2023-05-07 09:47:40
On many occasions it is believed that this disease is of the elderly, but it is not. Barcelona scientists develop a model based on stem cells that will facilitate the development of therapies for pathologies that affect dopamine. The symptoms of parkinsonism are, in general, difficult to detect before the first year of life.
A new model based on stem cells from patients will henceforth allow us to better understand rare diseases that affect dopamine (one of the most important neurotransmitters in the central nervous system) and cause symptoms typical of childhood parkinsonism and also test the usefulness of possible treatments for them.
The model, initially designed for one of these diseases, called Tyrosine Hydroxylase Deficiency (THD), has been developed by scientists from the Bellvitge Biomedical Research Institute (Idibell), the Sant Joan Research Institute de Déu (Irsjd), the Sant Pau Research Institute (IIB Sant Pau) and the University of Barcelona (UB).
They explain that parkinsonism is a variety of symptoms shared by a group of genetic diseases of which, adding those affected by all of them, there are more than a thousand cases described worldwide. Those diagnosed with THD (well described) are only 90.
Diagnosis by specialists has improved a lot in recent years, says the scientist. In the case of THD, there is a cerebrospinal fluid biomarker that reflects the decrease in dopamine in the brain that causes parkinsonism. Then a genetic study must be carried out to finish identifying the disease.
The symptoms of parkinsonism, from the outset, guide a lot: the most frequent are motor problems, dyskinesia (abnormal and involuntary movements, especially of the orofacial musculature), hypotonia (muscle elasticity is excessive and its consistency is soft, the joints are not together). well fixed) and not controlling the head; and the most serious, intellectual disability and absence of speech.
levodopa plus carbidopa
In any case, it is important to diagnose as soon as possible because, in many of these diseases, affected children find treatment with levodopa plus carbidopa useful (the latter allows the former not to break down before reaching the brain).
Two phenotypes of THD have been described (A and B) since 2010, but the scientist indicates that over the years it has been seen that “not everything is black or white; there are grays between one and the other”. In A, motor problems appear in early childhood and respond well to therapy, so that affected minors can speak, write and read and control their motor problem well.
Those with phenotype B, on the other hand, present problems before one year of life, their motor difficulties are more serious and they do not respond to therapy, so important cognitive impairments cannot be avoided in them. Between A and B there are patients with “intermediate” problems and more or less refractory to treatment.
a doctoral thesis
The THD model, which faithfully reproduces the pathological characteristics of the disease, has been created, specifically, from patients’ skin cells reprogrammed into pluripotent stem cells, which are capable of becoming any cell type and as a result They have differentiated into neurons.
This innovative model “allows many types of analysis to be done quickly and easily” and is very promising because, as Tristán-Noguero points out, it has already served to observe that, in the model that reproduces the most severe THD condition, Early administration of dopamine, when neurons are still differentiating, does prevent the defects that cause the disease. This result suggests that the treatment could work in the most severe patients if the treatment were applied preventively during brain development (in gestation).
This could be clinically useful if there were prenatal or neonatal diagnosis, in order to treat positive cases early and/or in the case of families in which a child with the disease has already been born, in order to avoid symptoms Serious to the next (brother). In fact, there is already a study in the medical literature that confirmed that, by treating the mother of an affected child with levodopa, her second child was born with the same disease, but with less severe symptoms.
The team (Irsjd, Idibell and UB) involved in this model is now using the innovative THD model to study several pharmacological chaperones from the University of Bergen, in Norway, of which at least one has given positive results comparable to those obtained from a mouse model (of Norwegian development) with the same disease.
Tristán-Noguero reports that the same model is used to test a possible gene therapy, which is something that, in fact, they have already done: “We corrected the entire phenotype with the CRISPR/Cas9 technique and all the alterations improved.” Although he points out that there is a relevant problem for this: “In this pathology there is not a good genotype-phenotype relationship.”
“This is the first THD model capable of differentially reproducing the characteristics of mild and severe patients, and which also reproduces their different response to treatment,” says García Cazorla.
Up to 70 causative genes described
Consiglio reports that in the diseases that cause pediatric parkinsonism there are up to 70 described causative genes, which gives an idea of the complexity and heterogeneity of this group of rare pathologies and the importance of developing personalized therapy for them, because even patients with a same disease (genetic mutation) may present differences (mild or severe phenotype) and not respond in exactly the same way to the same therapy. “That’s why it’s so important to be able to study them and learn.”
He believes that the best thing about the THD model is that they are cells from patients affected by the disease and that “with their fibroblasts (a type of cell that contributes to the formation of connective tissue) we can generate many other types of cells to be able to see what is what to correct and how to intervene”. It is also possible to find silent genetic variations or try to correlate neuronal morphological changes with functionality, emphasizes Consiglio. “We are optimistic. It may also be a model for other pediatric parkinsonisms due to a lack of dopamine”, he says. Carmen Fernandez (DM)
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