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

Periodic Reporting for period 2 - nTRACK (Multimodal nanoparticles for structural and functional tracking of stem cell therapy on muscle regeneration)

Reporting period: 2019-04-01 to 2020-09-30

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. 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 weakness of the available cell-based treatments. The goal of nTRACK is to develop a safe and highly sensitive multimodal nanoimaging agent enabling non-invasive, quantitative, and longitudinal stem cell tracking and whole body biodistribution. nTRACK is aimed to provide information on cell (long-term) viability using the combination of CT, MRI, and PET, which are imaging modalities that are clinically available. The synthesis of nTRACK NPs and cellular labelling processes are being scaled up and will follow good manufacturing practice (GMP) requirements. The results coming from scaling up showed challenges and demonstrate the difficult transition from lab to industry. The unforeseen difficulties found during the project execution forced to split the research that was being performed into the creation of a nanoparticle pipeline: (a) gold nanoparticles that have been scaled up being compliance with GMP conditions and are currently tested in in vitro and in vivo studies and, (b) gold shell-iron core nanoparticles that are also being analysed in vitro and in vivo to increase knowledge and reach the proof of concept at preclinical level. In contrast, the results delivered from in vitro such as the definition of standard operating protocol for cell labelling as well as research on nanoparticle intracellular fate of the nanoparticles and, in vivo models that resembles human lesions, provided encouraging results regarding the safety of the product as well as transplanted cells imaging under CT & PET. In vitro and in vivo exploratory toxicological studies came up with positive results to progress into the GLP-preclinical safety regulatory studies.
A 2nd goal was to establish a predictive model for early assessment of treatment effectiveness, based on short-term evaluation of the typical migration and biodistribution patterns of the stem cells. The in silico early assessment of treatment effectiveness has been reached and published in rat model to then reach it in the newly developed sheep model of skeletal muscle injury. This predictive model could improve overall management of the disease and move cell therapy treatment into the so-called precision medicine. From “one size fits all’ concept towards personalized treatment. The nTRACK technology will be demonstrated on a muscular injury model that resembles human injuries, using clinical imaging infrastructure used in hospital settings. Another key piece of activity is the non-clinical safety studies on the nTRACK nanoparticles will be conducted following the conclusions of a series of interactions with regulatory authorities, to allow the prompt shift into clinical.
Clinical imaging is a requisite for characterizing damaged tissue/organ and for measuring the safety and efficacy of regenerative medicine. According to the technology and IPR monitoring performed during this period, the ability to track the function and fate of transplanted cells with current technologies is still unsolved. Thus, nTRACK project could be placed in the front edge of stem cells nanolabelling.
It is worth to emphasize the milestone reached in product definition along with the regulatory framework. Though the consortium assumed that the definition of the nTRACK product would not be an easy task, it has been confirmed right after the very first meeting. To sort this out, multiple actions have been performed to reach a proper product definition. This action ended up in a meeting with the Innovation Task Force at the EMA where it was exposed the border line nature of this technology. It’s also been established relationship with key stakeholders: imaging companies, academia and regulatory authorities of two countries. And nTRACK consortium became member of the committee CT-TRACS (Cell Therapy - TRAcking, Circulation, & Safety) of the HESI (Health & Environmental Sciences Institute) which confirmed the uniqueness of the nTRACK’s technology: the existence of a regulatory gap to define this type of products as a medicinal drug or medical device.
The main results generated are:
- Technology transfer of nanoparticles synthesis from lab-scale to GMP-grade industrial scale.
- SOP for radiolabelling the lab-scale nanoparticles as well as PET assays have been done.
- Upscaling nTRACK GNPs, SOPs for manufacturing conditions, in process control and implementation of the QMS for complying with GMP requirements.
- SOP for staining PLX-PAD cells with nTRACK-NPs.
- Preliminary toxicity studies with GNP-GMP grade by intravenous and intramuscular route, showed no toxicity or minor toxicity effect in vitro & in vivo
- Novel surgically induced skeletal muscle injury model in sheep.
- Primary purpose of the nTRACK nanoparticles defined “the tracking of cell therapy with labelled stem cells to be used during development (non-clinical and clinical) of new cell therapies”.
- Regulatory roadmap defined and conducting regulatory procedures with the relevant authorities
- Open Day Workshop in Cambridge, (2019), 23 participants: companies & institutions.
- nTRACK consortium has promoted a cooperation push with iNanoBIT and StarStem H2020 funded projects on 3 main areas: Regulatory framework, Tox. characterization, and Joint communication/dissemination.
The progress beyond the state-of-the-art set at the beginning is being reached:
- Precisely tune and control the chemical and physical properties of contrast nanomaterials to enhance strength the sensitivity.
- Exhaustive list of characterization assays has been established: biological, physico-chemical and imaging.
- Correlation of intracellular fate, intracellular trafficking and, nTRACK NP effectiveness as contrast agents.
- A system to assess cellular dynamics, cellular kinetics (homing, migration) and efficacy.
- Advanced predictive model for early assessment of cell therapy effectiveness, based on easy-to collect data. Prediction lesion models have been developed and computational models to predict transplanted cells behaviour.
- Novel surgically induced skeletal muscle injury model in sheep which closely imitates human muscle lesions.
- Progress in medical regulatory guidance for the development of nanotechnology-based imaging. nTRACK is strongly contributing to this progress by close contact with the regulatory authorities and non-governmental associations.
The nTRACK progress will be the ground to tackle the socio-economic challenges faced by EU such as the progress of the regenerative medicine and such progress will impact on the healthcare systems improving patient outcome as well as reduction of drug expenditure; to expand nanomedicine market, the adaptability of nTRACK technology has the potential to exploit diverse market opportunities. nTRACK will also impact on the regenerative medicine and associated industry growth. nTRACK technology encloses the adaptation of this technology to other clinical indications requiring cell-based therapies and customized functionalized NPs to be used as novel contrast or theragnostic agents.
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