Lines of research
Lines of research
National and international research
Three lines of research
The TRANSLATIONAL Stroke Group is developing its own strategic and unique lines of research focused on the study of:
- Cerebral Ictus with translational perspective.
- Movement disorders (ALS) and development of new therapies.
- Chronic pain and risk factors.
National research lines
Our group is part of the National Network of Cerebral Vascular Diseases of the ISCIII (RICORS-ICTUS).
We coordinate 3 national projects, including an independent clinical research study (GOTIS/ICI19/00032) and two PI projects (PI17/00540, PI20/01014).
International research lines
At the international level, we participate as members of the Management Committee of the COST_IRENE Stroke Network, as well as of the European Translational Medicine Infrastructure (EATRIS).
In addition, we participate as coordinators of the European PLATMED project and as PI in the GOTTARG and MADIA projects.
Excellence, solvency, and productive capacity.
All the aforementioned projects are competitive, with a funding volume (approx.) of 2,200,000 euros between 2019-2021, which is a clear indicator of the Group’s excellence, solvency and productive capacity.
Cerebral Ictus with a Translational Perspective
After an ischemic stroke, there is an energy failure that leads to an excitotoxic effect as a result of increased glutamate in the extracellular space.
This increase in glutamate is a key factor in ischemic neuronal damage and is considered one of the most promising targets for the development of new treatments.
To this end, our group has described a new mechanism to reduce excitotoxic damage after stroke based on the reduction of blood glutamate concentration.
Blood glutamate reduction is achieved pharmacologically by exogenous administration through the activity of a plasma enzyme called glutamic oxaloacetic transaminase (GOT) (J Cereb Blood Flow Metab. 2016 Feb;36(2):292-301; Ann Neurol. 2018 Aug;84(2):260-273). This line of work is one of the most advanced within the Group.
We are currently in the clinical phase to validate the protective effect of the recombinant GOT enzyme in ischemic patients, and we even have a pre-agreement with the pharmaceutical industry for the possible licensing of the drug in the future.
This study was funded by the ISCIII Call for Independent Clinical Trials (GOTIS_ICI19/00032), the RICORS-ICTUS Network (RD21/0006/0003), the Xunta de Galicia Competitive Reference Group Grant (Project N607A2022/02) and the EraNet Complementary and International Action Grant through the GOTTARG Project (AC19/00066).
Therapeutic hypothermia represents one of the most effective experimental strategies to reduce inflammatory processes and neuronal damage in cerebral ischemic pathology; however, its benefits have not been effectively transferred to patients due to the adverse effects associated with low temperatures.
In this line of work, the TRANSLATIONAL ICTUS group has described a heat shock protein (RBM3) that actively participates in the therapeutic process of hypothermia and could be an alternative pharmacological target to hypothermia (Brain Commun. 2020 Jun 4;2(2):fcaa078. and J Clin Med. 2022 Feb 11;11(4):949).
For the development of this project, we are currently in active collaboration with Dr. Sven Wellmann from the University Children’s Hospital Regensburg (KUNO), Regensburg (Germany), in the search for a pharmacological tool capable of modulating RBM3 protein expression.
This line of research is funded by the RICORS-ICTUS network (RD21/0006/0003) and the Competitive Reference Group Grants of the Xunta de Galicia (Project N607A2022/02).
With the aim of increasing the therapeutic efficacy of drugs and reducing side effects in stroke patients, our group has been working for more than 5 years on a new strategy based on the encapsulation of drugs in nanostructures vectorized to the region of cerebral ischemia.
Our goal is to increase the efficacy and safety of the drug by releasing it in a controlled and targeted manner in the ischemic area (J Nanobiotechnology. 2022 Jan 21;20(1):46; Pharmaceutics. 2021 May 20;13(5):757 and J Control Release. 2019 Sep 10;309:94-105). The demonstration of this hypothesis will make it possible to start clinical trials in the short term to demonstrate its application in patients with acute ischemic stroke.
We are even in contact with private companies (Op2Lysis, France) that are interested in this new technology.
In collaboration with other groups from Canada, Spain and France, this line of work is funded by the EraNet complementary and international action grants through the PLATMED project (AC20/00031).
CADASIL is a severe genetic cerebrovascular disease caused by a mutation in the Notch3 gene, which mainly affects the cerebral arteries and leads to cerebral infarcts, migraines, and dementia.
In this line of research, we have succeeded in generating iPSCs from CADASIL patients and subsequently differentiating them into the affected cell lineage.
