Summary by Mari Luz González Casas

Translation by Marion Clark

To hear the entire presentation in Spanish on mp3, go to the following link:

Encuentro Ataxias (Ataxia Encounter) 2008

Organized by the

Colectivo Ataxias en Movimiento

(Ataxias on the Move Coalition)

Madrid, Spain



Madrid, April 29, 2008


First scientific presentation

Dr. Manuel Álvarez Dolado, Principe Felipe Research Center, Valencia, Spain:

“Advances in research into regenerative mechanisms for cellular fusion in ataxias”

Dr. Manuel Álvarez Dolado

What we mean by cellular therapy is any treatment that uses living cells for a therapeutic effect.  From this point of view, a simple blood transfusion could be considered as cellular therapy.  But it’s the advances being made with stem cells that really open new perspectives.

            Stem cells can act through different mechanisms.  The principal mechanism is the differentiation of these stem cells into other cell types.  In this way they can replace other cells that are dying and can supply the function that is being lost.  But secondly, other mechanisms or forms of treatment are known which can be performed by these cells, for example, the secretion of a series of factors which can improve the patient’s health.

            Recently a third mechanism of action for stem cells was discovered: cellular fusion.  This consists of the fusion between bone marrow cells and the mature cells of different tissues.  This fusion causes a repair of the genic damage that was found in these cells.  It has been shown that after doing a bone marrow transplant, elements of fusion are produced.  One type of cells that fused was the Purkinje cells or Purkinje neurons.  When both nuclei of the two cells fuse, if one of the new nuclei carries all the correct copies of the gene, it can reverse whatever recessive mutations the original nucleus was carrying.  It has been shown that this mechanism is effective in treatment of a recessive mutation in the case of the liver; that is, through bone marrow transplants it is already possible to save mice carrying a lethal mutation which caused a degeneration of the liver.  After the bone marrow transplant, these animals showed a reversal of this mutation thanks to cellular therapy.

            Given that cellular fusion also occurred in the cerebellum with Purkinje neurons, it was thought that this cellular fusion mechanism could serve for any pathology in which these neurons were affected, including the ataxias.

            In order to test the effectiveness of this, the model chosen was mice with a recessive mutation which caused them to develop a clinical picture of ataxia due to the progressive deterioration of the Purkinje neurons.  This deterioration also affects other types of cells such as the mitral cells of the olfactory bulb.

            We hoped to prove two things by doing these bone marrow transplants: 

--in the first place, to evaluate whether the animals’ health improved;

--and in the second place, to ascertain what mechanisms led to this improvement.

            By means of the bone marrow transplants, we were able to prolong the average lifespan of these mice.  In addition, different behavioral assessments were performed on the mice:

--Rotarod test:  The rotarod is a cylinder that rotates a little at the time, but faster and faster as the mouse moves it.  The healthy control mouse was the last to fall off the cylinder.  The PCD mouse (PCD = Purkinje Cell Degeneration, so the mouse with affected Purkinje cells, thus ataxic) which had received a bone marrow transplant was not able to stay on the rotarod for as long as the healthy control, but this transplant-treated PCD mouse stayed on the rotarod for a longer time than the untreated PCD mouse, which had not received a transplant.

--Speed test:  by measuring the time that the mice take to cover the same distance, it was shown that the ataxic mouse which had received the transplant was faster than the one which had not been transplant-treated.

--Test of standing upright:  This test consists of measuring the time the animals could stand upright on their hind feet.  The PCD (ataxic) mice could scarcely get up on their hind feet since they lacked the strength and the coordination to do so.  However, those PCD mice which had received transplants had better results, although even those did not reach the level of the healthy control group.

--Histological tests:  These tests are done to analyze what occurs in the cerebrum of these mice.  Basically, the tests show whether the bone-marrow transplant is able to increase the number of healthy cells in the regions where the cells were damaged.  It was shown that in the olfactory bulb there has been an increase in the number of cells that survive.  Currently we are verifying whether this phenomenon also occurs in the cerebellum.  For the moment we have not yet been able to confirm this.  It has been observed that the cells which survive in the olfactory bulb are polyploid, which suggests that elements of cellular fusion exist, and therefore, this could be the mechanism which is acting so that these cells survive.  It has been verified that the bone marrow cells are arriving in the area of the olfactory bulb and cerebellum.  But still at the level of the cerebellum we have not been able to observe any recovery of Purkinje neurons.  This is surely due to technical problems in the laboratory.  We will need to repeat the experiments.  Until now, the bone marrow transplants were conducted on mice 20-30 days old, and this is perhaps too late for the recovery of the affected Purkinje neurons.  With this in mind, we will be repeating the experiments, doing the transplants on newborn mice, one day old.

            Apart from nuclear fusion, it is possible that there are other mechanisms which may be intervening in the improvement of symptoms in the treated mice:  perhaps the transplanted cells are secreting a series of IGF-1 (insulin-like growth factor 1) factors.  Therefore, the technique still needs to be perfected in order to be able to bring these transplants to the clinical phase.


The legacy of Marie Schlau: literature to help cure Friedreich's Ataxia

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Research projects currently being financed by BabelFAmily

Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:

1) Gene Therapy for Friedreich's Ataxia research project:

The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.

2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.



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