What is NECTAR?

NECTAR at a glance

Coordinator:
Pavia University (UNIPV) Italy
Budget:
3.2 million euro
Duration:
01.04.2021 - 30.09.2025

ALZHEIMER DISEASE (AD) IS THE MOST COMMON CAUSE OF DEMENTIA BUT NO CURE OR EFFECTIVE TREATMENTS EXIST.

The majority of researched treatments are based on drug development program targeting the beta amyloid peptide (Aβ). The Aβ is considered to be the main culprit of the neurodegenerative process, characterized by progressive aggregation: oligomers (spheric aggregates with diameters of few nm) develop into fibrils (“chains” of oligomers of hundreds μm length and few nm diameter) up to plaques of tens μm diameter, that cause the irreversible decline of synaptic and cognitive functions.

NECTAR PROJECT PROPOSES AN ALTERNATIVE AND REVOLUTIONARY STRATEGY TO ADDRESS ALZHEIMER DISEASE, INVESTIGATING A THERAPY BASED ON IONIZING RADIATIONS.

NECTAR aims to prove the feasibility, safety and effectiveness of a Capture-Enhanced Neutron Irradiation (CENI) to structurally damage the Abeta aggregates: it exploits an external beam of low energy neutrons which selectively targets the amyloid beta aggregates through specifically engineered radiation enhancers, containing Boron-10 and Gadolinium-157 as capture agents. The nuclear capture reactions, induced by the neutron irradiation, generate a mixed high+low LET radiation field, expected to induce a bimodal treatment: (i) a local depolymerisation of Aβ aggregates by the highly biological effective charged particles and (ii) a long distance stimulation of the brain tissue by penetrating photons.

HOW NECTAR WORKS?

Work Packages

Work Package 1 - PROJECT MANAGEMENT

Lead beneficiary: Pavia University, UNIPV
Involved partners: UNITO, IRFMN, Raylab, IRSN, SU, UKESSEN, UKW
Objectives: to ensure the operational management of NECTAR project by:
1. organization of project meetings,
2. managing the Steering Committee, appointing and managing the Scientific Advisory Board (SAB),
3. piloting the project reporting activity.

Work Package 2 - CAPTURE-ENHANCED NEUTRON IRRADIATION (CENI) AGENTS

Lead beneficiary: Torino University, UNITO
Involved partners: IRFMN, IRSN, UKESSEN
Objectives:
1. synthesis of biocompatible probes based on Gd/B-enriched molecules able to (i) pass the health Blood-Brain Barrier (BBB) and (ii) selectively bind Aβ aggregates,
2. characterization of the probes (stability, binding affinity to Aβ protein and aggregates, spatial distribution of capture-enhanced nuclides around and inside the Aβ aggregates),
3. in vivo biodistribution.

Work Package 3 - DOSIMETRY AND CAPTURE-ENHANCED NEUTRON IRRADIATION (CENI) PLANNING

Lead beneficiary: Institut de Radioprotection et de Sûreté Nucléaire, IRSN
Involved partners: UNIPV, UNITO, IRFMN, Raylab, SU, UKW
Objectives:
1. to develop computational tools to predict and correlate the actions of ionizing radiations set in motion by CENI treatment to the effects (structural and biological) observed in post-irradiated Abeta aggregates;
2. to design proper set-ups for the irradiation of protein water solution, small animals and AD patients.

Work Package 4 - HIGH LINEAR ENERGY TRANSFER (LET) IONIZING RADIATIONS EFFECTS

Lead beneficiary: Raylab s.r.l., Raylab
Involved partners: UNIPV, UNITO, IRFMN, Raylab, IRSN, SU, UKESSEN
Objectives:
1. to ascertain the capability of Capture-Enhanced Neutron Irradiation (CENI) to induce structural depolymerization of Abeta species marked by Gd/B in a cell-free approach;
2. to study the residual neurotoxic effects of such aggregates in vitro and in vivo;
3. to perform micro- and nano-dosimetry measurements to compare with the computational tools developed in WP3.

Work Package 5 - CAPTURE-ENHANCED NEUTRON IRRADIATION (CENI) SAFETY

Lead beneficiary: Stockholm University, SU
Involved partners: UNIPV, UNITO, IRFMN, Raylab, UKESSEN, UKW
Objectives:
1. to define the cellular and cytogenetic effects of low energy neutron irradiation alone and in combination with Gd/B enhancement agents on neuronal and glia cells;
2. to identify eventual toxic effects of low energy neutrons irradiation alone and in combination with Gd/B enhancement agents in the brain of C57 naive and APP/PS1 AD mice.

Work Package 6 - CAPTURE-ENHANCED NEUTRON IRRADIATION (CENI) EFFECTIVENESS

Lead beneficiary: Mario Negri Institute for Pharmacological Research IRCCS, IRFMN
Involved partners: UNIPV, UNITO, Raylab, SU, UKESSEN
Objectives:
1. to test the therapeutic efficacy of CENI-mediated Gd/B treatment to restore memory in the APP/PS1 AD mice at both pre- and post-symptomatic stages;
2. to test the therapeutic efficacy of Gd/B to reduce the extent of neuropathology at the level of multiple neuropathological targets in APP/PS1 AD mice at both pre- and post-symptomatic stages.

