Base Editing: Curing The Incurable!

Credit: Yousef Espanioly/Unsplash

A groundbreaking new kind of therapy has successfully treated a teenage girl’s untreatable cancer for the first time, as reported by BBC.

Base editing

For Alyssa’s leukaemia, every previous treatment had failed.

In order to create a new live medication, physicians at Great Ormond Street Hospital performed a feat of biological engineering known as “base editing.”

Alyssa is still being watched in case cancer recurs even though it is no longer evident six months later.

Alyssa, a 13-year-old Leicester resident, was identified as having T-cell acute lymphoblastic leukaemia in May of 2016.

T-cells should protect the body by identifying and eliminating dangers, but for Alyssa, they had turned dangerous and were out of control.

Her cancer spread quickly. The bone marrow transplant and subsequent chemotherapy treatments failed to remove it from her body.

Without experimental medication, the only choice would have been to simply provide Alyssa with the best level of comfort.

I would have eventually died, Alyssa said. Her mother, Kiona, recalled that she had been dreading Christmas last year at this time, “thinking this is our last with her.” Then, in January, she “just cried” all the way through her daughter’s 13th birthday.

What happened next?

What happened next would have been unthinkable just a few years ago and has been made possible by incredible advances in genetics.

The team at Great Ormond Street used a technology called base editing, which was invented only six years ago.

Bases are the language of life. The four types of base – adenine (A), cytosine (C), guanine (G) and thymine (T) – are the building blocks of our genetic code. Just as letters in the alphabet spell out words that carry meaning, the billions of bases in our DNA spell out the instruction manual for our body.

Base editing allows scientists to zoom into a precise part of the genetic code and then alter the molecular structure of just one base, converting it into another and changing the genetic instructions.

Creating new variety

The vast group of medical professionals and researchers utilised this resource to create a brand-new variety of T-cells that could track down and eliminate Alyssa’s malignant T-cells.

They began by altering healthy T-cells that were obtained from a donor.

  • The first base edit disabled the T-cell’s targeting mechanism so they would not assault Alyssa’s body
  • The second removed a chemical marking, called CD7, which is on all T-cells
  • The third edit was an invisibility cloak that prevented the cells from being killed by a chemotherapy drug

The T-cells were given instructions to search for anything in her body that had the CD7 marker so that they could all be destroyed, including the malignant ones. This was the result of the final stage of genetic alteration. Because of this, the marking must be taken out of the therapy; else, it will self-destruct.

With the second bone marrow transplant, Alyssa’s immune system, including her T cells, will be regenerated if the treatment is successful.

Mum Kiona’s reaction after the plan was presented to the family was, “You can do that?” In May of this year, Alyssa made the choice to be the first person to get the experimental therapy, which contained millions of altered cells.

“She’s the first patient to be treated with this technology,” said Prof Waseem Qasim, from UCL and Great Ormond Street.

He said this genetic manipulation was a “very fast-moving area of science” with “enormous potential” across a range of diseases.

Left vulnerable 

Alyssa was left vulnerable to infection, as the designer cells attacked both the cancerous T-cells in her body and those that protect her from disease.

After a month, Alyssa was in remission and was given a second bone-marrow transplant to regrow her immune system.

Alyssa spent 16 weeks in hospital and couldn’t see her brother, who was still going to school, in case he brought germs in.

There were worries after the three-month check-up found signs of the cancer again. But her two most recent investigations have been clear.

“You just learn to appreciate every little thing. I’m just so grateful that I’m here now,” said Alyssa.

“It’s crazy. It’s just amazing I’ve been able to have this opportunity, I’m very thankful for it and it’s going to help other children, as well, in the future.”

She’s eyeing-up Christmas, being a bridesmaid at her auntie’s wedding, getting back on her bike, going back to school and “just doing normal people stuff”.

The family hope cancer will never return but are already grateful for the time it has bought them.

“To have this extra year, this last three months when she’s been home, has been a gift in itself,” said Kiona.

Dad James said: “I find it quite hard to talk about how proud we are. When you see what she’s gone through and the vitality of life she’s brought to every situation, it’s outstanding.”

Most children with leukaemia respond to the main treatments, but it is thought that up to a dozen a year could benefit from this therapy.

Clinical trial 

Alyssa is just the first of 10 people to be given the drug as part of a clinical trial.

Dr Robert Chiesa, from the bone-marrow transplant department at Great Ormond Street Hospital, said: “It is extremely exciting. Obviously, this is a new field in medicine and it’s fascinating that we can redirect the immune system to fight cancer.”

The technology, though, only scratches the surface of what base editing could achieve.

Dr David Liu, one of the inventors of base editing at the Broad Institute, told me it was “a bit surreal” that people were being treated just six years after the technology was invented.

In Alyssa’s therapy, each of the base edits involved breaking a section of genetic code so it no longer worked. But there are more nuanced applications where instead of switching an instruction off you can fix a defective one. Sickle-cell anaemia, for example, is caused by just one base change that could be corrected.

So there are already trials of base editing underway in sickle-cell disease, as well as high cholesterol that runs in families and the blood disorder beta-thalassemia.

Dr Liu said the “therapeutic applications of base editing are just beginning” and it was “humbling to be part of this era of therapeutic human gene editing”, as science was now taking “key steps towards taking control of our genomes”.


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Source: BBC