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Sunday, 25 March 2018

Spinal cord injury: hope on the horizon

Might stem cell grafting or 
neuromodulation enable spinal cord

A few years ago, I undertook a review of developments in spinal cord injury (SCI) repair that left a deep appreciation of how just how great (and complex) the technological challenge of restoring even partial function following SCI actually is. 

The spinal cord, like the brain, is normally biologically isolated from the rest of the body: injury breaches this barrier, triggering an inflammatory response and death of cells essential for repair and maintenance (oligodendrocytes). In the days and weeks following SCI, glial cell proliferation results in scarring which, while reducing inflammation and improving the integrity of the injury site, creates an environment hostile to repair.

Much hope has been placed in stem cell transplantation, and while early clinical studies in handful of SCI patients have shown hints of improvement in motor function, unknowns remain around the choice of stem cell with respect to efficacy and safety (tumour formation is a potential risk), dosing, and how to best create a favourable environment to encourage transplanted cell growth, either mechanically with 3D biocompatible “scaffolds” and/or pharmacological modulation. 

Intuitively, stem cells derived from the central nervous system tissue might be among the right tools for the job. University of California researchers have demonstrated that stem cells (neural progenitor cells-NPCs) prepared from human embryonic spinal cord are capable of surviving and maturing when transplanted in monkeys with SCI, with evidence of differentiation into key cell types (neuronal and glial cells), conductive nerve fibre (axon) elongation and bridging of the injury site, and synapse formation. Moreover, partial restoration of forelimb function was noted several months after months after transplantation.

The UC study is of note due to the large numbers of new axons observed extending out of the injury site and into the adjacent spinal cord, suggesting the feasibility of recreating circuitry essential for function. Regeneration of corticospinal axons, responsible for voluntary movement was also observed. Translation into the clinical setting will be slow, but the UC success should encourage further investigation and development of NPC transplantation. 

Complete severance of the spinal cord is rare, and a majority of SCI patients have potentially functioning nerve fibres spanning the site of injury, leaving the prospect, albeit of low probability, of some degree of sensory and motor function recovery. A growing number of clinical studies suggest than epidural electrical stimulation (“neuromodulation”) in combination with intensive physical rehabilitation might increase the odds for a least some SCI patients.

A group of Swiss researchers have investigated the mechanisms involved in SCI recovery in an animal model to better understand the how (re)-connectivity might be encouraged, with the finding that a combination of neuromodulation and intensive rehabilitation promotes the functional connection of the motor cortex to nerves below the injury site via the brainstem. 

Combining neuromodulation, drug treatment and mechanical means of encouraging locomotion may be a route to restoring some degree of function in SCI and a first-in-man study (“STIMO”: Epidural Electrical Simulation (EES) With Robot-assisted Rehabilitation in Patients With Spinal Cord Injury) is underway, with results anticipated mid-2018. 

There is still a long and hard road to be travelled before SCI can be considered as a generally treatable condition, but it’s encouraging to see translational research across different disciplines offering the prospect of new treatment options and perhaps becoming attractive to commercial healthcare players with needed expertise in cell-based therapy and spinal stimulation technology development. 

Saturday, 3 March 2018

Another “bugs and cancer” post. Can bacteria reduce the risk of skin cancer?

Melanoma lesion. Do bacteria contribute to 
our skin cancer defences?
Research into (and clinical and commercial exploitation of) our bacterial travelling companions has so far largely focused on the relationship between gut dwellers and health. As the largest organ of the body (at between 6% and 10% of total body weight), and with the function of keeping the inside safe from the outside, it’s perhaps not surprising that human skin has evolved a rich and complex microbiome which can influence the course of disease.

In common with Planet Earth as described in the “Hitchhiker’s Guide to the Galaxy”, skin bacteria are “mostly harmless”, although physiological changes can make us susceptible to blemishes and rashes caused largely by Staphylococcus aureus and, that bane of teenagers, Propionibacterium acnesSkin bacteria in the wrong place (the blood stream, newly-replaced hip joints) are always bad news.

But, by and large, the skin microbiome functions well to keep potential pathogens in check through a variety of mechanisms, including production of selective antibacterial agents and the downregulation of inflammation. One of the most studied of these “good guy “bacteria is Staphylococcus epidermis. Collaboration between researchers at the University of California, San Diego, and other institutes has uncovered a possible association between certain strains of S.epidermis and suppression of the skin cancer, melanoma.

While attempting to better characterise the selective antibacterial activity of S.epidermis, the UCSD group identified a strain producing 6-N-hydroxyaminopurine (6-HAP), a suppressor of DNA synthesis. S.epidermis 6-HAP was established to be non-toxic, with no evidence of the mutagenic effects associated with chemically-synthesised 6-HAP. When tested in the laboratory, 6-HAP was active against squamous cell carcinoma and melanoma cell lines, and to a lesser extent, lymphoma cells. 

Systemic treatment of mice in which human melanoma tumours had been established with 6-HAP resulted in a 60% reduction in tumour size, while colonization of the skin of mice with the 6-HAP-producing S.epidermis strain significantly reduced the occurrence of UV light-induced skin cancer over mice identically treated with a non-6-HAP-producing strain.

Early days, but this does raise the possibility that in addition to their established “anti-pathogen” role, S.epidermis and possibly other commensal skin bacteria might actively contribute to tumour suppression through early elimination of transformed cells. The 6-HPA-producing  strain appears to be common “in the wild” and epidemiological studies might perhaps someday establish an association between 6-HPA producers (or their absence) and melanoma prevalence. 

The UCSD researchers are hopeful of exploiting their findings through a start-up company, MatriSys Bioscience, with the notion of restoring or modifying the skin microbiome. Effecting colonization with a 6-HAP-producing S.epidermis strain could conceivably reduce susceptibility to melanoma and other skin cancers, but given the multifactorial nature of cancer, it’s not something that will be easy to establish in the context of clinical studies. Nevertheless, the UCSD study does underscore that outer microbiome research has an importance beyond better treatments for eczema and acne.

Photo credit: NCI