FDA suspends CAR-T clinical trials based on gene editing

In order to solve these problems of CAR-T therapy, many scientists and pharmaceutical companies have begun to develop ready-made CAR-T therapy based on CRISPR gene editing (off-the-shelf CAR-T), which is expected to be achieved by transforming T cells with CRISPR gene editing technology
.
Let cell therapy transform from complex autologous transplantation therapy to allogeneic transplantation drug therapy

In this regard, Caribou Biosciences, founded by Allogene Therapeutics and Nobel Prize winner Jennifer Doudna (Jennifer Doudna), is the fastest growing
.
The two companies have gone public and have conducted related clinical trials

However, recently, a patient with lymphoma received treatment with Allogene gene-edited anti-cd19 CAR-T drug candidate alo-501a
.
All his blood cells have decreased

Because chromosomal abnormalities may lead to cancer, considering this serious potential risk, the FDA has suspended all Allogene CAR-T clinical trials
.
Affected by this news, Allogene's stock price plummeted 46%

Spread to the entire field

So far, it is not known why these cells have chromosomal abnormalities
.
Chromosomal abnormalities may occur during gene editing or rapid cell expansion

Not only the share price of Allogene has plummeted, but the share prices of Cellectis and Caribou Biosciences, which are involved in CAR-T treatment, have also plummeted
.
This potential risk also makes people worry about the future of gene editing, and the stock prices of several listed CRISPR gene editing companies have also begun to fall

Potential risks of CRISPR gene editing

CRISPR gene editing is a beautiful tool
.
However, this tool is not perfect

On April 12, 2021, the David Perlman team of Harvard Medical School and others published a paper in the journal Nature Genetics [3]
.
Through single-cell whole-genome sequencing, it was found that CRISPR-Cas9 gene editing can destroy the structure of the cell nucleus, leading to the appearance of micronuclei and chromosome bridges, and ultimately leading to chromosome fragmentation

Prior to this, many studies have discovered various potential risks that may exist in CRISPR gene editing
.

On June 12, 2018, Nature Medicine published two papers (4, 5) back to back, pointing out that CRISPR-Cas9 gene editing can activate p53-induced DNA damage, which means that normal p53 genes inhibit CRISPR-Cas9 gene editing, which is Said that successful p53 gene-edited cells may be defective, and the risk of cell canceration will increase
.
If CRISPR/Cas9 gene-edited cells are used for treatment, there will be a potential risk of cancer

On August 8, 2018, a paper in the journal Nature pointed out [6] that a large number of base deletions (in base order) often occur in fertilized eggs of CRISPR/Cas9 gene-edited mice
.

On January 28, 2019, a paper in the journal Nature Medicine pointed out [7] that the human body has a pre-existing immune response to the Cas9 protein
.
Although this is not a safety issue, it will affect the effectiveness of CRISPR gene editing
.

This paper in the journal Nature Genetics pointed out that DNA double-strand breaks introduced during the CRISPR-Cas9 gene editing process may cause chromosomes to fragment
.
This is a very destructive form of genome rearrangement that may further lead to oncogenic fusion proteins
.
Occurrence or imbalance of specific gene expression
.

But at present, all companies that develop clinical treatments in the field of CRISPR gene editing have not considered this issue
.

David Pellman pointed out that the most studied CRISPR treatment for sickle cell disease and thalassemia is to edit CD34+ hematopoietic stem cells in vitro through the CRISPR-cas9 gene and then return to the patient
.
They estimated that there were some returned blood cells
.
Millions of cells have micronuclei caused by CRISPR-Cas9, which risks chromosomal fragmentation
.

Currently, there are very few people in the world receiving CRISPR-Cas9 treatment
.
With the popularity of CRISPR therapy, the problem of serious adverse events caused by genotoxicity is likely to follow
.
Of course, these studies are not to slow down the development of CRISPR, but to make people understand and value the new potential risks of CRISPR gene editing
.

in conclusion:

The most basic requirements for gene editing in clinical applications are accuracy and safety
.

As a gene manipulation involving DNA level, gene editing will undoubtedly cause serious harm to patients with its side effects
.
Therefore, we must be cautious when applying gene editing technology to the clinic
.

In terms of accuracy, since the birth of CRISPR gene editing technology, off-target effects have been worrying
.

Off-target effects are usually caused by incorrect DNA cleavage
.
In addition to improving the accuracy of the CRISPR system's targeting, it also lost the development of DNA cleavage activity
.
DCas9 and single-base editors that do not rely on DNA double-strand breaks are also important directions
.

For safety reasons, the human body’s immunogenic response to bacterial-derived Cas9 protein, DNA damage caused by CRISPR-Cas9 activation of p53, loss of large chromosomal fragments, enrichment of p53 inactivation mutations, etc.
, are all applications of CRISPR in the human body.
Huge obstacles
.

In recent years, clinical trials of CRISPR gene editing have emerged one after another, and some clinical trials have also shown good results
.

This shows that there is no insurmountable obstacle to the application of CRISPR gene editing technology in the human body
.
What we need to do is to solve these discovered problems and strive to develop a safe and effective clinical application of human gene editing
.

Due to serious safety issues, FDA suspended CAR-T clinical trials based on gene editing

(Source: Internet, reference only)