Scientists plan first human gene-editing trial next month

•Cancer patients to have immune cells changed with controversial technique
•Gene controlling coughing, wheezing, shortness of breath can be turned off to stop asthma

Scientists have achieved two major breakthroughs with the plan to conduct the first-ever human gene-editing trial next month to treat cancer and to stop asthma by turning off the gene controlling coughing, wheezing and shortness of breath.

According to a study published in the journal Nature but first reported in DailyMailUK Online, the world’s first clinical trial that will inject humans with genetically modified cells created with a ground-breaking Deoxy ribonucleic Acid (DNA)-editing technology is set to start next month.

Oncologists at Sichuan University’s West China Hospital in Chengdu have been given approval to begin the tests with cells modified using the CRISPR-Cas9 gene-editing technique.

It is hoped it might provide a new treatment against cancer for patients who have not responded to chemotherapy or radiation therapy.The researchers will extract immune cells known as T cells from the blood of the patients taking part in the trail and use CRISPR-Cas9 to knock out a gene in the cells.

This will disable a regulatory mechanism in the immune cells that prevents them from normally attacking other cells in the body.The researchers will extract T cells from the blood of patients taking part in the trail.

A gene coding for a protein called PD-9 will be knocked out in the cells using CRISPR-Cas9.The technique uses tags and an enzyme to cut DNA in a precise place, allowing small portions of a gene to be removed. This turns off the gene for PD-9, which will mean the T cells will loose some of the regulation that stops them from attacking cells belonging to the human body.

These edited cells will be multiplied before being injected back into the patient.Researchers hope they will then home in on the cancer and destroy it. However, there are concerns the cells could become overactive and mount an immune response against healthy tissue too.

The scientists hope that when these edited cells are reintroduced back into the patient’s bloodstream they will home in on the cancer and destroy it.Also, scientists have discovered a revolutionary approach which could lead to new ways of treating asthma.

Current methods of preventing attacks involve dealing with the main symptom – inflammation of the airways – which makes it difficult to breathe. But the treatments don’t stop asthma from developing in the first place.

Researchers at the University of Southampton believe by targeting a gene called ADAM33, they can prevent the disease. Some 300 million people worldwide suffer from asthma – which can be deadly in severe cases. Currently, most sufferers are treated using two inhalers. A blue ‘reliever’ is used to relax tightened airways while a brown ‘preventer’ contains steroids which relieves inflammation in the lungs. The researchers, writing in The Journal of Clinical Investigation, found the gene ADAM33 makes an enzyme, which is attached to cells in the airway muscles.

In people with a variant of the gene, the enzyme detaches from the cell surface and travels around the lungs.This then creates more muscle tissue and blood vessels around the airways, which causes breathing difficulties.But Hans Michel Haitchi, associate professor in respiratory medicine at Southampton, United Kingdom (U.K.) found switching the gene off stopped symptoms of asthma in mice.

He told the Daily Mail UK: “Current treatments do not treat the remodelling process in the lungs – the increase in muscle and blood vessels in the lung.“In future by blocking ADAM33 or preventing it from going rogue, the features of asthma – airway remodelling (more muscle and blood vessels around the airways), twitchiness and inflammation – will be reduced.”

He also said the finding dramatically changes their understanding of asthma. Haitchi added: “For years we have thought airway remodelling is the result of the inflammation caused by an allergic reaction, but our research tells us otherwise.”

In studies, they found a rogue ADAM33 gene caused airway remodelling, but it did not cause inflammation.But when scientists used a house dust mite allergen – a common trigger of asthma attacks – they found it led to more muscle and blood vessels in the lungs, and inflammation.This challenges the existing view that allergic inflammation leads to asthma in the first place.

Meanwhile, the first human trials of CRISPR-Cas9 gene-editing technique comes as several groups in the United States (U.S.) have also been given approval to carry out gene-editing trails in humans.Last month the US National Institutes of Health gave approval for a project that will use a similar approach in a trial involving 18 patients with several different types of cancer.

However, this trial also requires approval from the US Food and Drug Administration (FDA) before it can go ahead.In the Chinese trial, the trail will focus on patients who have metastatic non-small cell lung cancer where other treatments have failed.Lu You, an oncologist at Sichuan University who is leading the study, told the journal Nature: “Treatment options are very limited. This technique is of great promise in bringing benefits to patients, especially the cancer patients whom we treat every day.”

CRISPR-Cas9 is based on a gene-editing technique used by bacteria to help them remove sections of DNA introduced by viruses that infect bacteria, known as phages.Small chemical tags are used to get an enzyme to cut DNA in a precise place and ‘snip out’ a small piece of DNA.This can be used to turn off specific genes in an extremely precise manner that has not been available using previously less accurate gene editing techniques.

However, scientists now need to prove the technique can be used safely in patients before it can be used more widely and these initial tests will aim to show it does not harm those being treated.Future trials will then have to assess how effective the technique is compared to other types of treatment.

In the Chinese trial the researchers will use CRISPR-Cas9 to target a gene that produces a protein called PD-1 in T cells.This protein usually helps to regulate the T cell’s ability to launch an immune response and prevents it from attacking healthy cells belonging to the body.

By knocking out this gene with great accuracy, the researchers believe it will be possible to increase the immune response against cancerous cells, which are often overlooked by the immune system as they are made of the same cellular material as the rest of the body.

Previous trials have attempted to block PD-1 using antibodies but it is hoped silencing the gene that produces it will be more effective.Timothy Chan, an immunotherapy expert at Memorial Sloan Kettering Cancer Centre in New York, who is not involved in the trial, said the gene editing technique promised to be a more powerful way of targeting cancer than with the approach using antibodies.

The trial is being conducted with Chinese biotechnology company Chengdu MedGenCell.China has been pushing ahead with gene editing technology and is leading the world in using CRISPR techniques after being the first to use it to edit human embryos and in monkeys.

However, it has raised some fears that they may be moving faster than is perhaps safe.Chan said there was a chance the CRISPR-Cas9 editing of T cells could induce an excessive immune response that could lead to them attacking healthy tissues in the patient’s body.He told Nature: “That will be a concern.”