mechanisms by which the protein is produced at cell level. Finally, during the very last months of the project, a 3D in vitro model based on spheroids has been developed to further confirm the outcomes observed in the 2D in vitro studies.
NECTAR is a very ambitious project whose aim is the preclinical evaluation of the safety and effectiveness of a Capture Enhanced Neutron Irradiation in transgenic AD in mice. At the end of the project positive and promising outcomes about an actual restoring effect on the cognitive function has been observed.
These preclinical outcomes represent a huge progress beyond the state of the art: to the NECTAR Consortium knowledge, no other study has been performed or is ongoing investigating the use of a neutron-driven irradiation for the treatment of AD.
Under a more long-term perspective, our outcomes could become the base for the economic and social impacts that an innovative approach such as the one investigated by NECTAR could lead to in term of AD management.
These preclinical outcomes represent a huge progress beyond the state of the art: to the NECTAR Consortium knowledge, no other study has been performed or is ongoing investigating the use of a neutron-driven irradiation for the treatment of AD.
Under a more long-term perspective, our outcomes could become the base for the economic and social impacts that an innovative approach such as the one investigated by NECTAR could lead to in term of AD management.