For the first time, a bone organoid, i.e. a three-dimensional replica of human cartilage and bone tissue, was created in the laboratory using skeletal stem cells from patients with Hurler syndrome, in order to study the mechanisms and test more effective treatments for this rare genetic paediatric disease that affects one in 100,000 children in Europe.These are the findings from a study by the Fondazione Tettamanti in Monza, Lombardy, and Sapienza University of Rome, published in the international scientific journal JCI Insight.

The study was co-authored by Professor Shunji Tomatsu of the University of Delaware, one of the world's leading experts on mucopolysaccharidosis, a group of rare genetic disorders to which Hurler syndrome belongs.

This condition is caused by a mutation in a gene and the resulting absence of the enzyme that in the human body is responsible for the 'disposal' of certain sugar chains, called glycosaminoglycans. The accumulation of these molecules damages all organs and tissues and in particular, the bones, which are the part of the body most resistant to the therapies currently available: enzyme replacement, which consists of administering the missing enzyme; allogeneic haematopoietic stem cell transplantation; and gene replacement, which consists of infusing the patient's own haematopoietic stem cells in which the mutated gene has been 'corrected' in the laboratory.

The organoid, which replicates some peculiar features of the bones of patients suffering from this condition, is therefore a valuable model to observe the mechanisms of the disease with even greater precision and on which to test more effective drugs.

"The organoid was created from skeletal stem cells, cells that are essential for generating bone tissue, taken from the bone marrow of young patients," says Professor Marta Serafini from IRCCS San Gerardo dei Tintori Tettamanti Foundation in Monza and Professor Mara Riminucci from the Department of Molecular Medicine, Sapienza University of Rome: - "These cells generated cartilage, which was then transformed into bone tissue and bone marrow in the three-dimensional model. It was observed, also through molecular and histological analyses, that the organoid showed significant alterations compared to healthy subjects. This research represents an important first step towards further study of this pathology and, in perspective, of other rare genetic diseases with skeletal involvement. It is indeed essential to develop models to study rare diseases given the difficulty of obtaining and, therefore, analysing tissue samples, particularly from paediatric patients".

Hurler syndrome is the most severe form of mucopolysaccharidosis type 1, a rare genetic disorder that, in turn, is part of the broader family of mucopolysaccharidosis, characterised by the absence of the enzymes required to metabolise and dispose of complex sugar molecules in cells. The accumulation of these molecules damages organs and tissues and is at the root of severe symptoms, including growth problems, skeletal deformities, and malfunctioning of internal organs and the nervous system.

Bones are particularly resistant to the therapies used today to treat Hurler syndrome and, therefore, skeletal deformities are one of the most serious symptoms of this disease. Studying its mechanisms, also by using bone organoids derived from human cells, increases the chances of understanding Hurler syndrome in greater depth and testing more effective therapies in the future.

Professor Andrea Biondi, scientific director of the IRCCS San Gerardo dei Tintori, adds: "I would like to emphasise the importance of the results within the research on rare diseases and in particular congenital metabolic diseases, which has in the new IRCCS one of its most relevant areas of research and development both from a clinical and experimental point of view".

References: 

Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells - Samantha Donsante, Alice Pievani, Biagio Palmisano, Melissa Finamore, Grazia Fazio, Alessandro Corsi, Andrea Biondi, Shunji Tomatsu, Rocco Piazza, Marta Serafini and Mara Riminucci - JCI INSIGHT 2024 DOI: 10.1172/jci.insight.173449

Further Information

Mara Riminucci
Department of Molecular Medicine
mara.riminucci@uniroma1.it