The remainder of the morning covered some of the preclinical research that has laid the foundations for current and forthcoming clinicalstudies. Prof Clive Svendsen, from University Wisconsin-Madison, gave an overview of the strategy that helped lay the foundations for the current Neuralstem trial. This strategy involves the implantation of support cells (astrocytes) into the spinal cord. These astrocytes produce important nourishing (neurotrophic) factors that are essential to maintain the health of neurones. The strategy therefore is not about rewiring the nervous system, but instead providing the surviving motor neurones with a ‘boost’ to aid their survival.
He stressed the need for long and detailed study of the astrocyte cell lines if they are to be seriously considered as candidates for transplantation studies, using the comment “rubbish in, rubbish out”. He also provided very useful cautionary information in that some of the human cell lines show a tendency towards developing genetic changes over time, reminiscent of some types of tumours. By careful characterisation of the cell lines, his team was able to select only cells that demonstrated they were extremely stable. He has grafted these cells into the spinal cords of SOD1 rats, which does indeed help to protect the motor neurones.
However, it does not markedly alter the survival of the animals, probably due to the fact that the implanted cells can take months to mature into functional astrocytes, plus the fact that the motor neurones were still drawing back from the muscles and losing their connection. He is therefore looking at a ‘two-pronged attack’, treating both ends of the motor neurone through astrocyte implantation into the spinal cord, combined with nerve growth factor injections into the muscle.
Why stem cells derived astrocytes?
Astrocytes vastly outnumber neurones in the brain and spine: they are the cells that make up most of the ‘cellular neighbourhood’ and it is believed that in diseases such as MND, that neighbourhood is toxic to motor neurones. Prof Don Cleveland from University of California San Diego believes that if healthier, correctly functioning, astrocytes can be implanted into the spinal cord, it could turn the cellular neighbourhood into one that will protect the motor neurones and alter disease progression. The question is whether we can engraft enough cells to radically change the neighbourhood for good?
In colaboration with Prof Larry Goldstein, also from University California San Diego, his studies in SOD1 rats showed that injection of embryonic stem cell-derived human astrocytes can ‘clear the hurdles’ that need to be overcome in order to get astrocyte implantation studies into the clinic. Studies will move to a larger animal model and further work on producing, purifying and screening the cells needs to be done, in order to satisfy strict regulatory conditions.
He stressed the importance of setting milestones and getting the administration in place to deal with these hurdles. If all goes well in achieving these milestones, the plan is to be able to perform the first clinical studies in the next four years.