Results from the first human test of a gene-editing therapy were reported by Sangamo Therapeutics, a biotech company based in Richmond, California, on 5 September at the annual meeting of the Society for the Study of Inborn Errors of Metabolism in Athens. Gene editing was carried out on four patients in an attempt to treat a genetic disorder called Hunter syndrome that often kills people in their teens. The first patient was treated in November last year and two patients of the four enrolled in the trial have started producing small amounts of a crucial enzyme.
Hunter syndrome is a rare metabolic disorder caused by a mutation in the genome that disables iduronate-2-sulfatase (IDS), an enzyme responsible for breaking down certain complex sugars called glycosaminoglycans (GAGs). A buildup of these sugars can lead to damage of the lungs, heart, and brain and sometimes developmental delays and early death.
Gene editing, allows DNA to be altered by adding, removing, or modifying genetic material at a particular location in the genome. In this case, the treatment uses a gene-editing tool called zinc finger nucleases (ZFNs), which was developed earlier than CRISPR and is not considered “true” gene editing by some since it uses enzymes to rewrite the mutation.
The gene-editing enzymes are delivered into the cells of patients using a virus. The harmless virus is used to transport DNA for the nucleases into the liver cells, along with a good copy of the IDS gene. The nucleases then snip the DNA of cells in a specific location ― within the gene encoding for the protein albumin, which controls the IDS gene ― and the cells are then able to repair the mutation using the new copy of the IDS gene. Researchers will still need to confirm that the IDS genes are being inserted in the right place. Insertion of the gene in unintended locations could potentially trigger another disease like cancer.
No serious adverse effects have been reported so far and the results seem promising. While it is still too early to determine whether the therapy is working, so far, signs suggest the treatment has reduced levels of a biochemical marker used to assess the severity of Hunter Syndrome in patients. In two of the patients treated with medium doses, a decrease in the levels of GAGs ― by 39% and 63% ― in their urine was observed. However, no changes were experienced in the other two patients treated with a lower dose.
The data is difficult to interpret because the patients continued their usual IDS-replacement therapy while also receiving the gene therapy. Moreover, whereas the decrease in GAGs suggests some IDS expression, a lack of the IDS enzyme in the blood of patients seems to contradict this result. Sangamo suggests the standard assay for IDS may not be sensitive enough to pick up on low levels but others are sceptical. Sangamo is still a long way from proving the therapy works. The uncertainty of these results was accompanied by a drop of 22% in the company’s stock price of 22% shortly following the presentation.
An additional two patients have just received a higher dose of the gene therapy. The next step for Sangamo will be to take the middle-dose patients off their enzyme replacement therapy and observe whether their GAG levels remain low.