Over the past couple of years, base editing, a recent offshoot of the heralded CRISPR/Cas 9 technology, has been doing its rounds in the biotech space. Now, base editing has finally set foot into clinical trials for the first time in the U.S..
American precision medicine company Beam Therapeutics treated its first patient with its investigational CAR-T cell therapy that had four base-edited genes, as part of its phase 1/2 clinical trial. The drug is designed to treat aggressive blood cancers like relapsed/refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
How is base editing different from CRISPR?
Base editing is the mechanism employed to make single-nucleotide changes to a DNA sequence. In a bid to target single point mutations – as these can lead to inherited diseases that are usually caused by a single base pair error in the DNA – changes to the genetic code are made. This is performed with the help of a CRISPR/Cas 9 protein which is bound to a guide RNA, and a base editing enzyme called deaminase which carries out the specific edit in the DNA.
But, unlike CRISPR technology, base editing is regarded to be a safer gene editing method. This is because, in the case of base editing, only one strand of DNA is cut. Whereas, in contrast, CRISPR, relies on the Cas 9 enzyme to cut both strands of the DNA at the site, which can lead to accidental insertions and deletions of bases, and therefore, errors in the sequence. As base editors work to alter a particular nucleotide without chopping both strands, the process aims to eliminate errors.
“The main benefits of base editing technologies are that you avoid the potential safety complications associated with the introduction of a dsDNA (double-stranded DNA) break, and you can achieve single base correction without the need for an exogenous DNA repair template,” said Chris Vakulskas, senior director of Enzyme Development at Integrated DNA Technologies in the U.S..
That’s not to say that base editing is an error-free technique, as it can make edits outside the target region, at times. A study had found that base editing can still lead to double-stranded DNA breaks, although infrequent. Moreover, other random changes in the DNA sequence have also been detected, which raises concerns about genotoxicity – DNA damage – and warrants further research. However, as the technology evolves, scientists aim to come up with ways to have more control over the edits, and in turn, limit cell death caused by DNA damage.
Beam Therapeutics becomes frontrunner in U.S. base editing space with clinical trial debut
Making its debut in clinical trials in the U.S. is Beam Therapeutics’ BEAM-201, which is a base-edited, anti-CD7 allogeneic chimeric antigen receptor T cell (CAR-T) therapy. The four base edits have been designed to silence the expression of four genes, namely, CD7, TRAC, PDCD1 and CD52.
Through base editing, donor-derived CAR-T cells are able to tackle graft-versus-host disease, which is a disorder that occurs because of host rejection of the cells, as the cells are perceived as foreign by the patient’s immune system.
“We believe that the full therapeutic potential of CAR-T therapies, including the ability to utilize an allogeneic source of T cells, will only be unlocked through higher levels of cellular engineering enabled by multiple simultaneous genetic edits,” said John Evans, chief executive officer (CEO) of Beam Therapeutics. “Base editing is especially well-suited to this challenge, as it is designed to deliver highly efficient multiplex edits in cells without the double stranded breaks that can lead to frequent chromosomal rearrangements and loss of cell viability.”
Evolution of base editing: from inception to clinical trial entrance
While the technology is only making its clinical trial entrance in the U.S. now, base editing had its world premiere last year, when doctors at the Great Ormond Street Hospital in London in the U.K,. cured a teen’s acute leukemia.
It was when all other treatments had failed – including chemotherapy and a bone marrow transplant – that the doctors turned to T cell therapy – but with a twist. The DNA in the T cells were modified with the help of base editing, carrying out three edits. One was to disable the mechanism that targets T cells, so that the donor cells aren’t attacked when they are injected into the patient. Another was to silence the CD7 gene to protect the donor T cells, and the third was an edit that offered resistance against chemotherapy, so that the modified cells aren’t killed during treatment.
Although the therapy was deemed a success in being able to heroically thwart cancer in two children – both currently in remission – in a third child, it resulted in complications that led to his death. When the child had developed a fungal infection while he was undergoing CAR-T therapy, immunosuppression prevented his body from being able to fight the infection, and he eventually succumbed to it.
Now, more researchers are looking into how base editing can be made safer. Verve Therapeutics, based in the bustling biotech hub of Cambridge, Massachusetts in the U.S., has collaborated with Beam Therapeutics to develop three treatments that target familial hypercholesterolemia. The genetic disorder occurs due to high levels of ‘bad cholesterol’ clogging the arteries, putting patients at a higher risk of heart attacks. The most advanced in its pipeline is VERVE-101, which is currently in phase 1b trials. This candidate has been created to edit the base adenine to guanine at a specific site in the PCSK9 gene, thereby switching off the gene. This mechanism has been associated with lowering the amounts of bad cholesterol in the blood.
If successful in battling hypercholesterolemia, Verve looks to expand treatment for all those who are at risk for atherosclerotic cardiovascular disease (ASCVD).
But that’s not all that’s been going on in this fast-growing field this year. Base editing has shown that it could beat sickle cell anemia, an inherited blood disorder that is caused by a mutation in the hemoglobin-Beta gene found on chromosome 11. Researchers at St. Jude Children’s Research Hospital in the U.S., showed that by expressing the gamma-globin gene – which is turned off around the time of birth – gamma-globin can effectively replace hemoglobin in the blood. Having figured out how to restore the gene expression of fetal hemoglobin in preclinical studies, the scientists hope to move it to the clinic soon.
However, as the industry continues to see a rise in editing tools, which in turn magnifies options for research, according to Brandi Cantarel, vice president of Bioinformatics at U.S.-based Form Bio, this further complicates the job of scientists trying to navigate personalized medicine.
Does AI have a role to play?
Cantarel explained that if a person has genetic conditions and alterations in their genome that are either acquired or inherited, determining the right editing strategy becomes nearly impossible without the help of tools like artificial intelligence (AI).
“As more editing tools become available, we anticipate a parallel race emerge to develop tools that assist scientists with understanding the best method for editing, given the type of edit, target sites and enzymes available. All of this, while ensuring maximum efficiency,” said Cantarel, who believes that “AI is set to transform the landscape.”
Earlier this year, a study highlighted how AI helped discover hundreds of proteins similar to deaminase, possibly offering a broader range of base editing enzymes to potentially work with. So, like Cantarel suggested, AI could maybe even assist in the process of picking the best-suited therapy for patients, in the future.
As the number of cases of rare, genetic disorders are rising, including for diseases like cystic fibrosis, Duchenne muscular dystrophy and Friedreich’s ataxia, Vakulskas said: “…It is now more important than ever to keep seeking innovative new technologies like base editing. These powerful new techniques prove that we can continue to iterate and improve as we drive toward personalized medicines that are safer, accessible, and more rapidly taken to the clinic.”