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By Roger Highfield on

Pioneering gene editing trials extended to children

After a landmark regulatory approval, gene editing is now being trialled with children, reports Roger Highfield, Science Director.

Trials are now under way of a novel gene editing therapy to treat debilitating blood disorders in children aged as young as five, after success in using the method to treat 12–35-year-olds.

Last month, the UK became the first country to approve the use of Casgevy, which uses the innovative gene-editing tool CRISPR to treat serious disease, in this case to ‘rejuvenate’ blood of these patients.

The approval by the Medicines and Healthcare products Regulatory Agency (MHRA) was hailed as “a world-first and a significant moment” by Josu de la Fuente, a consultant haematologist at Imperial College Healthcare NHS Trust and professor at Imperial College London, who leads the UK wing of the international trials of Casgevy.

The success of the trial in 12-35 year olds has paved the way for approval by regulators in the United States and it has been recommended for approval in Europe too. Now even younger patients are being given the pioneering treatment by the Imperial team.

Throughout his career, Prof de la Fuente said that he had wanted to help communities affected by the blood disorders – sickle cell disease and β-thalassemia – painful, life-long conditions that in some cases can be fatal.

The disorders are caused by errors in the genes that carry the instructions to make the protein haemoglobin, which carries oxygen in the blood.

In the case of sickle cell disease, which is particularly common in people with African or Caribbean family background, but also prevalent in Middle Eastern and South Asian backgrounds, the abnormal haemoglobin makes blood cells misshapen and sticky, causing them to clump together which can cause damage to organs and severe pain.

Meanwhile, regular blood transfusions often have to be given to patients with β-thalassaemia, which mainly affects people of Mediterranean, south Asian, southeast Asian and Middle Eastern origin.

Until now, there have been few treatments, notably bone marrow transplants but they have traditionally only worked where there have been good matches – doctors match donors to patients based on their human leukocyte antigen (HLA) tissue type, where HLA are proteins on cells that make each person’s tissue unique.

More recently, in refinements of pioneering 1960s research at St Mary’s Hospital in London, safer and more effective techniques to use bone marrow with a poor match to the recipient have been perfected in the UK, working with colleagues in America and France, said Prof de la Fuente.

Now CRISPR offers a way to correct the DNA in a patient’s own bone marrow. “If you’d asked me about a treatment like this at the start of my career, I would have said it was science fiction,” said Prof de la Fuente.

With Katie Dabin, Curator of Medicine, I spoke to Professor de la Fuente, about the human gene editing trials.

Professor Josu de la Fuente

How does CRISPR work?

Scientists have been genetically modifying a range of creatures for decades, notably by the use of viruses, which multiply in the body by pirating the genetic machinery of cells to turn them into virus factories. The virus takes over a host cell by inserting its genetic instructions, which come in the form of the long chain-like molecules RNA or DNA, and can be adapted to insert other genetic instructions. Previous efforts to develop a lifelong treatment for blood disorders have, for example, used an HIV-like virus to introduce correct DNA.

Today, a more precise way to manipulate DNA comes from CRISPR, which stands for Clustered regularly interspaced short palindromic repeats, which evolved in nature to help bacteria to fend off viruses.

CRISPR’s inventors Profs Emmanuelle Charpentier and Jennifer Doudna shared the Nobel Prize in Chemistry in 2020 for their work on turning this bacterial defence into a useful tool.

Likened to ‘genetic scissors’, CRISPR has two parts: an RNA molecule that guides the second part, a Cas9 enzyme, to the correct region of DNA, which the enzyme cuts – enabling precision editing of the genetic code.

On hearing the recent news, Prof Doudna commented on X: “I am excited and a bit overwhelmed with emotion at the news of the approval of CASGEVY in the UK. Going from the lab to an approved #CRISPR therapy in just 11 years is a truly remarkable achievement.

I am especially pleased that the first #CRISPR therapy helps patients with sickle cell disease, a disease that has long been neglected by the medical establishment. This is a win for medicine and for health equity.”

How is CRISPR used to treat blood disorders?

