The “Neutron Capture-enhanced Treatment of neurotoxic Amyloid aggRegates” project
by Nicoleta Protti.
Approximately 50 million people worldwide are living with dementia. This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. The total estimated worldwide cost of dementia in 2015 was US$ 818 billion; in 2018, costs reached a trillion dollars and will rise to US$ 2 trillion by 2030. If global dementia care were a country, it would be the 18th largest economy in the world.
The social impact of dementia is tremendous: still a diagnosis of dementia can bring stigma and social isolation or family difficulties, affecting both patient’s quality of life as well as that of relatives and carers. Alzheimer Disease (AD) is the most common cause of dementia. 46.8 million people live with AD worldwide, with numbers projected to almost double every 20 years. In 2015, the estimation was that we had 9.9 million new cases of dementia equivalent to 1 every 3.2 seconds [1]. There is no cure and has been no new FDA approved medication since 2002. AD treatment current paradigm involves a combination of pharmacological an non-pharmacological treatments to mitigate progressive loss of cognitive and functional abilities: a symptomatic treatment enhancing the impaired cerebral functions but not addressing the causative agents.
The majority of AD-modifying treatments are beta amyloid peptide (Aβ)-centric based on a strong faith in the “Aβ Cascade Hypothesis” and they are based on a drug-mediated targeting of amyloidogenic and non-amyloidogenic pathways. The etiological mechanisms underlying the neuropathological changes in AD remain unclear. Aβ is considered to be the main culprit of the neuropathological processes, characterised by a process of progressive aggregation: oligomers are the initial spheric stage of few nm diameter considered as the most toxic species and the best correlate of synaptic and cognitive dysfunction; they then develop into fibrils (“chains” of oligomers of several hundreds μm length and few nm diameter) which finally condensate into plaques of tens μm diameter.
NECTAR
NECTAR project proposes an alternative and revolutionary strategy to address AD, investigating the safety, feasibility and effectiveness of NCT mediated by B-10 and Gd-157 to structurally damage Aβ aggregates, exploiting capture agent vectors specifically engineered to selectively target the various forms of Aβ aggregates and able to cross the intact BBB.
Thanks to the mixed high+low LET radiations field set in correspondence of Aβ aggregates by the neutron irradiation, a bimodal treatment is expected to take place:
(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 (prompt γ rays of Gd-157, 31% branching ratio, and B-10, 94% branching ratio).
NECTAR rational is based on a few scientific evidences. The effectiveness of External Beam Radiation Therapy (EBRT) in the treatment of localized TracheoBronchial Amyloidosis (TBA) is known such that photon RT is presently recommended as a first-line treatment for patients who are not eligible for bronchoscopic interventions. 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 in 2008 [2]. The capability of ionising radiations 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 doses per fraction over a prolonged treatment period can match the brain tolerance levels and still slows the cognitive impair.
The first experimental evidence of the positive effects of X-ray brain irradiation on Aβ plaques burden and memory impairment was reported in 2018 using an AD transgenic mouse model [3]. The observation of the better outcome after the highly fractionated regimen and the expression of genes and promoting factors connected with the activation of the brain immune system support the hypothesis that low dose and low dose rate irradiation can stimulate the clearance of the Aβ aggregates by the recruitment of glia cells.
FET-Open
NECTAR project has been selected and funded under the European Commission H2020 call “Future and Emerging Technologies – FET Open: novel ideas for radically new technologies”. FET-Open supports early stage science and technology research exploring new foundations for radically new future technologies by challenging current paradigms and venturing into unknown areas.
he Physics Department of Pavia University, Italy, is the Coordinator of NECTAR project. The work is based on an interdisciplinary EU networks of research teams from 7 academics: Pavia University (Coordinator; NCT neutron irradiation facilities and in vitro/in vivo NCT experience), Torino University (MRI-guided NCT probes, in vitro/in vivo NCT experience), Mario Negri Institute for Pharmacological Research (AD basic research and animal models), Raylab srl (neutron spectrometry, micro- and nano-dosimetry), Institut de Radioprotection et de Surete Nucleaire (ionizing radiation metrology and Geant4-DNA developers), Stockholm University (cellular effects of ionising radiations at low doses and low dose rates), University Hospital of Essen (AD clinics) and University Hospital of Jena (clinical radiotherapy including NCT).
NECTAR project has just started: on the 1st of April 2021. It will last for 42 months, until September 2024. More informations about the project, including the scheduled temporary positions, will be available at NECTAR official web site (to be released soon) and can be asked directly to the Principal Investigator, Dr. Nicoletta Protti of Physics Department of Pavia University (nicoletta.protti@unipv.it).
References
[1] alzint.org
[2] Bistolfi, Neuroradiol J 2008 21:683-692
[3] Marples et al, Radiother Oncol 2016 118:43-51