Editors' ChoiceGene Therapy

Smart CRISPR-Cas9 liver delivery repairs a genetic defect

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Science Translational Medicine  02 Mar 2016:
Vol. 8, Issue 328, pp. 328ec34
DOI: 10.1126/scitranslmed.aaf3854

Babies born deficient in the enzyme ornithine transcarbamylase (OTC) quickly experience lethal metabolic crises. In this common urea-cycle disorder, carbamoyl phosphate and ornithine cannot be converted into citrulline, a key intermediate in the urea cycle through which mammals excrete toxic ammonia. Gene addition therapy with nonintegrating vectors has proven unsuccessful; delivery of the healthy OTC gene into young liver cells resulted in little therapeutic benefit. Now, Yang et al. solve this problem by correcting the defective gene with CRISPR-Cas9 in young mice with a partial OTC deficiency. In newborn mice, this method fixed the mutation in a sufficient number of hepatocytes, which then proliferated to maintain therapeutic OTC enzyme levels through adulthood. The authors used two adeno-associated viruses (AAVs): one to express Cas9 and the other to bring in the guide RNA and the donor DNA. This dual system reversed the OTC mutation in about one-tenth of the hepatocytes, increasing survival in mice challenged with a high-protein diet that normally exacerbates the disease. The same type of gene correction performed later, in adults, was less effective and caused undesirable side effects—diminished protein tolerance and lethal excess ammonia. This study highlights key challenges in successfully correcting genes in vivo with CRISPR-Cas9 and also reveals therapeutic possibilities for lethal metabolic diseases that require treatment of newborn babies.

Y. Yang et al., A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 10.1038/nbt.3469 (2016). [Abstract]

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