The Casgevy therapy developed by Vertex Pharmaceuticals in Boston, Massachusetts, and CRISPR Therapeutics in Zug, Switzerland, uses CRISPR to target a gene called BCL11A, which usually prevents the production of a form of haemoglobin that is made only in foetuses.

Using CRISPR to disable this ‘gene brake’, Casgevy restores the production in the patient’s body of foetal haemoglobin, which does not carry the same abnormalities as adult haemoglobin in people with sickle-cell disease or β-thalassaemia.

Reactivating the production of foetal blood, which has higher affinity for oxygen, sounds like it might have unexpected consequences but Prof de la Fuente said that some people naturally make high levels of foetal haemoglobin with no ill effects.

Casgevy is not an ordinary therapy or drug, however, and demands many steps, beginning with collecting blood producing stem cells from the patient, which are mobilised with special medication onto the blood stream, then sending them to Vertex to be engineered, using CRISPR–Cas9 to edit their genes in the laboratory.

Meanwhile the patient has chemotherapy to wipe out their own bone marrow producing stem cells – meaning patients spend 6-8 weeks in isolation to avoid infection – before the gene edited, ‘corrected’, stem cells “are able to produce new, effective, blood cells,” said Prof de La Fuente.

Once given back to the patient, after their bone marrow has been primed to receive the CRISPR modified cells, the stem cells give rise to corrected red cells in which foetal haemoglobin constitutes around half of the patient’s haemoglobin in sickle cell disease and virtually all of it in the case of thalassaemia. Overall, it takes further three to six months for full recovery.

Red blood cells and DNA strands

How well does gene editing work?

Before approval, one trial for sickle-cell disease followed 29 out of 45 participants long enough to draw interim results and, remarkably, Casgevy relieved 28 of those people of debilitating episodes of pain for at least one year.

In a trial on a severe form of β-thalassaemia, 54 people received Casgevy, of which 42 participated for long enough to provide interim results. Among those 42, 39 did not need a red-blood-cell transfusion for at least one year. The remaining three had their need for blood transfusions reduced by more than 70%.

Participants involved in the ongoing trials did report side effects – including nausea, fatigue, fever and an increased risk of infection – however no notable safety concerns were identified.

Now the trial of Casgevy is now being extended to children aged 5-12 to understand its safety and efficacy. Eventually, it will be offered to even younger children.

Trials of cancer therapies using CRISPR are also under way, for instance to treat leukaemia in children and they hope that success will pave the way for further applications of CRISPR therapies in the future for the potential treatment, even cure, of many genetic diseases.

What are the hurdles?

Recruiting patients to these trials was initially challenging because it was an experimental therapy – Prof de la Fuente said the first participants are “brave people.” However, now that data show how effective the therapy is, patients have more confidence to participate in trials, he said.

At around $2 million per treatment, another hurdle is showing whether Casgevy is sufficiently cost effective to justify being made available on the NHS. NICE, the National Institute for Health and Care Excellence, will rule on this in the spring.

Another concern is that CRISPR–Cas9 can sometimes make unintended genetic modifications with unknown side effects. In these so called off-target effects, Cas9 sometimes slices DNA at regions in the genetic code that are similar to its target sequence and in theory these unwanted mutations could cause cancer or other disorders.

They had done studies to investigate this effect in animals where they got reassurance that the guide RNA in CRISPR does tend to ensure the editing is precise, said Prof de la Fuente.

What next for these treatments?

Waiting in the wings are more precise ways to remove the patient’s bone marrow without the use of chemotherapy, which causes infertility and other side effects.

Another development will come in the form of ‘second generation’ gene editing, for instance ‘base editing’, where one letter of DNA genetic code at a time can be altered, as is being developed by James Davies in Oxford, who collaborates with the Imperial team, among others.

Yet another approach is the development of gene edited stem cells – so called iPS cells – that are capable of making normal haemoglobin and that have been adapted so they match a wide range of patients.

In the long term, Prof de la Fuente said, he hoped gene editing could be delivered as an injection rather than require the expense of bone marrow cells being nurtured for months in the laboratory.