Longevity is bigger on the inside: CNS regeneration

We have seen nanotechnology being used to prevent, diagnose and treat various disease. Now its regenerative power is being harnessed in the central nervous system. We take a look at some of the therapies being developed.

The central nervous system (or CNS) consists of the brain, spinal cord and neurons; as well as receiving, processing, relaying and storing information, it controls most of the body’s functions and directs most of its actions.

CNS cells atrophy with age, causing plaques and tangles to form in the brain and the build up of a fatty brown pigment called lipofuscin to occur in nerve tissue. If the nerves begin to break down, this can cause reduced and lost reflexes or sensation, which in turn brings problems with movement and safety. Brain plaques and tangles are also associated with severe memory loss and dementia.

In order to counter these effects of aging, regenerative therapy – bringing about neurogenesis – for the CNS has been a key area of research. The regenerative pathways have to be identified and harnessed, while the growth-inhibiting processes that are stimulated by biological response to injury need to be suppressed.

To achieve neurogenesis, researchers need to map the numerous cellular pathways and extracellular cues, as well as ascertain how to stimulate it without using highly-invasive procedures. These hurdles mean that clinical successes of regenerative medicine for CNS injuries and deterioration have been extremely limited, so existing interventions concentrate on stabilising the neurons and trying to prevent additional neuronal death.

The innovations in nanotechnology has meant there has been substantial progress in the field of neurogenesis, including some FDA-approved therapies.

The innovations in nanotechnology has meant there has been substantial progress in the field of neurogenesis, including some FDA-approved therapies [1]. Working on a nanoscale means enhanced drug delivery being able to stimulate biological repair at a cellular level. We dive into CNS regeneration, from nanoparticles to nanoscaffolds, to take a closer look…

Targeting neuronsNeurons and other cells secrete biological factors that regulate neuronal growth and differentiation. Polymeric nanoparticles that deliver a targeted payload of brain-derived neurotrophic factor have shown encouraging results including reversal of cognitive deficits and the targeted delivery means the hurdle of crossing the Blood Brain Barrier (BBB) is avoided [2].

Multi-walled carbon nanotubes have been used to deliver caspase-3 targeting siRNAs which work by “silencing” the genes cause cell death (apoptosis) after injury [3].

Targeting glial cells
Glial cells surround the neurons, providing support and insulation for them. Exosomes (membrane bound extracellular vesicles produced by cells) loaded with BACE1 siRNA were able to knockdown a gene and cause a decreased expression of BACE1, the beta-secretase enzyme implicated in Alzheimer’s disease. This worked both in vitro and in vivo. Targeting was improved by adding superparamagnetic iron oxide nanoparticles (SPIONs), although toxicity concerns mean additional research in this area is needed.

PLGA nanoparticles carrying leukaemia inhibitory factor (LIF) have been used to increase myelin (the substance that coats and protects neurons), producing thicker mylination and and increased number of myelinated axons in vivo [4].

Neuroimmune modulation
Hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have demonstrated the ability to target activated microglia and macrophages, decreasing pro-inflammatory cytokines and enabling brain regeneration [5].

PEG-PLA lipid emulsions have been loaded with siRNA targeting complement protein 3 (C3) and were shown to confer neuroprotection from ischaemia-related toxicity. In experiments, the nanoparticles achieved ten-fold greater levels of siRNA in the brain compared with straightforward intravenous injection [6].

Neuroregeneration by extracellular modulation
Nanoscaffolds made from nanofibres of peptides have been shown to mimic the extracellular matrix, providing mechanical support and regulating cellular growth and repair. Although they find it harder to cross the BBB, nanoscaffolds are not rejected by the body’s immune system and degrade harmlessly once the job is done.

Polymer scaffolds have also been enhanced with growth factors that have a sustained release. These have been shown to significantly decrease the number of amyloid-beta plaques in the brain [7].

Hydrogels promote neuroregeneration by providing a substrate that promotes the growth of implanted cells. This is key in stroke recovery and experiments show they are twice as effective as just implanting the cells alone [8].

Carbon nanomaterials are electrically active and this can make for an ideal cell growth environment. Constructed with 3D printers, or electronspun into nanofibres, this nanotechnology improved cell proliferation through electrical stimulation.

Multifunctional nanosystems
Neural regeneration is incredibly complicated, so combining nano-approaches means that multiple pathologies can be targeted. PLGA nanoparticles that encapsulated NT-3 were embedded in hyaluronic acide methyl cellulose hydrogels that were carrying anti-NogoA antibodies. This resulted in a dual delivery platform that had a sustained release.

A hydrogel containing anti-NgR antibodies built into the nanofibres of a scaffold and microspsheres loaded with growth stimulating-molecules showed a good ability to cross the BBB, an ability to decrease glial scar formation and greater protein levels in spinal cord tissue [9].

Gold-dusted nanoparticles result in longer out-growth of neurites and when modified with peptides, promote cellular internalisation [10].

These preclinical trials have shown promising results; tissue regeneration has been stimulated and some of the challenges of working with the CNS have been overcome. The ability of nanotechnology to provide precise, targeted and delayed delivery means that multi-functional strategies can be devised – this is crucial in overcoming the complex structure and function of the CNS.

We are excited by the benefits of noninvasive approaches coupled with harmless post-therapy degradation and hopeful that nanoneuroregeneration will be a therapy available for Longevity in the not-too-distant future.

[1] https://www.pnas.org/content/112/47/14452
[2] https://www.tandfonline.com/doi/full/10.1080/10717544.2016.1199609
[3] https://www.pnas.org/content/108/27/10952
[4] https://www.sciencedirect.com/science/article/pii/S0142961215003221
[5] https://bit.ly/2IxD9bT
[6] https://www.sciencedirect.com/science/article/pii/S014296121830053X
[7] https://pubs.acs.org/doi/10.1021/acsami.8b12649
[8] https://journals.sagepub.com/doi/10.1177/1545968310361958
[9] https://link.springer.com/article/10.1007%2Fs00441-015-2298-1
[10] https://bit.ly/2PYpsqF

Image credit: Raman OzaPixabay