Periodic Reporting for period 4 - PANA (PROMOTING ACTIVE AGEING: FUNCTIONAL NANOSTRUCTURES FOR ALZHEIMER’S DISEASE AT ULTRA-EARLY STAGES.)
Reporting period: 2020-09-01 to 2021-08-31
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 Disease´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 Alzheimer´s Disease. In this scenario, it is imperative to develop effective procedures for the early diagnosis of Alzheimer´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 patient’s sample.
-A dual theragnostic contrast agent –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 method–PANA003- relying on theragnostic nanostructures, that will act as a delivery system for therapeutic agents while allowing close monitoring of the disease progress.
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 patient’s sample.
-A dual theragnostic contrast agent –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 method–PANA003- relying on theragnostic nanostructures, that will act as a delivery system for therapeutic agents while allowing close monitoring of the disease progress.
After the PANA full project implementation, several achievements have been reached in several fields such as the following:
• The development of high-affinity antibodies against p-Tau and ac-Tau.
• Epitote characterization and sequencing of novel (p-Tau) and (ac-tau) monoclonal antibodies with potential diagnostic and therapeutic propierties.
• GMP manufacturing plan of (p-Tau) monoclonal antibody.
• the development of reliable, stable and safe radiolabelled nanoconjugates that can be used as potential 1) novel contrast agents in MRI/PET and 2) innovative carriers for therapeutic compounds.
• novel in-vitro diagnostics methods (ELISAs) for specific tau isoforms (p-Tau and ac-Tau).
• Novel immunotherapy against phosphorylated Tau without toxic effects.
The development of potential patent applications to secure IP protection and/or future explotation actions for the custom-made antibodies have ben performed. rThe PANA consortium is committed to achieve further exploitation of the project results beyond the project implementation and will therefore continue to pay high efforts to the IP protection and further exploitation of the results. In addition to the IP work, a comprenhensive approach have been carried-out in order to gain in-depth knowledge of AD and in the specific Tau-based approached for in-vitro and in-vivo diagnosis, as well and in the filed of immunotherapy. Main competitors and compounds under development have been identified. The findings of this analysis have decisively contributed to help SERGAS to found a start-up that will exploit its own results. This company, named Lincbiotech SL.
Although it is not completely understood the contribution of genetics and environment to AD, current data suggests that AD is a continuum of several genetic and environmental factors where misfolding and aggregation of certain proteins such as tau. Tau phosphorylation have been related to reduced microtubule affinity and increased aggregation of tau. On the other hand, more recent findings have confirmed relevant roles of acetylations in tau microtubule assembly, degradation and aggregation. The products are expected to be formulated as solutions for injection or infusion. The dose level has not been determined. The posology is suspected to require multiple administrations at defined intervals. The route of administration is to be defined. The PANA consortium presented a regulatory roadmap for the development of E11 and B6 as a new therapy for the treatment of early AD.
Summarizing all the work carried out so far, PANA consortium has been able to provide solid proof-of-concept for the following PANA products:
• An innovative in-vitro system, based on tau oligomers, PANA001: Kits ELISA for detection of misfolded Tau in CSF were optimized and were clinically validated (in comparison to current gold-standards) showing promising results that have to be validated in further multicentric and larger clinical studies.
• A dual theragnostic contrast agents PANA002: Proof-of-concept for novel contrast agent based on both p-Tau mAb (89Zr, 125I ) and nanoconjugates (89Zr, 125I ) have been already tested in-vivo. Positive results in terms of signal were found, and biodistribution analysis was carried out. However, a remaining issue to be overcome is the limitated uptake of the brain. The consortium worked on different strategies to optimize these results, but unfortunately, no positive results were obtained. Novel developments focused on BBB cross are needed.
• –PANA003- a novel immunotherapy against tau aggregation proof-of-concept study to assess safety and efficacy was carried out showing promising data.
• The development of high-affinity antibodies against p-Tau and ac-Tau.
• Epitote characterization and sequencing of novel (p-Tau) and (ac-tau) monoclonal antibodies with potential diagnostic and therapeutic propierties.
• GMP manufacturing plan of (p-Tau) monoclonal antibody.
• the development of reliable, stable and safe radiolabelled nanoconjugates that can be used as potential 1) novel contrast agents in MRI/PET and 2) innovative carriers for therapeutic compounds.
• novel in-vitro diagnostics methods (ELISAs) for specific tau isoforms (p-Tau and ac-Tau).
• Novel immunotherapy against phosphorylated Tau without toxic effects.
The development of potential patent applications to secure IP protection and/or future explotation actions for the custom-made antibodies have ben performed. rThe PANA consortium is committed to achieve further exploitation of the project results beyond the project implementation and will therefore continue to pay high efforts to the IP protection and further exploitation of the results. In addition to the IP work, a comprenhensive approach have been carried-out in order to gain in-depth knowledge of AD and in the specific Tau-based approached for in-vitro and in-vivo diagnosis, as well and in the filed of immunotherapy. Main competitors and compounds under development have been identified. The findings of this analysis have decisively contributed to help SERGAS to found a start-up that will exploit its own results. This company, named Lincbiotech SL.
Although it is not completely understood the contribution of genetics and environment to AD, current data suggests that AD is a continuum of several genetic and environmental factors where misfolding and aggregation of certain proteins such as tau. Tau phosphorylation have been related to reduced microtubule affinity and increased aggregation of tau. On the other hand, more recent findings have confirmed relevant roles of acetylations in tau microtubule assembly, degradation and aggregation. The products are expected to be formulated as solutions for injection or infusion. The dose level has not been determined. The posology is suspected to require multiple administrations at defined intervals. The route of administration is to be defined. The PANA consortium presented a regulatory roadmap for the development of E11 and B6 as a new therapy for the treatment of early AD.
Summarizing all the work carried out so far, PANA consortium has been able to provide solid proof-of-concept for the following PANA products:
• An innovative in-vitro system, based on tau oligomers, PANA001: Kits ELISA for detection of misfolded Tau in CSF were optimized and were clinically validated (in comparison to current gold-standards) showing promising results that have to be validated in further multicentric and larger clinical studies.
• A dual theragnostic contrast agents PANA002: Proof-of-concept for novel contrast agent based on both p-Tau mAb (89Zr, 125I ) and nanoconjugates (89Zr, 125I ) have been already tested in-vivo. Positive results in terms of signal were found, and biodistribution analysis was carried out. However, a remaining issue to be overcome is the limitated uptake of the brain. The consortium worked on different strategies to optimize these results, but unfortunately, no positive results were obtained. Novel developments focused on BBB cross are needed.
• –PANA003- a novel immunotherapy against tau aggregation proof-of-concept study to assess safety and efficacy was carried out showing promising data.
Alzheimer’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.
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.