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Projects. Life and Earth Sciences

Cellular therapy for West's syndrome

Lead Researcher:
Manuel Álvarez Dolado

Research Centre:
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER). CSIC. Sevilla

Synopsis: 

Manuel Álvarez Dolado West's syndrome (WS) is the most common infantile epileptic encephalopathy, although its frequency leads to its being included among the rare diseases (1:5,000). It is characterised by recurring crises called spasms, progressive psychomotor retardation and a typical EEG denominated hypsarrhythmia. It is due to mutations in the ARX gene, which codes for a homeobox transcription factor that is fundamental for the generation, migration and development of the GABAergic interneurons of the striated body, cerebral cortex and hippocampus. Animals which are mutant for ARX present a reduction in the number of interneurons in the said areas.

The majority of children with WS are refractory to pharmaceutical treatment, so they need a therapeutic alternative. This may be in the form of cell therapy, as the neurons that have disappeared can be replaced. Previous results of this group show that fetal neural progenitors derived from the middle ganglion eminence (MGE) differentiate into GABAergic interneurons after being implanted into the neonatal and adult brain. These progenitors are able to integrate fully within existing circuits, modulating inhibitory activity within the regions they are implanted in. This makes it possible to reduce hyperactivity levels, and they also have an anticonvulsive effect.

At the present time, a series of transplants has commenced with these neuronal precursors in an animal model which is a transporter of the (GCG)10+7 mutation, the most frequent among WS patients. This model has studied the distribution, survival, differentiation and functionality of the cells deriving from transplant, as well as effects on the symptoms characterising this syndrome. It will also evaluate the potential and clinical interest of this type of cell therapy.


Scientific production
3 articles published in Journals
1 paper at international conferences


Researcher's web address:
http://www.cabimer.es/web/es/dept/tcmr/terapia-celular-en-neuropatologias


Manuel Álvarez Dolado

A graduate in Biology from the Autonomous University, Madrid (1992), he wrote his doctoral thesis in the Biomedical Research Institute of the CSIC, under the direction of Dr. Alberto Muñoz Terol. The subject of his thesis was the search for and characterisation of genes regulated by the thyroid hormone involved in the development of the brain. He passed his doctorate in 1997 and remained in the same laboratory with a postdoctoral grant from the Madrid Regional Government until 2000. Subsequently he went to the laboratory of Dr. Arturo Álvarez-Buylla (Prince of Asturias Laureate) as a visiting postdoc thanks to a MEC-Fulbright grant, initially in the Rockefeller University of New York and then in his new post at the University of California in San Francisco (UCSF). There he studied how neural stem cells migrate in adults and embryos, as well as the plasticity mechanisms of stem cells derived from bone marrow. At the end of 2003, he returned to Spain with a FIS ISCIII research contract, to work in the General University Hospital, Valencia, where he took charge of the development and installation of the Cellular Therapy Unit. In 2006 he obtained a Ramón y Cajal contract with which he was offered the post of head of a laboratory in the Prince of Asturias Research Centre in Valencia. After this, in 2008, he obtained the post of Tenured Scientist of the CSIC for the Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER) in Seville. At these centres he has developed new lines of research into cellular therapy, in which stem cells from a range of origins are used for the treatment of pathologies affecting the nervous system, with special interest in those connected with epilepsy and ataxia. These projects have been financed since 2004 by the King Charles III Health Institute, the Ministry of Science and Innovation, and several non-profit private foundations. He is the author of 27 international works, has supervised 2 doctoral theses and for three years he has been an Associate Professor at the Pablo de Olavide University (UPO).


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