The CRISPR genome editing revolution continues to advance at an astounding pace. As many as 20 human trials will be under way soon, mostly in China, New Scientist has learned.

One of these trials will involve the first-ever attempt to edit cells while they are inside the body. The aim is to prevent cervical cancers by using CRISPR to target and destroy the genes of the human papillomavirus (HPV) that cause tumour growth. This study is due to begin in July at the First Affiliated Hospital of Sun Yat-Sen University in China.

Gene therapy, which involves adding extra genes to cells, was first used to cure people in 1990, but it is mainly useful for treating rare genetic disorders. In contrast, gene-editing, which involves altering existing genes inside cells, promises to treat or cure a much wider range of conditions, from HIV infection to high blood cholesterol.

“One of these trials will involve the first-ever attempt to edit cells inside the body”
The first gene-editing trial in humans started in 2009. Doctors removed immune cells from people with HIV, disabled the gene for the CCR5 receptor – which the virus uses to get into cells – and returned the HIV-resistant cells to the body. The treatment appears to keep HIV in check.

Flurry of trials

But subsequent progress in gene editing was slow because developing a way to target each particular sequence is costly and time consuming. All that changed in 2012 when CRISPR genome editing was developed, making it cheap and easy to target almost any sequence.

The first clinical trial involving CRISPR began at the West China Hospital in Chengdu in October 2016. Doctors removed immune cells from the blood of a person with lung cancer, used CRISPR to disable a gene called PD-1 and then returned the cells to the body.

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PD-1 codes for an immune cell “off” switch. Tumours can flip this switch to prevent immune cells attacking – so if immune cells lack the PD-1 switch then cancer cells cannot manipulate them. However, there is a risk that the “always on” immune cells could begin attacking healthy cells.

The lung cancer trial isn’t due to finish until 2018, but other teams are forging ahead. Clinical trial registries show that a dozen more trials that will disable PD-1 with CRISPR are planned in China. These target conditions including breast, prostate, bladder, oesophageal, kidney, colorectal and Epstein-Barr virus-associated cancers.

Breaking new ground

The HPV trial, meanwhile, will break new ground. Instead of editing cells outside the body, a gel containing DNA coding for the CRISPR machinery will be applied to the cervix. The CRISPR machinery should leave the DNA of normal cells untouched, but in cells infected by HPV, it should destroy the viral genes, preventing them from turning cancerous.

“Targeting HPVs seems a sensible approach if they can deliver the genome-editing components to sufficient numbers of cells,” says Robin Lovell-Badge of the Crick Institute in the UK.

“It is tricky to do these experiments in animals as they are not infectable by HPV,” says Bryan Cullen of Duke University Medical Center in North Carolina, whose group also hopes to use gene editing to get rid of HPV. But there is a risk of off-target mutations leading to cancer, he warns.

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If these trials are successful, it could benefit millions of people. Vaccination against HPV is now possible, but there is no way to get rid of the virus in people who have it already. It can cause mouth, throat and anal cancers in both sexes, as well as being the main cause of cervical cancer.

A further four planned trials involve changing immune cells to make them better at killing cancers. First, a virus will be used to add a gene to immune cells that makes them attack specific tumours – creating so-called CAR-T cells. Then two or more genes – usually including PD-1 – will be disabled with CRISPR to make the cells even more effective.

Such UCART19 cells have already saved the lives of two girls, but these cells were created with an older gene-editing method. Now a clinical trial is due to start in the UK. “Our lab is moving over to CRISPR,” team leader Waseem Qasim of University College London told a meeting in February.

Two similar UCART19 trials are planned in China, with another in the US. Trials are also planned for Duchenne muscular dystrophy, says Lovell-Badge, but these are probably some way from starting.