The first rat model recapitulates all the disabling alterations suffered by patients with Morquio A disease
A research team from the Universitat Autònoma de Barcelona (UAB) generated the first rat model recapitulating all the debilitating alterations experienced by patients with mucopolysaccharidosis type IVA, also known as Morquio A disease. team developed gene therapy that completely corrects severe whole-body alterations in the rat model after a single intravenous viral vector administration. The research opens the door to a future therapy that could be administered at a young age in patients diagnosed with this rare disease, thereby preventing bone deformities, osteoarthritis complications and other life-threatening alterations.
Mucopolysaccharidosis type IVA, also known as Morquio A disease, is a rare disease caused by a deficiency of the GALNS enzyme, which causes alterations in bone growth (skeletal dysplasia), rapid deterioration of cartilage, and complications in the heart and trachea that lead to cardiorespiratory complications that can lead to premature death. The first symptoms are detected in very young children (around 2 years old), and in the most severe cases, death usually occurs around the age of 20. There is no cure for this disease and current therapy, based on enzyme replacement, cannot correct skeletal abnormalities.
UAB researchers generated the first rat model of Morquio A disease that fully mimics the severity of the disease, unlike existing mouse models, especially skeletal dysplasia, early cartilage deterioration and valve alterations. heart and trachea, in the same way as human patients. Using CRISPR / Cas9 genome editing technology, the authors generated a rat with a mutation in the genome that causes the most common and severe form of the disease in humans.
Subsequently, the researchers developed the first gene therapy approach that reversed the entire plethora of pathological alterations in Morquio A disease in the new rat model. This gene therapy is based on the intravenous administration of a viral vector encoding the GALNS enzyme. Gene therapy induced widespread biodistribution and ubiquitous expression of the therapeutic gene, particularly throughout the skeletal system. This allowed the long-term production of the enzyme in all affected tissues, thus preventing damage to the bones, as well as to the cartilage, trachea and heart.
Administration of gene therapy to four week old Morquio A rats completely reversed the clinical signs of the disease, such as alterations in bone growth, dental deformities and brittleness, pathology of joint cartilage, as well as respiratory and cardiovascular complications. “
Fatima Bosch, UAB researcher and study director
Currently, no gene therapy approach is applied to treat Morquio A patients. This new therapy developed at UAB results in sustained production of the enzyme throughout the body and in particular in the bones. Therefore, it could be used to treat children diagnosed with the disease at an early age, when bone formation is very active and the skeletal changes are not irreversible.
“The gene therapy developed by our team has the potential to correct the crippling Morquio A disease in humans. Nevertheless, studies examining the biodistribution and the long-term safety of the therapeutic vector in large animals are needed before moving the treatment to the clinical phase, ”Dr. Bosch concludes.
The study, published September 9 in Nature Communications, was coordinated by UAB researcher Fàtima Bosch, who is also director of the Center for Animal Biotechnology and Gene Therapy (CBATEG) at UAB. The work was carried out by researchers from CBATEG and from the Departments of Biochemistry and Molecular Biology, Animal Health and Anatomy, UAB School of Veterinary Medicine; the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM); and the Molecular Imaging Unit of the Spanish National Cancer Research Center (CNIO).
Universitat Autònoma de Barcelona