Work Package 7 - DISSEMINATION, TRAINING & EDUCATION

Lead beneficiary: Pavia University, UNIPV
Involved partners: UNITO, IRFMN, Raylab, IRSN, SU, UKESSEN, UKW
Objectives:
1. to disseminate project results to the different audiences impacted by the research,
2. to ensure the internal and external communication around the project,
3. to train end-users of the innovative AD treatment strategy.

Work Packages in Years

1

2

3

4

NECTAR scientific background

The effectiveness of External Beam Radiation Therapy (EBRT) in the treatment of localized TracheoBronchial Amyloidosis (TBA) is known[1-3] such that photon RT is presently recommended as a first-line treatment for patients who are not eligible for bronchoscopic interventions[4]. The total dose is generally 20Gy, 2Gy/fraction in 2 weeks. All the patients showed improvement or stabilisation of the symptoms with mild and manageable side effects.
The mechanisms by which RT is effective on TBA is still unclear. Several hypotheses have been proposed, although none clearly supported by clinical data. The most discussed one is that RT acts on local plasma cells which are considered the culprits of the amyloid deposits due to the up regulated secretion of peptide light chains. However, the analysis of amyloid deposits showed scarce presence of plasma cells thus a radiation effect on their function or turnover is unlikely to be the only mechanism in action.
Taking into account the common amyloidosis nature of TBA and AD, the rationale for a radiation induced depolymerisation of Aβ aggregates was suggested[5]. The capability of IRs to change amyloid structure by depolymerise associated scaffold molecules (glucosaminoglycans, GAGs, invariably associated with amyloid fibrils) is a DNA-independent mechanism, thus a regimen based on very low dose per fraction over a prolonged treatment period can match the brain tolerance levels and still slows the cognitive impair.

Bibliography:
[1] Kalra et al, Mayo Clin Proc 2006 76:853-856;
[2] Kurrus et al, Hest 1998 114:1489-1492;
[3] Monroe et al, Hest 2004 125:784-789;
[4] Neben- Wittich et al, Chest 2007 132:262-267;
[5] Bistolfi, Neuroradiol J 2008 21:683-692.

Compared to the literature available at NECTAR project submission and start, the papers testing preclinically the effectiveness of conventional radiotherapy in the treatment of AD are steadily increasing. Considering the earliest one [1] which evaluated the effects of X-rays RT on in vitro preformed Aβ1-42 fibrils and on their initial formation using the Thioflavin-T assay and acute regimes of radiations (single fractions from 5 up to 20Gy) with poor significant effects by the irradiation, nowadays the papers studying the effects of photons in murine models of AD are several [2-5].

Despite further investigations are needed, the expression of genes and promoting factors connected with the activation of the brain immune system is the dominant hypothesis supporting that low dose and low dose rate of conventional irradiation can stimulate the clearance of the Aβ aggregates by the recruitment of glia cells.

Bibliography:
[1] Patrias et al, Radiar Res 2011 175:375-381; [2] Marples et al, Radiother Oncol 2016 118:43-
51; [3] Kim et al, Int J Mol Sci 2020, 21, 3678; [4] Kim et al, Int J Mol Sci 2020, 21, 4532 ; [5]
Wilson et al, J Alzheimers Dis 2020, 75(1):15-21.

A case report[1] described for the first time the remarkable improvement observed in a patient with advanced AD who received 5 CT-scans of the brain (about 40 mGy each) over a period of 3 months.

The underling mechanism appears to be the radiation-induced up-regulation of the patient’s adaptive protection systems[2], which partially restored cognition, memory, speech, movement and appetite. More recently the same research group tested these results in a single-arm pilot clinical trial to examine through a more quantitative approach the effects of low-dose ionizing radiations (LDIR) in severe AD[3]. Minor improvements on quantitative measures were noted in 75% of patients, despite the qualitative observations of cognition and behaviour
suggested remarkable improvements within days post-treatment, including greater overall alertness.

In the wake of these encouraging results, other trials have been initiated and are currently underway [4]. In general, nowadays the international scientific community is informed of the exciting possibilities that conventional RT can offer in the treatment of AD [5-6].

Bibliography:
[1] Cuttler et al, Dose Response 2016:1-7; [2] Feinendegen et al, Health Phys 2011 100(3):247-259; [3] Cuttler et al, J Alzheimer's Dis 2021 80:1119-1128; [4] Rogers et al, Int J Radiat Oncol Biol Phys (article in press); [5] Wilson and Marples, Radiat Res 185(5):443-448 (2016); [6] Wilson et al., Radiat Res 199(5): 506-516 (2023).

Contact

nicoletta.protti@unipv.it
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About FET-OPEN program (now evolved in EIC Pathfinder Open)

FET (Future and Emerging Technologies) Open European program provides support for the earliest stage of new cutting-edge researches in any field of science and technologies. It is now evolved in the EIC Pathfinder Open, that continues the mission embracing high-risk, high- gain projects and interdisciplinary collaborations that drive technological breakthroughs. The program aims to go beyond existing knowledge and encourages visionary thinking to pave the way for innovations, radical new ideas and novel technologies, with potential to create new markets and opportunities.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 964934

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