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Summary by Mari Luz González Casas
Translation: Marion Clark
To hear the entire presentation in Spanish on mp3, go to the following link: http://download.yousendit.com/73B8B9D86A5CDE69
Encuentro Ataxias (Ataxia Encounter) 2008
Organized by the
Colectivo Ataxias en Movimiento
(Ataxias on the Move Coalition)
Madrid, April 29 2008
Fifth scientific presentation:
Dr. Salvador Martínez, Alicante Institute of Neurosciences, Miguel Hernandez University
“Plans for applying stem cells in spinal ganglia in Friedreich’s ataxia”
Dr. Salvador Martínez
The best approach to a neurodegenerative disease is the one which is the simplest and the most feasible. In a neurodegenerative disease, a series of neurons—and along with them a series of functions—disappears. In trying to maintain these functions, then, we have to prevent the death of these cells.
Unfortunately, neurodegenerative diseases often manifest themselves only when many cells have already disappeared; so we must prevent this process. Dr. Salvador Martinez has spent years applying his knowledge of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), fighting against the neuronal death that occurs in this disease. His approaches are as follows.
In the human body we have an almost inexhaustible source of stem cells in the bone marrow. In vitro, stem cells can convert into neurons, but up until now, no one has shown that this process can be replicated in the central nervous system (in vivo). When these stem cells are transplanted from bone marrow into the damaged part of the body, they do not convert into neurons, but instead they surround the dying neurons and prevent them from dying. They can exercise this protection thanks to the fact that the bone marrow stem cells give off a substance called GDNF (glial-cell derived neurotrophic factor). This growth factor acts like a drug on the neural cells, preventing their apoptosis (programmed cell death). The bone marrow stem cells thus act as an ideal drug, exercising their effect in just the very place that it is needed.
Currently there is a clinical trial going on which is showing very encouraging results and will soon be published.
Cellular therapy with bone marrow has been done all over the world for many years. Hematologists have a great deal of experience in handling bone marrow. Therefore it was only necessary that a hematologist be convinced of the suitability of this trial.
The team of Dr. Martinez followed the entire process of regeneration from the time of the bone marrow transplant in ALS patients. They observed that the damaged cells recover their functioning and that the whole process follows very controlled rules, without producing tumors or any uncontrolled growths.
The next step was to establish whether these injected stem cells could find for themselves the location in the body where they needed to act in order to prevent neuronal death. There were two options: inject them in the spinal cord, where the damage was located, or inject them into the cerebrospinal fluid. By injecting the bone marrow stem cells into the cerebrospinal fluid, the following was confirmed.
The spinal ganglia (or dorsal root ganglia) are a group of cells, the primary sensory cells of the nervous system, that is, those which receive all the sensations of the body. They are found on both sides of the spinal cord. In Friedreich’s ataxia, it has been observed that neuronal death is especially critical in the spinal ganglia. Therefore, this would be the region of the body to treat.
When stem cells are injected into the cerebrospinal fluid, it is seen how the spinal ganglia fill up with these injected stem cells. This can be observed thanks to a cellular marker, injected along with the stem cells, a protein marker which appears a fluorescent green on imaging, and which allows the ganglia to appear stained green. The question is whether these cells which surround the spinal ganglia can prevent the death of the neural cells in FA patients.
With this framework, Dr. Salvador Martinez proposes a very simple study.
As in the previous study, it’s necessary to obtain a good animal model of FA in which it can be proven that the cells of the spinal ganglia are dying. After that, bone marrow stem cells will be injected in the cerebrospinal fluid of the animal. The spinal ganglia will fill up with these beneficial cells, and thus neuronal death will be prevented.
If a good animal model is obtained, then bringing all this to the clinical trial phase is easy enough, now that all that is needed is to give the patient a lumbar puncture.
Experience shows us that cellular therapy nowadays is fundamentally a neuro-protective treatment, one that prevents disease progression. This is no small thing, in fact, it is important, especially in a disease like FA which can often be diagnosed early enough.
But in addition, we’d like to know if this same process occurs in vitro. There is a very simple model which consists of obtaining neurons, not only from the central nervous system but also of the peripheral nervous system (for which a biopsy is necessary), or attempting to make other cells change into neurons in vitro. Bone marrow stem cells, under specific conditions, change into neurons in vitro.
For this process, the ideal method is to select very immature cells from an easily accessible site. One very accessible site would be the periodontal ligament. When we have a tooth extracted, around that tooth we have a fleshy tissue, the periodontal ligament. It is a structure which conserves very many primitive cells from the neural crest—a component of primitive ectoderm---which have remained there since the embryonic stage; they have stayed as if encapsulated there throughout our whole lives. We can extract them from the periodontal ligament and place them in culture, and because of their neural potential, they can be converted through multiple manipulations into neurons of various types, just like those which are found in the central nervous system.
We can perform tests using these human neurons from individuals with identified genetic mutations. If a patient with Friedreich’s ataxia has a tooth extracted and gets it to us under the proper conditions, we can remove FA neurons in culture and investigate selected cellular effects or molecular effects with these neurons. This is already being done with other diseases and it works well without excessive technical complications.
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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.