February 9, 2012

expert reaction to research on the potential use of genetically modified monkeys for modelling human brain diseases, as published in Scientific Reports

Scientific Reports published a proposition that genetically modified monkeys might be used to conduct research into human brain diseases.

Dr. Laurence Tiley, Senior Lecturer in Molecular Virology at the University of Cambridge, said:

“This report highlights the impressive efficiency of the AAV9 system for delivering transgenes to neuronal cells in the brain of rhesus macaques. However, as the authors point out, ‘it would provide a promising research tool for delivering genes in nonhuman primates only if we could reach all structures with comparable efficiency’.

“This is a tall order for most viral transduction systems as it is a major challenge to control transgene copy numbers in the more accessible cells, while simultaneously reaching the less accessible ones. The biology of AAV could be exploited to get around this, but the present report does not provide enough technical detail to establish whether the authors have done so.

“This looks like a promising approach, but I think they still have some significant hurdles to overcome.”

Dr. Robin Lovell-Badge, Head of Developmental Genetics, MRC National Institute for Medical Research, said:

“It is important to find ways to deliver genes to the brain of animals, to provide basic understanding of how the brain develops and functions, to study what goes wrong in disease, and to develop treatments for disease of trauma. The types of genes that might be introduced include those encoding simple markers, such as green fluorescent protein (GFP), which allows cells to be followed over time, those that may change cell behaviour, encourage cell division and repair, or counteract disease.

“Transgenic methods have been developed that allow genes to be introduced into the very early embryo, such that they are in all cells of the resulting animal. But the research in this paper (by Dehay and colleagues) uses techniques more familiar to the field of gene therapy. They made use of a virus as a vector to deliver a foreign gene to the brains of newborn monkeys (Macaques). This follows on from earlier work in mice and a little in monkeys, which suggested this particular virus could simply be introduced into the bloodstream and it would find its own way to the brain. In this case, the foreign gene just encoded GFP, and is being used as an easy way to monitor success. The authors found GFP was expressed (active) specifically in nerve cells rather than their supporting (glial) cells. A few cells were also found to express GFP in other parts of the body, but it was neurons that were most often infected. This suggests some “tropism” for the virus – meaning that neurons must have on their cell surface a molecule (receptor) to which the virus like to attach.

“This is a beginning. It is not a way to manipulate the adult brain; indeed, the method only works in newborn animals because the brain changes soon after birth, with far fewer new nerve cells being made and the establishment a more strict barrier between the blood and the brain. Moreover, the frequency of incorporation of the virus into nerve cells as judged by GFP expression was very low (less than 0.25%). This is unlikely to be sufficient for gene therapy and to test treatments for disease or trauma, but it will allow some important questions of basic biology to be addressed, and it might allow the establishment of better models of human conditions. And this is why the experiments were carried out with Macaque monkeys.

“The brains of mice and most common experimental lab animals are less complex and in places substantially different from those of monkeys and humans. Therefore monkeys will sometimes be the most appropriate animal in which to explore how human syndromes develop, such as congenital brain defects, and to look for treatments. The choice of which animals to use in research is one taken with care, and it is important to justify why monkeys are needed as opposed to alternatives, whether these are cell cultures or involve fish or frogs or mice. The current work was a proof-of-principle and although there is a way to go, they have shown that their methods are a reasonably efficient and, importantly, a minimally invasive way to introduce genes into nerve cells. This offers promise for future studies on the role of specific genes in brain function and disease when it is necessary to mimic the human situation.”

Systematic scAAV9 variant mediates brain transduction in newborn rhesus macaques’ by Dehay, B. et al., published in Scientific Reports on Thursday 9th February.