Skeletal and skull deformities, short stature, malfunction of various organs and cognitive delays: these are just some of the problems that afflict children who suffer from Hurler syndrome, the most severe of the rare diseases called mucopolysaccharidosis. With this in mind, researchers from the Tettamanti Foundation and Sapienza University of Rome used skeletal stem cells, taken from patients, to recreate for the first time a three-dimensional reproduction of human cartilaginous and bone tissue. The aim was to better understand the pathological mechanisms underlying the incorrect ossification characteristic of this disease. The results were published by the international scientific journal JCI Insight.
Hurler syndrome and genetics
Hurler syndrome is the most severe form of mucopolysaccharidosis type 1, a rare hereditary disease that affects one in 100,000 children in Europe. Those affected have two mutated copies of the Idua gene, resulting in the lack of an enzyme that has the function of degrading some sugar chains, called glycosaminoglycans. This defect leads to the accumulation of glycosaminoglycans in lysosomes (cellular structures responsible for the degradation of molecules), which would damage various organs and tissues such as bones. Symptoms appear shortly after birth, progress and, in the absence of treatment, can lead to death as early as adolescence due to cardiovascular and respiratory complications.
Studies done on experimental animal models of mucopolysaccharidosis are difficult to confirm in human patients, since taking bone biopsies in growing skeletal tissues in pediatric patients is not advisable. Therefore it is necessary to find experimental systems based on human cells that reproduce the different phases of cartilage formation. Hence the desire for the joint group of various research institutes to develop an “organoid” (human cellular model, which simulates real tissue) in the laboratory, starting from patients’ skeletal stem cells, to replicate their characteristics. “These cells generated cartilage which then transformed into bone tissue and bone marrow in the three-dimensional model. It was observed that the organoid showed important alterations compared to healthy subjects. It is indeed essential to develop models to study rare diseases given the difficulty of obtaining and, therefore, analyzing tissue samples, particularly from pediatric patients”, they explain Marta SerafiniTettamanti Foundation of the IRCCS San Gerardo dei Tintori of Monza e Mara RiminucciDepartment of Molecular Medicine, Sapienza University of Rome, both authors of the work.
The process of bone formation, in non-pathological conditions, involves an intermediate passage of cartilage (process called endochondral ossification). Thanks to the bone cell model of the rare disease, researchers were able to observe the different phases of cell aggregation and cartilage differentiation. In particular, in the last stages of maturation, structural changes appeared that compromised the ability of the cartilage to complete its maturation and remodel itself into bone and bone marrow. Hence the first demonstration that mutations in the Idua gene negatively influence cartilage plasticity and other critical phases of ossification processes. “The research – conclude the authors – represents an important first step to deepen the study of this pathology, evaluate new therapeutic strategies, and in perspective, other rare genetic diseases with skeletal involvement”.