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Multimodal nanoparticles for structural and functional tracking of stem cell therapy on muscle regeneration

Periodic Reporting for period 3 - nTRACK (Multimodal nanoparticles for structural and functional tracking of stem cell therapy on muscle regeneration)

Reporting period: 2020-10-01 to 2022-03-31

Cell therapy offers promising opportunities to approach several diseases for which no effective therapies are currently available. However, the prognosis of the treatment efficacy commonly only relies on the progression of the disease symptoms. There is a need of tools to evaluate and predict the safety and success of cell-based treatments in earlier stages. This limitation may hinder the development of cell therapies. The current lack of methods providing real-time tracking of transplanted cells and knowledge on their early biodistribution and viability, is one of the major weaknesses of the available cell-based treatments. The main goal of nTRACK was to develop a safe and highly sensitive multimodal nanoimaging agent enabling non-invasive, quantitative, and longitudinal stem cell tracking and whole body biodistribution. nTRACK will also provide information on cell (long-term) viability using the combination of CT, MRI, and PET, which are imaging modalities that are clinically available.
In this regard, nTRACK nanoparticles (NPs) are biocompatible nano-imaging agents that can support the development of new cellular therapies. The NPs developed by a consortium in the context of an EU H2020 grant in the topic “Nanotechnologies for imaging cellular transplants and regenerative processes in vivo” under the title of “Multimodal nanoparticles for structural and functional tracking of stem cell therapy on muscle regeneration (nTRACK)”; nTRACK project achieved the main goal set.
The NPs have been carefully characterized and scale-up according to the GMP standards. From the safety and toxicological perspective, it’s been demonstrated that standardized nanoparticle cell loading is safe and non-toxic. No observable adverse effects have been found nor cellular functionality has been affected or modified by the cytosolic presence of the nanoparticles. A complete set of in vitro and in vivo studies under GLP rules has been carried out that there were no remarkable toxicological effects.
The in vivo imaging studies with small and large animals reached the proof-of-concept for the stem cell visualization longitudinally. Machine learning algorithms have been developed and trained based on the imaging studies (radiomics) delivering reliable for cell quantification and early assessment of treatment effectiveness. All the experimental activities conducted in accordance with the regulatory context, although undefined at the beginning of the project, but improved upon project completion after consultation with competent authorities such as EMA, FDA, BfArM and Paul-Erlich Institute.
In summary, nTRACK NPs are safe and sensitive to track transplanted cells aiming to foster any cell therapy under preclinical and clinical development.
The nTRACK NPs have been widely characterized from the physical and chemical standpoint. Technological transfer from lab-scale to large scale has been successfully conducted according to the GMP standards. Moreover, extensive characterization of the scale-up nanoparticles has been run according to the regulatory recommendations. From the safety and toxicological viewpoint, it’s been demonstrated that standardized nanoparticle cell loading is safe and non-toxic. No observable adverse effects have been found nor cellular functionality has been affected or modified by the cytosolic presence of the nanoparticles. Head-to-head (nps loaded cells vs non-nps loaded cells) in vitro assays established that no changes in the cytokine secretion of the cells used. Moreover, the subcellular fate of the nanoparticles and protein corona after nanoparticle cell internalization have been demonstrated. A complete set of in vitro and in vivo studies under GLP rules has been carried out that there were no remarkable toxicological effects. The in vivo imaging studies with small and large animals reached the proof-of-concept for the stem cell visualization longitudinally. Machine learning algorithms have been developed and trained based on the imaging studies (radiomics) delivering reliable for cell quantification and early assessment of treatment effectiveness. All the experimental activities conducted in accordance with the regulatory context, although undefined at the beginning of the project, but improved upon project completion after consultation with competent authorities such as EMA, FDA, BfArM and Paul-Erlich Institute. Beyond the project, a working group focused on defining a regulatory framework for this type of nanomaterials will be set up.
The nTRACK project has been broadly disseminated to different stakeholders: EU citizens, scientific audience, industry, and authorities. The project dissemination has been through scientific conferences, regular newsletters and thematic articles for scientific popularization, peer-reviewed papers, open day events with specific focus on biotech and pharma industry and, thematic conferences on Stem Cell NanoImaging and a Regulatory Workshop. Moreover, it’s been promoted a collaborative push with other EU-funded under the same topic: StarStem and iNanobit projects.
In order to define a competitive landscape, patent search has been performed every 6 month. During the lifetime of the project around 800 patents have been found using the established set of key words and analysed. From these patents, 155 have been selected as relevant and presented in an internal report. Besides patent search, literature overview, clinical trials documents and press releases have been used as method to determine the key players in the fields of stem cell production, imaging, and nanoparticles for biomedicine use. Based on this analysis, a general and individualized businesses plans have been defined. One patent application is currently under review.
The aspiration of this project was to open a novel research and medical field in nano-scale cellular contrast agents. These multimodal nano-contrast agents will respond to the concerns on efficacy and safety raised by regenerative medicine and cell therapy. To enable researchers and physicians to non-invasively assess the transplanted cells' fate, to predict therapeutic efficacy and to tackle potential safety issues. The main project outcome has been a comprehensive package of studies of nanoparticles as contrast agents that differs from other published nanoparticles in that nanoparticles have been considered as a drug due to the definition of such product as borderline according to current regulatory framework. Therefore, GMP compliance has been considered, extensive nanoparticle characterization and regulatory preclinical safety pharmacology and toxicology studies under GLP rules have been performed which is unprecedented in a single project. Complementary, unique large animal model to assess muscle regeneration has been set up and it will be published. Additionally, extensive work to depict a proper regulatory framework has also been done aligned with the feedback received from EMA, FDA, Paul-Erlich Institute and BfArM. The activity performed is a steppingstone for future development in the nano-scale contrast agents that will benefit novel cell-based therapy and ultimately the society in general.
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