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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - PANA (PROMOTING ACTIVE AGEING: FUNCTIONAL NANOSTRUCTURES FOR ALZHEIMERâ€™S DISEASE AT ULTRA-EARLY STAGES.)

Teaser

Summary

More than 7.5 million European citizens aging between 30 and 99 years suffered from different types of dementia in the EU27, most of these being of the Alzheimer DiseaseÂ´s variety. Demographic changes (progressive aging) and improvement in the quality of health care systems in Europe are conditioning an increase in the incidence and prevalence of AlzheimerÂ´s Disease. In this scenario, it is imperative to develop effective procedures for the early diagnosis of AlzheimerÂ´s Disease in order to improve the treatment and/or prevention of appearance of severe neurodegenerative symptoms.

PANA project focuses on developing multifunctional nanostructures that specifically recognize very-early molecular markers of AD (Tau oligomers) for in vivo diagnostic purposes. Nanostructures will be detectable by means of non-invasive imaging methodologies (MRI and/or PET) and will have the potential to include treatments against the disease for theragnostic purposes.The ultimate goal is the realization of a comprehensive preclinical study to test the efficacy and toxicity of GMP-like nanostructures, so results of PANA project lay the groundwork for a future clinical trial in phase I. As main outcome of the project, the consortium expects to path the way to the future delivery of the following products:

-An innovative in-vitro system, based on tau oligomers -PANA001-, for early-detection of AD on CSF by recognizing Tau oligomers in patientâ€™s sample.
-A dual theragnostic contrast agent â€“PANA002- based on nanostructures that specifically recognize Tau oligomers, and can be detected by means of non-invasive imaging methodologies (MRI and PET, which are already common techniques accessible in most hospitals).
-A novel therapeutic methodâ€“PANA003- relying on theragnostic nanostructures, that will act as a delivery system for therapeutic agents while allowing close monitoring of the disease progress.

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Work performed

PANA project focuses on developing theranostic nanostructures that specifically recognize very-early molecular markers of AD, and can be detected by means of non-invasive imaging methodologies (MRI and/or PET, which are already common techniques accessible in most hospitals) and eventually provide a therapeutic action if needed. To achieve this final goal, firm steps were taken in this first reporting period.

The definition of high specific antibodies for Tau oligomers recognition and functionalization of iron-oxide nanoparticles have been the key activities for the period. There have been significant advances regarding specific antibodies against tau oligomers which is an achievement that have paved the way for the future development of an in-vitro system for early diagnosis of AD from a CSF patientâ€™s samples. In this regard, PANA consortium has been able to achieve the following so far:
â€¢ PANA project develops at least two new highly-specific monoclonal antibody against tau oligomers that has the potential to contribute for an early-stage diagnostic of AD.
â€¢ Monoclonal antibodies (mAbs) are able to detect tau oligomers in CSF samples, so these results justify the development of an ELISA kit with utility in the early diagnosis of AD.

Based on these results, nowadays, PANA has designed a development plan for a high sensitivity ELISA kit (with 2 mAbs against tau oligomers) that will be tested in very well characterized biobanks of the clinical partners of PANA consortium. This product, the so-called PANA001 has the potential to be rapidly adopted by the market due to the fact that it enables easy and early detection of mild cognitive impairment. This product is based on a technique â€“ELISA- communly used and it is suitable on clinical routine since taking a CSF is an established procedure for those suspected to suffer from cognitive impairment. Further assays are needed to confirm the actual potential of the project, but these features may contribute to a early license-out deal with biotech or pharma companies.
On the other hand, the mAbs have shown other important characteristics for the development of dual theragnostic contrast agents:
â€¢ mAbs against tau oligomers does not detect ac-Tau & p-Tau oligomers in blood so these results are very positive because they demonstrate that the blood levels of these oligomers are tiny and this is important in order to increase the bioavailability of biofunctionalized nanostructures in the blood circulation.
â€¢ Custom-made Tau antibodies reveal specific/detectable p-Tau pathology that was evident already at cortex of one-month-old Tau.P301S mice and it was exacerbated significantly in the six-month-old Tau.P301S mice. Likewise, p-Tau pathology was the more prominent in the brainstem of Tau.P301L mice as compared to cortex of the same mice. Therefore, both custom-made p-Tau antibodies (B6/D4), but specially B6 are excellent candidates to be used in the WP1 /biofunctionalization of nanostructures)
These particular characteristics of the antibodies, make more feasible and closer the challenge of developing a new medicinal product relying on theragnostic nanostructures, which will act as a delivery system for therapeutic agents while allowing close monitoring of the disease progress.
In addition to the fact that early results regarding the affinity of the developed antibodies are promising, it should also be mentioned that, depending on the level of the affinity, another additional impact of the project might consist of the possibility of using those antibodies as an immunotherapy against the disease.

Final results

Alzheimerâ€™s disease (AD) is the leading cause of dementia and loss of autonomy in the elderly, implying a progressive cognitive decline and limitation of social activities. Progressive aging of EU population will increase the magnitude of this problem in the next decades. In this scenario, it is imperative to mitigate and delay AD related adverse effects. For that, it is essential and imperative to develop new effective early diagnostic tools in order to get subsequently effective therapeutic strategies. However, currently, there is not an effective method for the early diagnosis of AD. Therefore, there is an urgent need to develop new effective early diagnostic and therapeutic strategies to help in delaying the appearance of the most adverse symptoms of this disease. To defeat this challenge, PANA project bases its approach on the importance of tau oligomers in the early pathophysiological processes of AD. The effective strategy is based on two fundamental pillars; on one hand, efforts are focused on multimodal PET/MRI imaging which is gaining relevance as the best solution for diagnostic purposes due to the complementary advantages of both technologies, combining the high structural characterization of tissue provided by MRI with the enhanced sensitivity of PET imaging. On the other hand, the challenging development of a theragnostic nanostructures will be focused on tau oligomers detection, which would have to deliver theragnostic agents into the brain to provide in situ diagnostic and therapeutic effects.

Therefore, PANA project focuses on developing theranostic nanostructures that specifically recognize very-early molecular markers of AD, and can be detected by means of non-invasive imaging methodologies (MRI and/or PET, which are already common techniques accessible in most hospitals) and eventually provide a therapeutic action if needed.