They discover a possible therapy for ELA with stem cells

Researchers from the CASE University of the Western Reserve (United States) have used stem cells of patients with a Very rare type of amyotrophic lateral sclerosis (ELA) To attack a key gene that contributes to the disease, a strategy in which they trust for the development of future therapies.

Although the work, published in ‘Molecular Medicine’focused on Patients with a hereditary type of ELA caused by the mutation in the membrane B protein associated with vesicles (VAPB gene), more frequent in Brazil, its authors emphasize that I could help lay the bases for clinical trials With genetic information.

As explained, The VAPB gene provides instructions for production of a protein that helps connect different parts of the cell so that they can communicate and respond to stress: “This is especially important in nerve cells,” said the principal researcher, Helen Cristina Miranda, who has specified that, deteriorating, Neurons become more vulnerable to degeneration.

For the study, they used induced pluripotent stem cells (IPSC), a cell type created in the laboratory from the skin or blood of a person which can be transformed into almost any type of body cell. The IPSC of ELA’s patients served to cultivate their motor neurons in a cultivation plate, which allowed scientists Study the disease with real human cells.

The ‘integrated response to cell stress as a basis for a possible therapy

Among the findings, the researchers discovered how A mutation in the VAPB gene can interrupt communication between key parts of the cellspecifically between the endoplasmic reticulum (RE), which acts as a cell quality control center, and mitochondria, which generate the energy that cells need to live and perform their functions.

This alteration leads to the chronic activation of a protection mechanism called Integrated stress response (ISR)that although at first it is useful, In the long term, it reduces protein production and harms cell survivalultimately damaging motor neurons and contributing to this rare hereditary form of ELA.

In this regard, ID identified as a potential therapeutic objective: “We also demonstrate that blocking this response to stress can reverse damage to the laboratory, A promising step towards future treatments“Miranda, associate professor of Geoming Genetics and Sciences at the Case University of the Western Reserve, has highlighted.

From these results, the team has been proposed Continue studying the response of motor neurons to stress: “We are currently testing ISR inhibitors in more complex neuromuscular models and exploring how this approach could benefit other ELA subtypes,” Miranda detailed.

This advance is a “good approach”

The clinical head of neurology of the University Hospital of Donostia, Adolfo López de Munuain Arregui, stood out in statements to SMC Spain that This is a “solid” study but with “limitations”being an artificial recreation of what happens ‘in vivo’.

As detailed, work results can Open the door to therapeutic approaches With stress integrated response inhibitors, such as the ISribr or similar molecule, as well as trying to analyze in clinical context What is the weight of this mechanism in cases of sporadicin order to stratify patients in trials.

Even so, it has pointed out that the model used by the researchers, who used derived motorcycles assuming that this disorder occurs in vivo ‘in these cells, entails limitations by obviating that there are similar mechanisms in glia support cells. Therefore, he has urged to analyze the effect of the mutation on muscle cells and glia to see the effect by conditioned mutation in a single cell lineage in other animal models.

The study is a first step to continue investigating

For his part, the research professor Ramón y Cajal at the University of Barcelona Juan Alberto Ortega Cano has explained to SMC Spain that the study contributes as a novelty the direct association between mitochondrial dysfunctionmutation-specific, for the reduction in its contact with the endoplasmic reticulum, and a greater activation of the ISR.

“It remains to be understood how, mechanistically, the reduction in contact between endoplasmic and mitochondria reticulum caused by the mutation generates greater stress in these compartments, which leads to a higher activation of the ISR,” added the expert, than It stands out among the limitations that the results focus on a genetic subtype of ELA which represents less than one percent of patients.

For Ortega, The clinical implications of the study are “clear”since it supports the stratified treatment of the ELA based on the genetics of the patient, and proposes the modulation of the ISR as a viable therapeutic target in specific subgroups, something especially relevant after the Failure of clinical trials with ISR inhibitors in unstartified populations.

“In addition, it should be studied in depth how these treatments can correct the degeneration of motor neurons Without affecting how the rest of the body cells deal with cellular stress“The specialist has finished.