Treatment of a new rat model of Morchio A with gene therapy

Histological analysis of sections of the growth plate (GP), which is an active bone growth area. Left panel, GP of healthy rats. The central panel, GP of Morchio A rats, shows a significant decrease in growth activity. Right panel, GP of Morchio A rats treated with gene therapy. Growth activity is restored, similar to healthy rats. Credit: UAB

A research team at the University of Barcelona (UAB) has created the first rat model to reproduce all the impaired changes experienced by patients with mucopolysaccharidosis type IVA, also known as Morchio A disease. The team has developed a gene therapy that completely corrects severe systemic changes in a rat model after a single intravenous dose of viral vector. This study opens the door to future treatments that can be given to patients diagnosed with this rare disease at a young age, thereby preventing bone malformations, osteoarthritis complications, and other life-threatening changes. increase.

Mucopolysaccharidosis type IVA, also known as Morchio A disease,teeth Rare disease Caused by a deficiency of the GALNS enzyme, which Bone Growth (Skeletal dysplasia), Rapid cartilage deterioration and cardiac and tracheal complications cause cardiorespiratory complications that can lead to premature death. The first symptoms are detected in very young children (about 2 years old), and in the most severe cases, they generally die around 20 years old.There is no current cure for this disease Treatment, Based on enzyme substitution, skeletal abnormalities cannot be corrected.

UAB researchers have created the first rat model of Morchio A disease. It perfectly reproduces the severity of the disease, as in human patients, in contrast to existing mouse models, especially skeletal dysplasia, early cartilage deterioration, heart valve and tracheal changes. Using CRISPR / Cas9 genome editing technology, the authors generated rats with mutations in the genome that cause the most frequent and severe forms of the disease in humans.

Then the researchers developed the first one Gene therapy An approach that undoes the overall excess of pathological changes in Morchio A disease in a new rat model. This gene therapy is based on the intravenous administration of a viral vector encoding the GALNS enzyme. Gene therapy mediated widespread biodistribution and ubiquitous expression of therapeutic genes, especially throughout the skeletal system. This allowed long-term production of enzymes in all suffering tissues, preventing changes in bone, cartilage, trachea, and heart.

“Gene therapy in 4-week-old Morquio A rats provides complete clinical signs of the disease, including altered bone growth, tooth malformations and fragility, articular cartilage pathology, and respiratory and cardiovascular complications. It’s back, “explains Fatima. Bosch, UAB researcher and director of research.

Currently, no gene therapy approach has been applied to treat patients with Morchio A. Developed by UAB, this new treatment results in sustained production of enzymes throughout the body, especially in the bones. Therefore, if bone formation is very active and skeletal changes are not irreversible, it can be used to treat children who are diagnosed with the disease early.

“Gene therapy developed by our team may correct the nullification of human Morchio A disease. Nevertheless, therapeutic vectors in large animals before moving treatment to the clinical stage. Research is needed to investigate the biodistribution and long-term safety of the disease. ” Bosch concludes.

Studies support gene therapy as a promising treatment for soft bone disease

For more information:
Joan Bertolin et al, Treatment of mucopolysaccharidosis type IVA skeletal and non-skeletal changes by gene therapy via AAV, Nature Communications (2021). DOI: 10.1038 / s41467-021-25697-y

Quote: Gene therapy treatment of Morquio A’s new rat model (September 10, 2021) https: // Obtained from September 10, 2021.

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