Hamburg June 3-6th 2009
I was introduced to Batten Disease (also known as NCL) in 2008 during my honours year at the University of Otago. I have continued this work in 2009 as a research assistant and recently had the fantastic opportunity to travel to the NCL Congress held in Hamburg, Germany.
The Batten diseases (NCLs) are a group of neurodegenerative lysosomal storage diseases. Onset of these diseases is from early childhood and patients suffer from a wide range of debilitating symptoms, ultimately leading to premature death. This disease is devastating for a family. The NCL research community is a group of dedicated clinicians, scientists and students who work extremely hard towards understanding how these diseases work as well as devising and testing possible therapies. The vibe I felt during the conference was one of desperately wanting to make a difference for all those affected by this disease, and this was extremely motivating for a young scientist.
Below is a small selection of research highlights from the conference. The conference abstract book can be downloaded from http://www.ncl2009hamburg.de/ (link no longer active).
1. Understanding the disease
Research into how the different NCL proteins function in cells is ongoing. This includes looking at the candidate genes for the different forms of Batten disease and how those genes would normally interact; giving insight into what effect a particular non-functioning gene has in the disease. There is a hypothesis of a common cellular pathway which the different NCL genes are part of, and that disruption to different parts of the pathway (by the different NCL genes) causes the distinct forms of NCL. An example supporting this common pathway is that the mRNA expression level of other normal NCL genes have been reported to be altered due to the dysfunction of one NCL gene. Another example is CLN5 (which underlies the vLINCL form of Batten disease) has been shown to interact with two other NCL proteins; CLN2 and CLN3. This research supports the hypothesis that a common cellular pathway underlies the NCL diseases.
Also interesting was the observation that astrocytes (the support cells of the brain) are activated first in disease and that these astrocytes act as a predictor of neurodegeneration. The hypothesis is that astrocytes are trying to help the brain cope with the loss of cells. Earlier work in mice has shown that astrocytes have both positive and negative roles in Batten disease; a big question now is ‘what will be the therapeutic effect of targeting astrocytes?’
How autophagy (the removal of old and unneeded cellular components) is involved in different NCL forms was also discussed. This is important as there is abnormal build up of proteins in the neural cells of affected patients. This presents a potential therapeutic target if the normal process of autophagy can be enhanced to promote clearance of the additional storage material. However, little is currently known about the process of autophagy and so this is an important area of research.
Many potential types of therapies were discussed, these included;
Grafting Human Neural Stem Cells into the brain of human patients. There is an ongoing phase I clinical trial in LINCL patients which was designed to test whether this therapy is a possibility from a safety point of view. Results thus far are promising in terms of safety, however there are still many years of research before this will be considered as a treatment.
One feature of Batten disease is severe visual impairment or blindness due to retinal degeneration. Viral gene therapy to treat retinal disorders in humans so far supports further research into viral gene therapy in the eyes of children with a variety of inherited retinal disorders. The phase I/II clinical trial by Robin Ali used 3 young adults (not with Batten disease) and their results suggest that this approach is safe, and improves visual function. The best results were obtained using a type of virus known as AAV. They showed that gene therapy improves sight even in advanced cases of disease. They are moving on to phase II trials. There is also a well-characterised mouse model for NCL retinal disease which could be used to test therapies.
Ronald Crystal is looking at the administration of AAV containing a functional copy of the deficient lysosomal enzyme, directly into the central nervous system; CNS or brain, of children with the late infantile (CLN2) form of Batten disease. Their results so far have shown that there is stability of the CNS disease in the majority of the treated children. They are currently looking into toxicology studies involving AAV-10 (another type of AAV) as it reputedly has better efficacy of infection into the CNS. They also want to look into using this strategy to treat juvenile (CLN3) Battens which has an added barrier because the defective CLN3 protein is not secreted. The CLN2 enzyme is secreted and this means that if one cell is making functional enzyme, then it will be able to ‘share’ this enzyme with cells around it. The CLN2 approach will therefore need to target a much larger number of cells than the CLN3 approach.
I had the opportunity to present my research as a poster titled ‘Viral Gene Therapy for Ovine Batten Disease’ (poster 47 in the abstract book). This work involves utilizing naturally-occurring sheep models of Batten disease to investigate the potential of using viral gene therapy to treat two forms of Batten disease. Our results show the ability of the virus to infect a variety of cell types found in the brain in vitro (in cells) and in vivo (in live sheep).
Overall the conference was excellent for increasing my awareness of the (very) wide field of NCL research. I had the opportunity to meet many different scientists, some of whom were like ‘celebrities’ as I had read many of their papers during my Honours research.
The conference put on a really enjoyable social program, which involved two conference dinners and a boat trip around Hamburg, further increasing the chance to get to know everyone.
I spent a couple of days wandering around the beautiful city of Hamburg, and drinking in the stunning architecture (which is quite different to that of NZ). It was great to have the chance to do this.
I made the most of being on the other side of the world by spending a week in Jon Cooper’s Lab at Kings College London. I learned techniques his lab specialises in which will be useful for our work. His group are fantastic and made me feel right at home. We are starting a collaboration with his lab and getting to meet everyone and see what they do was an excellent opportunity as well as important for our future work.
The next NCL congress is to be held somewhere around London in 2011, and based on this experience, I am really looking forward to it!
I owe a very big Thank You to Jenny and John and the LDNZ for providing financial support for me to attend this conference. Thank you, it was fantastic!