Severe generalized junctional epidermolysis bullosa (JEB) is a lethal skin disease that is caused by loss-of-function mutations in genes that encode for the protein laminin-332 (LAMA3, LAMB3, and LAMC2). Retroviral gene therapy and induced pluripotent stem cell therapy have been proposed to treat lethal diseases such as JEB. Nonetheless, these therapies have not been widely accepted due to the fact they are both viral-based and have potential toxicities. Bone marrow transplantation (BMT) is an alternative therapy that has proved effective in another variant of EB called recessive dystrophic epidermolysis bullosa (RDEB). Clinical trials have started with JEB patients, but the results are not as promising as for RDEB patients. BMT cross-corrected the genetic deficiency in JEB patients with the LAMA3 mutation but not in patients with the LAMB3 mutation. We hypothesized that this is due to unwarranted cleavage of the β3 chain by upregulated pro-migratory enzymes such as matrix metalloproteinases (MMPs). To study this, we used fibroblasts from healthy (control), LAMA3 deficient, and LAMB3 deficient patients and extracted RNA to determine changes in gene expression of candidate MMPs via real-time qPCR. Our data shows a tendency in downregulation of our candidate MMPs in the LAMB3 deficient patient and upregulation in the LAMA3 deficient, except for MT4-MMP. BMT outcomes could be potentially subject to this difference in gene expression between the two variants of JEB. Our study clearly shows that the basement membrane zone of the JEB patients is altered and unusual quantities of its components might be interfering with the process of laminin-332 production and retention.

Role of matrix metalloproteinases in the outcome of bone marrow transplant for junctional epidermolysis bullosa

251st National Meeting (2016)

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