A collaborative group of scientists from different academic centres in the USA and China led by James Wilson tested a possibility of success in curing a rare and dramatically severe inborn error of metabolism Ornithine Transcarbamylase deficiency (OTCD) using a combination of adeno-associated viral delivery system and the CRISPR-Cas9 genome editing tool.
OTCD is an X-linked urea cycle disorder that causes neonatal death in most affected males due to excess levels of ammonia in the blood (called hyperammonaemia) resulting in neurotoxicity. The children that survive beyond neonatal period can be treated by liver transplantation as the defect is almost completely confined to the liver. Because of the rapid growth of the liver size in the first few months of life gene therapy treatment with non-integrating vectors is unlikely to provide long-term benefits for the patients. The use of genome editing tools for correction of somatic mutations in the hepatocytes offers the potential of permanent cure for this disease.
Wilson et al. (2016), used the mouse model of OTCD carrying a mutation in the OTC gene in order to test their hypothesis. Two AAV8 delivery vectors were used to incorporate all the components of the CRISPR Cas9 genome editing system. Both vectors were injected into mice at 2 days of age. Further analysis showed this genome editing approach allowed correction of approximately 10% the OTC gene copies in the treated mouse livers. This level of gene correction was maintained long-term. Moreover, all the mice treated by the genome editing approach survived a protein challenge whilst all the untreated mice developed lethal hyperammonaemia.
Interestingly, the treatment of older mice was not as successful and the mice experienced adverse effects.
This study provides evidence for therapeutic potential of in vivo genome editing approach to treatment of single gene liver-based disorders. Further work, however, is required to improve the methods and better understand the potential risks of this exciting technique.
Yang, Y., Wang, L., et al. (2016). A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nature Biotechnology. 34(3):334-338.