| Autor: |
Lau, Chun Hang, Rouhani, Maral J., Maughan, Elizabeth F., Orr, Jessica C., Kolluri, Krishna K., Pearce, David R., Haughey, Elizabeth K., Sutton, Liam, Flatau, Sam, Balboa, Pablo Lopez, Bageta, Maria Laura, O’Callaghan, Christopher, Smith, Claire M., Janes, Sam M., Hewitt, Richard, Petrof, Gabriela, Martinez, Anna E., McGrath, John A., Butler, Colin R., Hynds, Robert E. |
| Zdroj: |
Molecular Therapy; May 2024, Vol. 32 Issue: 5 p1497-1509, 13p |
| Abstrakt: |
The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom’s national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitrolentiviral overexpression of LAMA3Ain EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB. |
| Databáze: |
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