Gene Therapy Is Facing Its Biggest Challenge Yet: Nature

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Heidi Ledford, Gene Therapy Is Facing Its Biggest Challenge Yet; After finally gaining traction as a potential treatment for certain genetic disorders, gene therapy tackles the challenge of sickle-cell disease. Nature 576, 22-25 (Dec 4, 2019' in the News Feature section).
https://www.nature.com/articles/d41586-019-03698-8

Quote:

(a) "some felt that it was premature to apply gene therapy to sickle-cell disease, says haematologist David Williams at Boston Children's Hospital in Massachusetts. 'Sickle cell is not an immediately lethal disease,' he says. 'In some ways, it wouldn't be ethical to treat those patients with a highly risky experimental approach.'

"Furthermore, the tools were not yet up to the task, says Donald Kohn, a specialist in paediatric [British spelling] bone-marrow transplants at the University of California, Los Angeles. If researchers were to shuttle in a normal haemoglobin gene, it would need to be able to crank out large amounts of protein to sufficiently mute the effects of the sickled version. Early gene-therapy technologies were not able to express genes in human cells at such high levels, says Kohn.

"But despite the setbacks, some gene-therapy researchers pushed on, developing safer and more potent ways to shuttle genes into cells. They broke through in 2016, when the European Commission approved a gene therapy for treating ADA-SCID, a rare immune disorder that often kills children before their first birthday. Then in 2017, the US Food and Drug Administration approved a gene therapy to treat a rare form of blindness.

(b) "Before the cells are replaced, participants are typically treated with a chemotherapy called busulfan to destroy the remaining diseased stem cells and help the reintroduced, genetically altered cells to take over.

"That kind of regimen is risky: participants can develop acute and severe anaemia [British spelling]. The treatment wipes out their white blood cells, and wreaks havoc on the lining of the gut, potentially leaving them dependent on intravenous nutrition. Many will need to stay in the hospital for more than a month. The chemotherapy also causes infertility, and can cause cancer later in life.

"This means that gene therapy would probably be used only in those with the most serious forms of sickle-cell disease. Yet many of those people will also have heart, kidney or liver damage [because sickle cells block blood flow to these vital organ also] that would make the chemotherapy too dangerous.

(d) "For [Grajevis] Bakatunkanda [born in Democratic Republic of Congo but emigrated to South America], his salvation turned out to be ageing, not medicine. Some people with sickle-cell disease fare worse as children than as adults, he says, and he thinks he is one of them. He still has crises, but not nearly as often.