Advances in metachromatic leukodystrophy described by Pr. Volkmar Gieselmann

Written on Wednesday 17 April 2013

Pr Gieselmann, member of the Scientific Committee of the ELA Foundation and director of the Institute for Biochemistry and Molecular Biology at the University of Bonn (Germany) is an expert specialized on lysosomal storage disorders and in particular metachromatic leukodystrophy (MLD). In this interview, he looks back at the important discoveries his laboratory reported for MLD this past 20 years.



When started your interest on MLD?

My interest in MLD started when I joined the Kurt von Figura group in Göttingen. They had started to work on MLD and he offered me to take over the project. Since I am an MD the project appealed to me since it had a medical background.


Cloning the ARSA gene by your lab was also a very important step for MLD research. Can you explain us why?

Cloning the gene is a prerequisite for understanding the genetic basis of a disease. Without knowledge of the structure of the gene it is not possible to identify mutations. The mutations allowed to define a genotype / phenotype correlations for MLD. It became clear why some patients develop the disease already in early childhood and others as adults. More importantly cloning of gene is absolutely necessary for all gene therapy trials which are going on at the moment. The revelation of the gene sequence also allowed to generate several mouse models of MLD.


Why is it so important to develop animal models of the disease?

This was particularly important because the disease has only been described in humans whereas many other disease also occur in dogs, cats, sheep and other animals. The lack of a naturally occurring animal model of MLD has been a disadvantage in research. That changed with the MLD mouse. It resulted in improvement of the pathophysiology of mice and thus provided a basis for clinical trials. Moreover, this mouse is important for therapy development because you need to demonstrate efficacy of therapy in the mouse before you can turn to clinical trials in humans. The regulatory authorities require animal testing before they allow clinical trials. A number of research groups including biotech companies  worldwide use our mouse model and try various therapeutic approaches such as stem cell, gene, enzyme replacement and substrate reduction therapy.


You tested and are still testing different therapeutic approaches in animal models for MLD. Can you briefly present them and their potential application in humans?

When trying enzyme replacement via intravenous injection in the MLD mouse model we had positive results which surprised us a lot. Enzyme which is injected into the blood usually does not reach the brain because the brain is separated from the rest of the organism by the blood brain barrier which is very tight.

Based on these results a clinical trial was launched which unfortunately did not result in therapeutic benefit for the patient. This first of all demonstrates that although animal models are very helpful not all results obtained in animal experiments can be automatically transferred to humans. In addition, the dose of enzyme which was used in humans was much lower than the dose used in the mice, which in my opinion is probably one of the reasons for the different outcome of  human and mouse trials. Another way to overcome the blood brain barrier is the direct injection of the enzyme into the cerebrospinal fluid of the central nervous system. We have tried these again in mice and got positive results. Sulfatide storage was clearly reduced in the treated mice. Such results may provide a basis for clinical trials in foreseeable future [clinical trial IDEAMLD].

We are also trying substrate reduction therapy at the moment which means that we will try to inhibit the synthesis of sulfatide. This project is not yet at a stage that it can be tested in mice. In the best of all scenarios such a therapy would enable treatment with drugs rather than very invasive therapies such gene therapy or enzyme infusion into the cerebrospinal fluid. 


How did all these discoveries impact the lives and care of the patients?

If you asked for the direct profit for patients which so far came out of our work and work done by other groups using e.g. our mouse models the benefits so far may see limited.

The improvement of the diagnostic procedures by genetic testing has helped to establish clear diagnoses of MLD in particular prenatally. This certainly applies only to a fraction of MLD affected families but for them resulted in a clear benefit.

As far as therapy is concerned I completely understand that it appears rather frustrating for families. Developing a therapy, however, is much more complicated than developing a genetic test. Compare it to diabetes mellitus, a frequent disease. It was in 1889 when it became clear (by animal experiments) that it was a disease of the pancreatic gland. From there it took more 33 years to treat the first patient experimentally by insulin injection. The defect in MLD was identified in the late 1960’s, the gene cloned in 1988, mouse models generated in 1996 and improved in 2007 and now we do see the first clinical trials in patients. I know that these time periods seem endless for parents. From a merely scientific point of view we are actually moving forward rather quickly.


How do you see the field of MLD research advancing in the future?

I predict that we will see more clinical trials in near future and I am optimistic that within this decade we will find possibilities which may not cure MLD but improve the life of patients considerably.