Potential drug to annul ADAM-17 protein activity needed

Over the past four years, in the installations of the Faculty of Medicine, University of Cadiz, a group of researchers, headed by Doctor Carmen Estrada, has been studying neurogenesis - the process of forming new neurons from mother cells - in the adult mammal brain. The purpose of this research project is to contribute to the knowledge of this process with the object of finding some additional mechanism that would facilitate the treatment of pathologies of the central nervous system (CNS) that are suffered in consequence of neuronal death. In other words, this work concerns diseases of huge personal and socioeconomic implication, such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ELA), and the consequences of cerebrovascular accidents and neuronal loss from severe cranial shock.

The investigations carried out in the area of Physiology of the Faculty of Medicine have made sufficient advances that the UCA has now applied for a patent on the use of specific agents, inhibitors of the action of the protein ADAM-17, for the preparation of a drug to increase the neuronal regeneration of the central nervous system.

To appreciate the importance of this patent, it should be understood that in the brain there are two types of cells: neurons and glial cells. Contrary to popular belief, the glial cells constitute the majority cellular type within the central nervous system. However it is the activity of the neurons that underlies the mental functions, some of which give rise to our consciousness in the form of sensations, emotions, memories, thoughts and decisions. The glia constitute tissue whose principal functions are those of support, and essentially they enable the neurons to perform their activity with exceptional efficacy.

"When a lesion is suffered and both types of cell are lost, the neural mother cells that reside in the adult brain are activated. These mother cells multiply by dividing and take on the role of new glial cells but not of new neurons. We have demonstrated that this limitation is due to the activity of a protein with enzymatic activity (i.e. an enzyme) known as ADAM-17. When we block the activity of this enzyme in neural mother cells in vitro, more neurons and fewer glial cells are generated (which is contrary to the normal effect of the enzyme). Furthermore, we have also confirmed that, in the brain zone where damage has taken place, there is an increased presence of the protein ADAM-17, which in the normal undamaged brain is either not present at all or, if so, only in very small amounts. Specifically, ADAM-17 is produced in the mother cells that are dividing and multiplying around the lesion, and is the factor responsible for the formation of new glial cells but not neurons. For this reason we think that the inhibition of ADAM-17 will facilitate the emergence of new neurons and thus facilitate the recovery of the lesion", explains Doctor Carmen Estrada, of the Faculty of Medicine.

To enable this process to take place "one of the alternatives that could contribute to resolving, or at least to alleviating, the clinical problems presented by diseases and injuries that involve neuronal loss, is the transplanting of mother cells that could help to form new neurons once exposed to the micro-environment of the appropriate nervous tissue". However, to do this, we have to modify the non-neurogenic niche of the lesioned zone and convert it into a neurogenic niche in which both the endogenous and the transplanted mother cells can become mature and functioning neurons". In other words, "a cellular therapy would have to be applied to the tissue through the implanting of mother cells in the lesioned zone simultaneously with treatment to inhibit ADAM-17 which would encourage these transplanted cells to transform themselves into neurons", adds Doctor Carmen Castro, one of the researchers who has worked on the development of this patent.

"The ideal is to be able to find a potential drug that would serve to annul the activity of ADAM-17 but that would not have secondary effects in humans; this is an objective that several pharmaceutical laboratories are currently working towards".

From in vitro to in vivo research.

To date, the experiments carried out have been done in vitro, since "we are faced with the problem that we have not yet obtained a drug that inhibits ADAM-17, and so the work has been done with an interference RNA", states Carmen Estrada. However, "to take the research forward to the in vivo stage, interference RNA cannot be used because the techniques for its application in experimentation animals are not yet very well-developed". This is something that, in recent weeks, has been resolved by these researchers, and the team is already working on a new way to carry out the in vivo work. These advances suggest that at least four more years of research are needed.

A team of six persons has worked on this complex and important project. Having explained what has been achieved to date, the researchers want to clarify that the next objective of the group is to demonstrate that the inhibition of ADAM-17 in vivo really does facilitate the generation of new neurons and so helps the brain to recover from a lesion. Thus, if a specific inhibitor of ADAM-17 that does not have adverse secondary effects in humans could be found, a drug could be developed that would inhibit the process of glial differentiation and enhance neuronal differentiation, during the process of cell regeneration either from the individual's own (endogenous) neural mother cells, or from transplanted cells, or from both, in cases of lesions of the central nervous system.

If all this works, in the not-too-distant future, there should be a clinical application in humans affected by a lesion of the central nervous system (of the brain or the spinal cord). In addition, the possibility would be opened for the employment of transplants of neural mother cells. A new proposal for facilitating neuronal regeneration.