The research groups in Cell and Gene Therapy and the Diagnosic and Molecular Therapy - also linked to the Blood and Tissue Bank (BST)- of VHIR, have succeeded for the first time modelling haemophilia B by using the technology of induced pluripotency with stem cells (iPSCs). In this way, they have clarified some details of this disease that affected a large number of descendants of Queen Victoria of England, and that for this reason it is also called the Royal Disease, and that European royal families suffered from up to the middle of the 20th century. The details of the illness were an absolute mystery until a few years ago since the last affected descendant, Prince Waldemar of Prussia, died in 1945 at the age of 56 years, and it was not known if it was a haemophilia A or B, nor its severity. In fact, it has always been a cause for debate by historians if the relatively high longevity of those affected was due to better living conditions of royalty in a time when there was no effective treatment, or whether it was a moderate haemophilia. In previous studies carried out in Russia, from the DNA extracted from the bones of members of the Romanov family, the last tsars shot in 1918, they managed to identify the mutation that originated in the form of haemophilia that affected the Royal houses. Specifically, the mutation was found in the gene for factor IX (FIX) of the coagulation and consisted of the change of a nucleotide -a single letter of the sequence of the DNA in a non-coding region, and predicted that the disease would be serious because corrupted all the splice pattern in the process of removal of non-coded fragments (introns) when mature RNA is formed. Now, the VHIR team coordinated by Dr. Jordi Barquinero, together with a group of the Centre of Regenerative Medicine of Barcelona (CMRB) and two other groups of France and Italy, has been able to create a physiological cell model of the Royal Disease that has allowed the study of the FIX gene expression at a RNA level. The researchers worked with haemophiliac patients with mutations that could only be studied in the RNA (such as those that affect the splicing) and found that one of them had the same mutation as royal families without being related. "The study was based on a small skin biopsy of both the patient and his mother (carrier of the mutation) and from there the iPSCs were generated that differentiated in hepatocytes (cells of the liver) to be able to analyse the FIX RNA, since it is this type of tissue that the FIX produces physiologically," explains Dr. Jordi Barquinero. The study, published at https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.13808" Journal of Thrombosis and Haemostasis, confirmed the prediction that " the mutation altered splicing and it was shown that mutated RNA is degraded by a cellular degradation mechanism of mutated RNAs, which makes it very difficult to detect," emphasizes the Dr. Francisco Vidal, head of the Diagnostic and Molecular Therapy group. "We have highlighted the enormous capacity of reprogramming technology to create models of human disease," says Professor Angel Raya, head of the CMRB group. On the other hand, the publication has also provided clues that could help explain the apparent discrepancy between the severity of the disease and the longevity observed in some affected members of the royal families, showing that despite the presence of the mutation, a small and absolutely normal proportion of messenger RNA of the FIX is generated in the liver cells. In this type of mutation, it has been described that the splicing cell machinery can work very differently in different people, so that the same mutation can result in a more or less serious disease, which would also be applicable to those affected by the Royal Disease. Haemophilia B Haemophilia B is a hereditary disorder of the blood clotting caused by the deficiency of a protein called factor IX (FIX) The severity of the symptoms is variable and normally the most serious forms are detected in the first months of life. Bleeding is the most important characteristic of this disorder. The current treatment consists in the periodic infusion of recombinant factor IX. The disease originates from a recessive trait linked to the X chromosome that is where the FIX gene is located. Therefore, it only affects men, although women can be carriers and transmit them to their children. Haemophilia B is 5 times weaker than A, which is due to a defect in the factor VIII gene, and this is related to the size of it, which is 5 times longer than that of FIX. The latest gene therapy trials based on the use of adeno-associated vectors directed to the liver are giving very positive results in both forms of haemophilia.