Growth factors in the limelight once again after the discovery of a new gene.
Interview of Prof Pezzoli, Director of the ICP Parkinson Institute after the Press Conference on 10 April 2008

The hypothesis that growth factors are involved in Parkinson's disease is old, isn't it ? 

Yes, it is.  That hypothesis was set forth for the first time 20 years ago. 

Growth factors are polypeptides that regulate the reproduction and maturation of cells, as well as their survival in the body.  Dopaminergic nervous cells may degenerate in patients with Parkinson's disease because they are not supported adequately by growth factors. 

After several animal studies had yielded encouraging results, a clinical trial was started in which glial derived neurotrophic factor (GDNF) was infused directly into the brain of patients with Parkinson's disease via an indwelling catheter.  Important clinical improvements were documented (reduction in the severity of symptoms by about 40% after one year of treatment), but complications due to the indwelling catheter obliged the investigators to stop the study; the benefits achieved regressed 9 to 12 months after discontinuation of treatment.  

I have heard that you carried out research on the role of growth factors in Parkinson's disease yourself.  Tell me what you did.  

I produced supportive evidence in animal studies.  In the early 1990s I obtained encouraging data in rats in which experimentally induced lesions reproduced symptoms similar to those of Parkinson's disease.  The administration of epidermal growth factor produced a significant increase in the number of dopaminergic neurons and sustained improvement in motor function.  

Dr Goldwurm said that further evidence is required to confirm the discovery of the new gene.  In the capacity of experienced neurologist, do the data convince you or not?

The data convince me because they are consistent with the results of other studies.  

In the last decade many studies have shown that the IGF1 growth factor plays an important role in the development of the nervous system.  It has been shown that it promotes both the proliferation and the differentiation of nervous cells and that it plays an important role also in their survival, preventing death by apoptosis (a cell process that regulates survival as it triggers their death at a pre-set time).    At the molecular level growth factors are the equivalent of docks in a harbour.  If there are no free docks ships cannot stop in the habour and unload their cargo, which is essential for cell survival.

Regarding insulin, it has been documented that it is involved in the maintenance of nervous cells, in neurogenesis, in neurotransmitter regulation and in cognitive function.  The results of a preliminary study, in which 25 patients with Alzheimer's disease were treated with intranasal insulin for 3 weeks, are encouraging. 

A few years ago geneticists wondered why neurons degenerate only in the substantia nigra and not in the areas in its proximity, namely the medial and ventral tegmentum.  In order to answer this question, they decided to measure the expression of many genes in the two groups of neurons.  They found that 42 genes were more expressed by neurons in the substantia nigra, out of which 5 were related to growth factors:

3 were related to the fibroblast growth factor,

1 was related to epidermal growth factor
and one was related to IGF1. 

They set forth the hypothesis that neurons in the substantia nigra may degenerate because they are more dependent on the levels of growth factors, such as IGF1, than the neurons nearby.  Therefore, in the presence of factors that reduce IGF1 levels, such as genetic mutations or aging, they degenerate before the others. 

The discovery of the involvement of a gene that encodes proteins responsible for IGF1 signalling regulation closes the loop and is a clear indication that the lack of IGF1 is a factor that contributes to the development of Parkinson's disease.
Other genes have already been discovered, which have lead to the discovery of other mechanisms that appear to be involved in the development of Parkinson's disease, such as the accumulation of misfolded alpha-synuclein.  Several years have elapsed and I believe that there are no ongoing clinical trials with investigational drugs based on this hypothesis.  According to you, how long will it take to start clinical investigations with the IGF1 growth factor? 

This time clinicians will take advantage of the new information rapidly and clinical trials should start soon.    Whilst the synthesis of new compounds, followed by years of investigations in animals designed to verify their safety before administration to man, is needed to exploit the other hypotheses, in this case IGF1 is already available for administration to man.  At present a clinical trial with IGF1 has just been completed in another neurodegenerative disease, Amiotrophic Lateral Sclerosis (ALS)  in the US.  Its outcome is not known yet, but I am optimistic.