Three pediatric researchers focusing on serious childhood diseases receive grants from Daniel Bravo Foundation

Six hospitals and research centers have received the grant for three studies being conducted by world-renowned researchers in the first call for Daniel Bravo Projects in pediatric research. Each study has received funding valued at €300,000.

The Vall d’Hebron Research Institute and the Sant Pau Institute of Biomedical Research have been selected for a project on spinal muscular atrophy. The Girona Biomedical Research Institute and Hospital Sant Joan de Déu are leading a study on sudden-death syndrome and the Catalan Institute of Climate Sciences –in conjunction with Hospital Sant Joan de Déu– is working on a study into Kawasaki disease.

Of the 54 projects received, the Foundation valued the proposals that generate collaborative research including basic and clinical researchers, that are patient centered, that address unmet medical needs in children and young adults, and that will be applicable in the near future.

Childhood spinal muscular atrophy

The teams led by Eduardo Tizzano (VHIR) and Pablo Fuentes-Prior (IIB Sant Pau) are working on a minority disease that is currently the second most common serious hereditary disease affecting children and has no specific treatment.

Spinal muscular atrophy is a neuromuscular disease that affects the motor neurons on the anterior grey column of the spinal cord and leads to progressive wasting of muscles caused by a decreased production of the SMN protein (Survival of Motor Neuron).

The condition is caused by a defect in the SMN1 gene, whose function is partially covered by the SMN2 gene. The SMN2 gene attempts to produce the same proteins as SMN1 but can only generate full proteins less than 50% of the time (the rest are missing exon 7, which is excluded mainly due to the interaction of two inhibitor proteins).

The research project seeks to understand the molecular interactions between the mRNA coded by exon 7 of the SMN2 gene and the two key factors that work together to exclude this exon. With this information, the group hopes to find solutions that can interfere with the protein-RNA interactions to liberate exon 7 (isolating it from the ternary complex) and to ensure proper levels of full SMN proteins are created. The final goal of the research is to find a molecule that is effective when taken orally.

The joint research with IIB Sant Pau will be conducted in collaboration with Pablo Fuentes, a biophysicist who studies isolation of the ternary complex and protein crystallization. In fact, Eduardo Tizzano began the research at the IIB Sant Pau, where he worked previously. “With the Daniel Bravo grant, we’ll be able to consolidate established points and delve deeper into everything we have to be able to isolate the complex and test drugs,” says Tizzano. The doctor has set the goal of finding personalized solutions for patients, as the SNM2 copies aren’t always functional equivalents in every case.

Sudden-death syndrome

Sudden-death syndrome is a condition that affects 7.5 out of 100,000 children in the world. The project is led by Ramon Brugada (IDIBGI) and Josep Brugada (HSJD), who are working on the first project of its kind in Catalonia with 60 families that have experienced a sudden death that can't be explained after an exhaustive genetic analysis of the 77 main genes associated with the disease.

Ramon Brugada explains that 25% of the cases of sudden death are due to genetic causes. “We evaluate the biopsy from those who have suffered a sudden death and do a genetic study with the families. This way we can discover the genetic cause of the mutation and develop a drug to prevent it. It also helps us find out which family members don’t have the mutation and then discard them as patients.”

The IDIBGI Cardiovascular Research Group, which has been doing genetics research for more than 20 years now, has the only diagnostic laboratory of its kind in Catalonia, where they do genetic studies with a tool that uses Next Generation Sequencing technology, developed through an agreement with Ferrer laboratories and available in 25 other countries. With this technology, researchers can study 100 genes in 3 weeks at optimal diagnostic speed.

This tool, available to the clinical community, sends the patient’s diagnosis to their doctor for treatment and follow-up in the hospital. “We realized that the line between research and clinical practice is very thin and patients want answers,” says Brugada. This is why IDIBGI is working with Hospital Sant Joan de Déu, where children with genetic problems are hospitalized and evaluated.

This research includes discovering other genes associated with sudden death –so far they’ve found half– and, above all, understanding why some members of the same immediate family with the same family genetics –meaning the same mutation- experience sudden death and other don’t.

“We believe that, in addition to the genetic component, there are other epigenetic and environmental factors that affect gene interaction. In order to establish this, we would need much larger groups of patients and we can't do this yet because families that have suffered a sudden death tend to be small. Plus, we would need cardiac tissue to analyze how the genes interact and which genetic modulators are decisive, but we’re limited because we can't do biopsies. We use animal and cell models,” explains Brugada.

Kawasaki disease

In the past three years, the team led by Dr. Xavier Rodó at IC3 has headed up an international consortium to study different aspects of Kawasaki disease. The cause of this disease is still unknown and it is the leading cause of acquired heart disease among children in developed countries.

The research has attempted to discover the cause of the disease by studying environmental samples from places where it is most prevalent, including Japan. The best hypothesis is that it is caused by an airborne microorganism.

Xavier Rodó explains that right now the research is looking to definitively confirm the results obtained. “We haven’t fully established whether it is just one microorganism or several –or more likely environmental toxins derived from these microorganisms. Nor can we discard the idea that there may be other associated factors involved, like for example the chemical characteristics of the air when it is inhaled.”

In Japan, the consortium will continue working on on-site sampling in areas that may be the cause of the disease agent, which are basically agricultural areas with intensive crops. In Catalonia, Hospital Sant Joan de Déu has been collaborating on the project for the past two years, following up with new patients, providing coordination for obtaining and analyzing samples for a specific Biobank and creating a database of patients with Kawasaki disease that have been hospitalized there over the past 10 years. “Creating the Biobank and analyzing all of the samples we’ve collected here at the hospital also gives us the chance to immediately test new hypotheses as we come up with them,” says Rodó.

The qualitative leap the team has made came in creating a warning system to anticipate high-incidence periods. “This system should allow us to develop a mathematical system to warn the medical community and public health managers when specific masses of air arrive that could contain the etiological agent of the disease,” says Xavier Rodó.