First trial of gene-editing treatment for haemophilia

First trial of gene-editing treatment for haemophilia

The first attempt to edit the genes of cells inside the human body is about to take place. The technique being trialled aims to cure haemophilia B, a clotting disorder that can result in spontaneous internal bleeding.

The trial was announced in Washington DC this week at the International Summit on Human Gene Editing. Much of the meeting will focus on a revolutionary genetic engineering technique called CRISPR – specifically its application to human beings.

CRISPR can delete, add, or alter DNA in precise spots in a genome. Cheap, easy and fairly precise, it has the potential to treat numerous diseases, and has already been used in cases of leukaemia and HIV infection – although cells have been removed from the body first for their genes to be edited.
The forthcoming trial will use a DNA-cutting tool called a zinc finger nuclease, that can be injected straight into the bloodstream to do its work.

Haemophilia B is caused by a mutation on a gene that instructs the liver to produce a clotting protein called Factor IX. People with the mutation do not make enough Factor IX and have to avoid activities that may lead to cuts and physical trauma, including contact sports. Factor IX transfusions, done either regularly or intermittently, help manage the condition, but many people can have complications such as joint pain and are at an increased risk of other diseases.

Viral delivery
But now it may be possible to insert a corrected version of the mutated gene into the genome, using zinc finger nucleases created by Michael Holmes and Thomas Wechsler at Sangamo, a biopharmaceutical company in Richmond, California. They have already used a harmless virus to deliver the nucleases to the livers of mice and primates with a missing Factor IX gene.

The researchers designed the tool to insert the Factor IX gene next to a promoter for a gene coding for albumin, a major constituent of blood. A promoter is a bit like a volume knob – it regulates the activity of nearby genes. Placing the Factor IX gene nearby means the liver starts producing lots of clotting protein.

The treated mice and primates started producing regular levels of Factor IX, which caused their blood to clot as normal. The team will now trial the technique in adults with haemophilia B. “Our dream, once we do the adult trial, is to transition to paediatrics,” says Fyodor Urnov, also at Sangamo.

Keeping on target
One of the major concerns with all types of gene editing is off-target effects: the possibility that the DNA-cutting enzyme will make cuts in unwanted places. This week saw the publication of a technique for reducing off-target effects in CRISPR, developed by Feng Zhang at the Massachusetts Institute of Technology (Science, DOI: 10.1126/science.aad5227).

Matthew Porteus, a founder of biotech company CRISPR Therapeutics in Cambridge, Massachusetts, says he has “very serious concerns” about potential off-target effects in the upcoming haemophilia trial because the treatment is permanent. “Expressing [a nuclease] for years in the liver doesn’t sound to me like a good idea. Over time, any nuclease would eventually bind and cut an off-target site.”

Urnov says Sangamo’s DNA-cutting enzyme only has one off-target effect, and this is in a gene called Smchd1, which produces a protein that helps turn other genes on and off. Wechsler says they have done “a whole bunch of assays” in accordance with the US Food and Drug Administration’s wishes, to prove that their procedure meets safety requirements.

“Every scientist is worried,” says Wechsler. “If you’re not worried then you shouldn’t be a scientist. The worry drives you to make the best components possible.”

Should their approach prove effective, Urnov thinks they will be able to use it as a treatment for other conditions that involve a missing protein. Wechsler is already working on targeting lysosomal storage diseases, rare inherited conditions in which people lack enzymes for breaking down parts of a cell. Most children with these diseases die at an early age.

(Image credit: Bildhuset/plainpicture)

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