MAGNEURON Research Program

The Parkinson disease

Neurodegenerative disorders are expected to surpass cancer as the most common group of medical conditions by 2040. A prominent example of neurodegenerative disorders is Parkinson’s disease, a medical condition that already affects 6.5 million people worldwide, a number expected to more than double by 2030. Curative treatment of Parkinson disease and other neurodegenerative disorders is considered as one of the great challenges to medical science and alternative medical routes needs to be devised since current therapies are not yet satisfactory.

Among these, cell replacement therapy is considered the most promising approach. It consists of transplanting fresh cells into the brain to replace the degenerating neurons. The transplantation of neurons derived from developing embryos into Parkinson’s patients has already been tested in clinical trials. Despite promising results, practical and ethical concerns restrict the use of human foetal tissue. To overcome this limitation, researchers have developed a way to reprogram the patient’s own cells into stem cells that can be differentiated in neurons, thus providing a promising alternative source of neurons.

Yet, one of the great challenge for replacement therapy using fresh neurons is to control the behaviour of these newly implanted neurons. Indeed, the degenerative neurons that need to be replaced have their bodies in a particular region of the brain and extend their “arms” (long protrusions called axons) in another region of the brain, which is several centimetres away. In order to be functional, the implanted neurons need to rewire themselves in the brain in a specific manner.

Our idea

The MAGNEURON project aims at developing a novel technology for magnetic actuation of cellular functions to treat Parkinson’s disease. The innovative concept of our technology is to remote-control the behaviour of cells using bio-functionalized magnetic nanoparticles. Nanoparticles are very small objects, in the nanometre range, usually known to be harmful but they can be also used in a positive way. By attaching on the surface of them some specific biomolecules, it is possible to interact with the cellular molecules to instruct specific signals to cells. Using nanoparticles that are magnetic, it is possible to use magnetic devices to act on them at distance in order to trigger cellular responses.The MAGNEURON project aims at developing a novel technology for magnetic actuation of cellular functions to treat Parkinson’s disease. The innovative concept of our technology is to remote-control the behaviour of cells using bio-functionalized magnetic nanoparticles. Nanoparticles are very small objects, in the nanometre range, usually known to be harmful but they can be also used in a positive way. By attaching on the surface of them some specific biomolecules, it is possible to interact with the cellular molecules to instruct specific signals to cells. Using nanoparticles that are magnetic, it is possible to use magnetic devices to act on them at distance in order to trigger cellular responses.

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To tackle the challenge of remote-controlling neurons at distance, we propose the use of bio-functionalized magnetic nanoparticles engineered to function as intracellular “hotspots” that will tell to the cellular machinery what to do. Once delivered into the cytoplasm of neurons, these magnetic nanoparticles will activate specific biochemical reactions inside the cells in response to external magnetic fields such that the nanoparticles will promote and orient the growth of neuron’s arms.

 

How we propose to cure Parkinson’s disease?

research-p img3 With this novel technology, our long-term goal is to fundamentally advance cell therapies for Parkinson’s disease. The general routine we are proposing is to get somatic cells from the patient and to reprogram them into stem cells. Then we will use magnetic nanoparticles in two means, first to induce the differentiation into neurons and then to direct the growth of neuron’s arms in the right direction after the engineered cells will be implanted in the brain of the patient.


How can we control cells with magnetic nanoparticles?

The remote-control of cell behaviours with magnets is key to our project. We propose the use of two modalities of magnetic actuation, the “temp” mode and the “space mode”.

The “temp” mode rely on a temporal variation of a uniform magnetic field. Magnetic nanoparticles are attached to the outer surface of stem cells on specific molecular receptors that respond to mechanical stimuli. Cells are then stimulated with an external magnet which is repeatedly approached and removed. This mechanical stimulation promotes the differentiation toward neuronal fate.


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The “space” mode rely on the manipulation of magnetic nanoparticles inside cells. Like moving a piece of iron through a sheet of paper with a magnet hidden bellow, the magnetic nanoparticles are accumulated on one side of the cell. Thanks to specific proteins attached to their surface, the magnetic nanoparticles induce a signaling cue that orient the growth of cells.


SEE MOVIE SPACE MODE

 

Our MAGNEURON project is divided in 7 work packages that are summarized bellow:

WP2: Preparation of synthetic and recombinant MNPs

This workpackage is focused on the preparation of magnetic nanoparticles, either by synthesis of small aggregates of superparamagnetic iron oxide nanoparticles coated by a fluorescent silica shell, or by the use of recombinant ferritin cage.
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WP3: Biofunctionalization and intracellular delivery of MNPs

The objective of this workpackage is to develop surface coating and biofunctionalization of MNPs that enable efficient cytoplasmic delivery towards target cells, sustained magnetic control of MNP and signalling activity inside cells.
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WP4: Tools for MNP manipulation in single-cell assays

The objectives of this workpackage are as follows:
To develop the tools for the manipulation of functional MNPs inside living cells,
To implement high-throughput single-cell assays for magnetic manipulation of signalling,
To quantitatively measure the sensitivity of the cellular response to magnetically-induced signalling perturbations.
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WP5: Biomagnetic control of stem cell differentiation

The main objective is to design optimal binding sites for activation of key intra- and extracellular receptor targets on the Fz receptor to achieve remote-controlled differentiation of DA neurons from precursors.
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WP6: Directed fibre outgrowth of neuronal cells

This workpackage aims at establishing the magnetic control of morphological differentiation and oriented outgrowth in neurons derived from neural stem cells or from direct conversion of somatic cells.
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WP7: Magnetic manipulation of cellular signalling in organotypic brain slices and in vivo models of Parkinson’s disease

The main objective is the investigation of stem cells or FACS-sorted stem cell-derived precursor neurons, previously manipulated with MNPs, for neuronal differentiation and directed axonal outgrowth following transplantation to rodent organotypic slice cultures of nigrostriatal circuitry, and transplantation in vivo to a rodent model of PD. We will also investigate the ability of MNPs, to protect nigral dopamine neurons in a partial lesion model of PD.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 686841.