PD treatment poses one of the great medical challenges – and existing solutions are unsatisfactory. Cell replacement strategies - transplanting fresh cells into the brain - have shown promising results, but ethical concerns over their foetal origin restrict their use. Alternative approaches such as the reprogramming of patient cells in vitro can generate autologous neurons. In both cases, the next challenge is to control their in vivo behaviour following transplantation.
Magnetic nanoparticle to guide axon growth in neurons
The EU-funded MAGNEURON project proposes to restore connections between neurons in the brain by a method that promotes and directs the outgrowth of neuronal axons. “Our concept relies on the use of magnetic nanoparticles functionalised with signalling proteins that are internalised inside cells and direct the growth of axons,” explains project coordinator Mathieu Coppey. Since the nanoparticles are magnetic, it is possible to localise them using magnetic devices, thereby triggering spatially directed cellular responses. The idea is to use these magnetic nanoparticles initially to reprogramme patient somatic cells into neurons, and then after transplantation, to guide axon growth in the right direction. In the first instance, referred to as the ‘temp’ mode, nanoparticles are attached onto surface mechanoresponsive receptors. An external magnet is then used to provide mechanical stimulation and promote differentiation toward neuronal fate. The ‘space’ mode refers to manipulation of cell growth once magnetic nanoparticles have been internalised (‘magnetogenetic’ approach) or have been passively internalised by endocytosis. They accumulate on one side of the cell, and through surface proteins or directly through force, they induce a signalling cue that directs the growth of the cells. The approach was tested in vitro in cell lines and primary neurons, with promising results.
Restoring brain connections
Undoubtedly, there is a need today for methods that can manipulate cell function. Optogenetics and microenvironment modulation are two promising approaches that have been proposed to treat neurodegenerative disorders. Although still in its infancy, the MAGNEURON concept has opened a new window for magnets in therapy – especially since magnetic fields are functional over long distances and do not interfere with biological material. Neurodegenerative disorders are characterised not only by neuronal death but also by loss of the brain circuitry. “If we find a way to spatially direct the growth of an axon while keeping the neuronal cell body in place, then we could restore the electrical connection between neurons in the brain. It is like when you want to repair an electrical component in a board that dysfunctions: if you replace the component without restoring its connections, it would be useless,” stresses Coppey. Partners are keen to pursue the magnetic nanoparticle approach to the therapeutic level. The MAGNEURON approach cannot activate cells that are several centimetres away: thus, owing to its size, the brain presents a challenge. Partners will explore the potential of magnetic nanoparticles to restore neuron connectivity after spinal cord injury where the distances are smaller, and the innovation can make a breakthrough. “The project was initiated by Maxime Dahan, an amazing scientist, extremely creative and with remarkable leadership, who sadly passed away in 2018,” closes Coppey, devoting the project to his memory.
MAGNEURON, magnetic nanoparticles, axon, PD, neurodegenerative disorders, Parkinson’s, cell therapies