Conditioning

Conditioning is the chemotherapy given before the edited cells go back in. It is the hardest part of the treatment, and it is where the lasting consequences come from.

It is worth being clear about that. Almost everything people find difficult about gene therapy, feeling ill, the infection risk, the long hospital stay, the loss of fertility, comes from this stage rather than from the gene editing.

Why it is necessary

Your bone marrow is already full of the stem cells you were born with, the ones making the faulty haemoglobin. If the edited cells were simply added, there would be nowhere for them to go.

Conditioning clears space by wiping out the existing bone marrow, so the treated cells have somewhere to settle and take over. It is the same principle as a transplant, and it is why gene therapy is a months-long process rather than an injection.

What is given, and for how long

The chemotherapy used in this pathway is busulfan. The dose is adjusted to the individual using blood tests, and the exact regimen is set by your treating centre following national guidance rather than being fixed by the licence.

The infusion follows closely: at least 48 hours must pass after the last dose of chemotherapy, and the cells must be given within seven days of it.

If you read about conditioning for a donor transplant you may see a longer list of drugs and a longer schedule. That is a different procedure. Ask your own team what yours involves rather than reading across.

How it feels

The following describes conditioning for stem cell transplant generally, the effects are the same because the chemotherapy does the same job.

• Mucositis: painful ulcers and a sore or dry mouth, which can make eating and swallowing hard. Mouth care is started early, soft brushes, rinses, and anaesthetic gels for the worst of it.

• Nausea and vomiting, usually lasting a week or two, managed with anti-sickness drugs.

• Taste changes, which can make food unappealing for a while.

• Hair loss.

• Deep tiredness.

• Some people cannot eat enough for a period and are fed through a tube or a drip. This is expected and planned for, not a crisis.

You are given antibiotics, antifungals and antivirals alongside, because the treatment strips out your defences as well as your marrow.

Fertility: the part that cannot be undone

This chemotherapy can permanently end your ability to have children. The regulator's wording is that infertility has been observed with this kind of conditioning, and the patient leaflet says it may not be possible to become pregnant or father a child afterwards.

In the one published follow-up study of people who had gene therapy for these conditions, every one of the 17 women followed for more than a year afterwards had signs of ovarian failure.

Preserving fertility has to happen before this stage begins. Once conditioning starts, that option is gone.

Pregnancy and contraception

• A negative pregnancy test is required before conditioning, and before each earlier round of stem cell mobilisation.

• This treatment must not be given during pregnancy, because of the chemotherapy.

• Effective contraception is needed from the start of mobilisation until at least six months after the infusion.

• Breast-feeding has to stop during conditioning.

What comes next

After conditioning you have almost no immune system until the new cells engraft, which is why the hospital stay and protective isolation follow immediately. That period, and what recovery looks like, is covered in the next two stages.

Questions you might take to your team

• What exactly will my conditioning involve, and over how many days?

• What side effects should I expect, and which ones should I tell you about straight away?

• What can be done about mouth pain and sickness?

• What are my fertility options, and by when do I need to have decided?

• Will I be able to eat, and what happens if I cannot?

• What does this chemotherapy mean for my health in ten or twenty years?