Our group was the first to obtain a human cellular model of this cerebrovascular disease (Stem Cell Res. 2018 Apr;28:16-20).
As the leader of the ISCIII project PI20/01014, we are currently working on the genetic correction of the Notch3 mutation using the CRISPR technique to evaluate the therapeutic use of these cells in mouse models of this disease and, in the future, in patients.
CADASIL disease is an inherited disease that affects the blood vessels of the brain. The NOTCH3 gene, which is located on chromosome 19, has a mutation that leads to this condition. In the cells that make up the walls of the tiny blood vessels in the brain, changes to this gene result in an aberrant protein buildup. As a result, blood vessels constrict and lose some of their elasticity, which can affect blood flow and reduce the amount of oxygen and nutrients reaching the brain. CADASIL symptoms are diverse and include migraines, cognitive problems, stroke, dementia, and emotional problems like despair and anxiety. Early or middle adulthood may mark the onset of symptoms, and the disease’s severity varies among affected individuals. CADASIL is a rare and complex genetic condition for which there is currently no effective treatment. The goal of treatment is to reduce symptoms and avoid consequences. Induced pluripotent stem cells (iPSCs) are a helpful tool that has been developed because all previous research using animal models has not been particularly successful. We have been advancing the research on this disease in our lab for a few years as part of a project supported by the ISCIII. The approach “disease in a dish” provides a mechanism to investigate the disease in a controlled and reproducible environment. To achieve this, we were able to create iPSCs from the somatic cells of CADASIL patients (from the Neurology Service of the Santiago Clinic Hospital and the Vall d’Hebrón Hospital, under the collaboration established in this project with the Stroke Pharmacogenomics and Genetics group from the IIB Sant Pau) that can then be differentiated into the cell phenotypes impacted by the disorder, such as endothelial cells (VECs) and smooth muscle cells (VSMCs). The synergy with the Molecular Diagnostics and Clinical Genetics Unit (Hospital Universitari Son Espases) and the Fundación Pública Galega de Medicina Xenómica helped to achieve the cellular characterization that is required for this research with iPSCs. This provides the opportunity to research the effects of the NOTCH3 gene mutation on these specific cells, as well as explore potential biomarkers (proteomic studies carried out by the Proteomics Service of IDIS), try out new treatments, and understand the underlying causes of the disease.
Currently, the only available treatment for cerebral stroke aims to recanalize the occluded vessel to reperfuse the ischemic brain tissue. However, reopening of the occluded vessel (defined as recanalization) does not necessarily guarantee complete tissue reperfusion, which is known as futile reperfusion and severely limits the functional recovery of patients.
The mechanisms underlying futile reperfusion are complex and not fully understood.
Therefore, a more complete understanding using state-of-the-art methods is needed to study the mechanisms of the vascular response that occurs after the process of vascular reperfusion.
Within the framework of the National Stroke Network (RICORS-ICTUS), we are developing a clinical study focused on the search for new biomarkers that help predict futile reperfusion and stratify patients who respond better to recanalizing therapies.
This line of research is funded by the RICORS-ICTUS network (RD21/0006/0003).
Movement disorders (ALS) and development of new therapies
Excitotoxicity caused by altered glutamate homeostasis is one of the most prominent hypotheses in ALS disease.
In fact, preventing the increase in glutamate levels may be the key to protecting motor neurons and preventing disease progression.
In relation to the therapeutic study of GOT in cerebral ischemic pathology (line 1 research), in this new line of work and in collaboration with the Movement Disorders Unit of our hospital, we have proposed to evaluate the protection provided by the recombinant human form of GOT1 in animal models of ALS and to analyze blood GOT levels in ALS patients in relation to disease progression.
Our long-term hope is to be able to translate this new therapy to ALS patients with the intention of delaying disease progression and improving the quality of life of these patients.
This project has recently received financial support from the ALS Foundation (adELAnte) and is also funded by the group itself through the competitive reference group grants of the Xunta de Galicia (Project N607A2022/02).
Chronic Pain and Self-Care Study
Chronic pain is a disease of great public health relevance, both because of its high prevalence and incidence, and because of its consequences in terms of reduced quality of life, associated comorbidities, high health care demand, and medication use.
The main objective of our study is to test whether the practice of Qi Gong (read Chi Kung), a type of physical activity belonging to the so-called “mind-body” disciplines, used as a self-care practice, reduces clinical manifestations, improves quality of life, and reduces the need for care and medication in patients with chronic pain.
We will also identify genetic profiles that may modify the response to the intervention and study the influence of the intervention on the presence of inflammatory markers.