Moving forwards? Where is Spielmeyer-Vogt research going?
Dr Jonathan Cooper, Institute of Psychiatry, King’s College London, July 2008
Progress in understanding juvenile Batten disease or Spielmeyer-Vogt (SV) disease often seems painfully slow, especially compared to progress in the other major forms of Batten disease. However, at the NCL2007 Congress last summer we heard that scientists are now taking steps that are moving us closer towards devising therapies for SV. These studies largely come from a mouse model of SV in which mutations have been introduced into the Cln3 gene so that these mice will develop the disease. These mice have been very useful in allowing us to get a better understanding of what is happening in the SV brain. It is the discovery of two key events in the brain of these mice that have lead to these new advances.
The first of these important events is the autoimmune response in which the immune system mistakenly makes autoantibodies that can potentially attack the SV brain and cause damage. David Pearce at the University of Rochester, who first discovered this autoimmune response, has now been asking whether blocking these autoantibodies would be helpful in SV. This was first done genetically by making a mouse with SV that couldn’t make the autoantibodies and asking what happens to the expected course of their SV disease. Last summer we heard that these ‘double knockout’ mice do better in a simple ‘rotarod’ test of balance and motor performance. Since then we have been analysing the brains of these mice here in London and it appears that the inflammatory response in their brains is also partially improved, even if it is not completely reversed. These results were promising enough to ask whether an immunosuppressant drug would have similar effects in mice with SV?
These immunosuppression studies have been going on during the last year using the drug mycophenylate, which is given to children who are having organ transplants. It is now clear that mycophenylate has more marked effects on rotarod performance in SV mice and we have been busy in London asking what effects this drug has upon the disease process in the brain. Our latest results suggest that the immune response is also partly suppressed in these treated SV mice. We are now asking the critical question of whether we have also been able to rescue brain cells that would normally die during the disease? We should know this answer very soon and will then be better placed to judge if this drug really gives any benefit to SV mice. We will also need to ask whether mycophenylate can do the same thing in older and sicker SV mice and how long lasting these effects might be. Indeed, it is possible that other ways of blocking immune responses will prove more effective and we must remember that immunosuppressive drugs may also have unwanted side effects especially in a child who is already ill. Nevertheless, the results so far suggest that we are moving in the right direction.
The second promising step towards new therapies for SV also comes from the University of Rochester. Some time ago it was suggested that the balance between excitation and inhibition in the brain is altered in SV, with too much of the excitatory neurotransmitter glutamate present in the brains of SV mice. Glutamate is normally used by most brain cells to communicate with each other, but in excess it can overexcite these cells leading to their death. David Pearce’s lab showed that blocking the binding of glutamate to one specific class of its receptors can protect SV brain cells grown in a culture dish. The next step was to find out if this drug would do something similar in an SV mouse and early this year the results of this study were published showing an improvement rotarod performance in EGIS-8332 treated mice. This is an encouraging step forwards, but we still don’t yet know completely if this drug has actually protected brain cells or changed other aspects of the disease in these mice. However, these results open the door for testing other similar drugs that may have even better effects in mice, perhaps leading eventually to a clinical trial.
Meanwhile, a lively debate is taking place amongst SV scientists about the precise effects of different mutations in the CLN3 gene. We know that it is mistakes in the DNA that make up this gene which cause SV, with the vast majority of mutations being the deletion of a large piece of DNA within the CLN3 gene. It has always been assumed that this ‘1kb’ or ‘big’ deletion results in a CLN3 protein that has no remaining function. This idea has recently been challenged by data from Sara Mole’s lab at University College London, which suggests that the mutated CLN3 protein maybe has some remaining function after all. This issue remains controversial and is not helped by the fact that we don’t actually know what the CLN3 protein normally does, never mind how it is changed by its mutation in SV.
Answering this seemingly very simple question is likely to give us the best way to cure SV, but this has proved to be a very difficult task. Most of the methods normally used to produce an answer have not been successful with CLN3, largely because of the type of protein it is. Spanning the wall of compartments inside the cell CLN3 is very hydrophobic making it very hard to work with by normal methods. For this reason scientists are turning to making an SV model in fruit flies. These very simple creatures allow us to perform some very powerful genetic tricks to find what other proteins may normally interact with CLN3 inside the cell. These studies are progressing well and may finally tell us more about the mysterious roles played by CLN3 and also give us models for rapidly testing large numbers of drugs to find new therapeutic agents.