To CRISPR or not to CRISPR

Duarte, A.J.; Amaral, Olga; Bragança, José

http://hdl.handle.net/10400.18/4754

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Authors

Duarte, A.J.

Amaral, Olga

Bragança, José

Abstract(s)

The CRISPR/Cas9 genome editing system is a most promising tool but the application of this method to Lysosomal Storage diseases (LSDs) still needs to be explored. In LSDs, enzyme replacement therapy (ERT, regular supplementation of the defective enzyme) is the most common treatment to clear the accumulated substrates in patient cells and it is effective in a few diseases. However, there are many limits to its cost-effective application. The lack of good in vitro models hinders R&D and the understanding of the human pathophysiologic mechanisms. Using CRISPR/Cas9-mediated gene editing, to either make a model and test therapeutic approaches or to correct a causal mutation and examine the potential effects on the cellular environment will likely provide important information for functional studies. Induced pluripotent stem cells (iPSCs) from patients, with several genetic diseases, including LSDs, have been successfully established. Patient-derived iPSCs present the advantage of having the patient’s genetic background with all corresponding influences on the disease’s mechanism. Therefore, these iPSCs, differentiated into the disease specific target cell types, offer an ideal model for studying pathogenic mechanisms and therapies. Gene editing using CRISPR/Cas9 in combination with iPSCs seems like a perfect match. Currently, we are generating iPSCs from human fibroblasts and intend to proceed with gene editing. However, despite the apparently simple approach, there are still problems with CRISPR. Besides the ethical problems, there are practical problems such as diminishing off-targeting. Therefore, the question is, how feasible will CRISPR/Cas9 be? No doubt it is promising and valuable but will it be safe enough?