Research on rare diseases at the Institute for Advanced Chemistry of Catalonia

Within all the research lines carried out at the Institute for Advanced Chemistry of Catalonia of the Spanish National Research Council (CSIC), seven research groups dedicate part of their efforts to the study “Rare Diseases”.

Rare diseases are diseases which affect a small number of people compared to the general population and specific issues are raised in relation to their rarity. In Europe, a disease is considered to be rare when it affects 5 people per 10,000. Therefore, they are rare disorders or conditions that affect a small part of the population, but which in global terms affect 26 million people in Europe, and therefore constitute a global health problem. To date there are 6,172 rare diseases described.

Rare Disease Day has been celebrated on the last day of February, since 2008. The date was chosen because February is a “rare month”, and for this particular characteristic the last day of Febreary was chosen to associate this rarity with the disease.

With the aim of making this type of disease more visible, the IQAC-CSIC joins the commemoration of this day by explaining the latest advances in the field.

The Nucleic Acid Chemistry group led by the researcher Ramon Eritja, advises the group of Drs. R. Artero and B. Llamusí on a Prometheus project of the Generalitat Valenciana, which aims to develop oligonucleotides that serve for the treatment of myotonic dystrophy type 1 or Steinert’s myotonic dystrophy. It is a serious, degenerative neuromuscular disease that can affect various systems such as the muscular, respiratory, cardiac, endocrine, ocular and central nervous system. Among its most characteristic symptoms is muscle weakness, which together with cardiac arrhythmias are its main causes of mortality. This disease, which currently suffers from 90,000 Europeans, and which affects children and adults alike, still does not have an effective treatment, although a first candidate for clinical studies has already been obtained.

Ramon Crehuet, belonging to the Theoretical and Computational Chemistry group, works with a neurodegenerative disease, called Kennedy disease or spinobulbar muscular atrophy. It is part of the family of polyglutamine disorders to which Huntington’s disease belongs. “These disorders take place when the polyglutamine fragment of a protein exceeds a limit. These limits depend on each protein and the reason is not known ”, explains Dr. Crehuet. “The reason why toxicity basically affects neurons, and not all cells of the body, is not known either,” the researcher clarifies. The group of Theoretical and Computational Chemistry, study the structure of the polyglutamine fragment and how the neighboring amino acids of the protein can determine the structure. This aspect is key, since the structure it adopts determines its propensity to aggregate and interact with other biomolecules, and it is in these interactions that the key to understanding its toxicity.

Cystinosis is a metabolic disease characterized by the accumulation of cystine crystals (Cys2) – an oxidized dimeric form of the amino acid cysteine (Cys) -, inside the lysosomes of different organs and tissues. It is a hereditary genetic disease that can lead to different pathologies such as rickets, Fanconi syndrome, blindness, kidney failure, lung, brain or muscle dysfunction and premature death. Ignacio Alfonso, Jordi Solà and Daniel Carbajo, from the Supramolecular Chemistry group, are working on the development of an inexpensive fluorescent method for the quick and easy quantification of intracellular cystine, which could complement the sophisticated methods currently used in the main hospitals. “The proposal aims to carry out an evolution of the method developed and patented by our group in 2018, which selectively detects Cys and Cys2 in human urine, using a simple protocol and in just one hour”, explains Alfonso.

Also in the field of diagnosis, Lluisa Vilaplana and J.-Pablo Salvador are focused on the development of new diagnostic systems based on antibodies, to achieve an early and rapid detection method for cystic fibrosis. It is a rare genetic disease characterized by the abnormal accumulation of thick mucus in the lungs, which progressively limits respiratory capacity. This fact is associated with an important predisposition to suffer persistent infections, mainly caused by the bacterial species Pseudomonas aeruginosa and Staphylococcus aureus. These infections are the main responsible for the high levels of mortality suffered by this type of patients, who have a life expectancy close to 45 years. “An early diagnosis is essential for a better prognosis of these diseases, and in this specific case, having early detection tools will be crucial to avoid the chronification of these infections,” explains M. Pilar Marco, head of the Nanobiotechnology group for Diagnosis.

The advancement of nanomedicine opens up new new possibilities in the development of drugs, such as the one recently developed for the rare disease Fabry, with improved efficacy compared to existing authorized treatments. This important achievement has been achieved within the European Smart4Fabry project, which is now ending after four years of work and in which researchers from the Multivalent Systems for Nanomedicine group, led by Miriam Royo, have participated. Fabry disease is a chronic debilitating disease due to recurrent episodes of severe pain that are difficult to control with conventional analgesics, and it is life-threatening. The newly developed drug improves current treatments and helps reduce costs and improve the quality of life of patients.

Amyloidoses associated with transthyretin are characterized by the appearance of deposits of this protein, either in its native form or in the form of a point mutant, and can affect different organs. One of them is amyloid familial polyneuropathy (FAP) or Andrade’s disease, a rare hereditary disease that begins at an early age and affects the peripheral nervous system. To date, one of the therapeutic strategies to treat this disease is based on the stabilization of the native state of transthyretin with small molecules. The Glycoconjugate Chemistry Unit has focused its research on a drug discovery project to treat this type of transthyretin-related amyloidosis. “The interdisciplinary project has been funded by the Fundació Marató de TV3”, explains Gemma Arsequell, head of the Unit.

Gemma Fabriàs, Josefina Casas, José Lus Abad and Antonio Delgado, from the Bioactive Molecules Research Unit, also work developing diagnostic tools for different types of rare diseases. Both Farber’s disease and the syndrome of spinal muscular atrophy with progressive myoclonic epilepsy are caused by mutations in the ASAH1 gene, which encodes acid ceramidase. In this case, they are working on the development of compounds that allow the activity of this enzyme to be measured quickly, easily and robustly directly on cells from patients.

Another research line is focused on hereditary movement disorders, such as spastic paraparesis, cerebellar ataxias, or peripheral neuropathies. The lipid metabolism is deregulated in this spectrum of diseases, so they try to carry out the characterization of the lipids of the patients’ cells in order to identify biomarkers and therapeutic targets. Lastly, they work on the treatment of Niemann Pick A / B disease. It is a group of inherited diseases, in which lipids accumulate in the cells of the spleen, liver and brain. Currently, the existing therapy is enzyme replacement, but this therapy is not always useful, so they are focused on finding a therapy based on pharmacological chaperones.

Much remains to be done, but fortunately, more and more research groups and funding are dedicated to the study of rare diseases. This is totally necessary since it is important to emphasize that although the prevalence of these pathologies is low, it affects millions of people around the world and is a serious global health problem.

IQAC-CSIC Communication