Of LAMA3 and LAMB3: A novel gene therapy for epidermolysis bullosa

The phenotype we most commonly associate with epidermolysis bullosa (EB) is generally limited to cutaneous blisters with severe fragility of the affected skin; however, a myriad of less common and more severe phenotypes also exist. Among these rare and severe EB phenotypes, airway and laryngotracheal involvement, tracheal stenosis, and tracheal obstruction are particularly devastating and typically present at a young age. 1 Fine J.D. Mellerio J.E. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J. Am. Acad. Dermatol. 2009; 61: 367-386https://doi.org/10.1016/j.jaad.2009.03.052 Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar Notably, individuals with EB and airway involvement often harbor pathogenic mutations in genes encoding components of the laminin-332 heterotrimeric protein complex (LAMA3, LAMC2, and LAMB3). 2 Kiritsi D. Has C. Bruckner-Tuderman L. Laminin 332 in junctional epidermolysis bullosa. Cell Adh. Migr. 2013; 7: 135-141https://doi.org/10.4161/cam.22418 Crossref PubMed Scopus (81) Google Scholar Leveraging this knowledge, Lau et al. have performed pioneering investigations, which are described in this issue of Molecular Therapy, into the effect of LAMA3A gene replacement on primary airway basal cell attachment in children with airway-involved EB. 3 Lau C.H. Rouhani M.J. Maughan E.F. Orr J.C. Kolluri K.K. Pearce D.R. Haughey E.K. Sutton L. Flatau S. Balboa P.L. et al. Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa. Mol. Ther. 2024; https://doi.org/10.1016/j.ymthe.2024.02.032 Abstract Full Text Full Text PDF Scopus (0) Google Scholar The authors were able to coalesce a cohort of 16 children with this rare EB subtype, identify pathogenic LAMA3 mutations in 10 of them, generate primary airway epithelial cell cultures from four of them, and investigate the efficacy of lentiviral-mediated LAMA3A gene replacement in these primary cell cultures. 3 Lau C.H. Rouhani M.J. Maughan E.F. Orr J.C. Kolluri K.K. Pearce D.R. Haughey E.K. Sutton L. Flatau S. Balboa P.L. et al. Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa. Mol. Ther. 2024; https://doi.org/10.1016/j.ymthe.2024.02.032 Abstract Full Text Full Text PDF Scopus (0) Google Scholar Restoration of LAMA3 gene and protein expression in vitro in these patients' primary epithelial cells restored a profound cell adhesion defect, offering a glimmer of hope that future gene therapy interventions may be a viable option for children grappling with poor prognoses and limited therapeutic alternatives.