The future of gene editing has been questioned. Due to serious safety issues, the FDA has suspended CAR-T clinical trials based on gene editing!

Since its birth in 2012 , the CRISPR gene editing technology transformed from the defense system of bacteria / archaea has attracted the attention of scientists all over the world.
With the help of CRISPR technology, people can quickly and accurately manipulate genes and change lives .
Get rid of hereditary diseases, conquer cancer .
.
.
These once-out-of-reach dreams have since become within reach .

Since its birth in 2012 , the CRISPR gene editing technology transformed from the defense system of bacteria / archaea has attracted the attention of scientists all over the world.

With the help of CRISPR technology, people can quickly and accurately manipulate genes and change lives .
Get rid of hereditary diseases, conquer cancer with precision .

In October 2020 , CRISPR gene editing ushered in a bright moment, and this technology was affirmed by the Nobel Prize only 8 years after its
birth .

Since then, CRISPR gene editing has made a series of milestones in clinical treatment, especially in June 2021 , the New England Journal of Medicine NEJM published the world's first clinical trial results of CRISPR gene editing therapy in individuals [ 1 ] .
Nobel Laureate Jennifer · Dude Na ( Jennifer Doudna ) foundedIntellia Therapeuticsdeveloped to treat transthyretin amyloidosis ( ATTR ) of CRISPR gene therapy editor at 6 safe and effective in clinical trials in patients .
This also allows the world to see the powerful power and prospects of CRISPR gene editing technology in the treatment of genetic diseases .

In October 2020 , CRISPR gene editing ushered in a bright moment, and this technology was affirmed by the Nobel Prize only 8 years after its

As CRISPR technology has passed all the way in the field of genetic diseases, more and more scientists and pharmaceutical companies have begun to explore the application of CRISPR in the field of cancer treatment

As early as 2016 Nian 6 months, Professor Lu uranium West China Hospital of Sichuan University to begin CRISPR gene editing T treatment of cancer cells 1 clinical trial in 2016 Nian 10 Yue 28 days to complete the world's first gene-edited cells in human injection

We all know that CAR-T CAR-T cell therapy is a powerful tool for cancer treatment and has shown impressive and powerful effects in a variety of blood cancers

In order to solve CAR-T these issues therapies, many scientists and pharmaceutical companies began developing based CRISPR spot gene editing CAR-T therapy ( OFF at The-Shelf-CAR-T ), by CRISPR gene editing transformation T cells, is expected to achieve Let the cell therapy change from a complex therapy of autologous transplantation to a drug for allograft transplantation

In this regard,Caribou Biosciences, founded by Allogene Therapeutics  and Nobel Prize winner  Jennifer Doudna  , has developed the fastest  .

However, recently, after a lymphoma patient was treated with the gene-edited anti- CD19 CAR-T drug candidate ALLO-501A of Lymphoma  Allogene  , all his blood cell lines were reduced, and biopsy analysis found that his body had Anti- CD19 CAR-T cells with abnormal chromosomes .

Because chromosomal abnormalities may lead to cancer, considering this serious potential risk, the FDA has suspended all CAR-T clinical trials of Allogene  .

Affected by this news, Allogene  's stock price plummeted 46% .

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

Allogene shares fell 46%

Allogene shares fell 46%

Spread to the whole field

Spread the entire field Spread the entire field

So far, it is still unknown why these cells have chromosomal abnormalities.

Chromosomal abnormalities may have occurred during gene editing or rapid cell expansion

So far, it is still unknown why these cells have chromosomal abnormalities.

Not only the stock price of  Allogene  plummeted, but also the stock prices of  Cellectis and  Caribou Biosciences  , which are also engaged in  spot CAR-T therapy, 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 .

Cellectis  shares fell 24%

Cellectis  shares fell 24%

Caribou Biosciences  shares fall 15%

Caribou Biosciences  shares fall 15%

Intellia Therapeutics shares fall 10%

Intellia Therapeutics shares fall 10%

Editas Medicine shares fall 8%

Editas Medicine shares fall 8%

Potential risks of CRISPR gene editing

CRISPR potential risks of gene-editing CRISPR potential risks of gene editing

CRISPR gene editing is a beautiful tool.

However, this tool is by no means perfect.
Since its birth, CRISPR has been accompanied by off-target concerns

CRISPR gene editing is a beautiful tool.

2021 Nian 4 Yue 12 days, Harvard Medical School,  David Pellman  teams, etc.
in  Nature Genetics  published journals [ 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
.
This study shows that our understanding of the safety risks and related mechanisms of CRISPR-Cas9 gene editing technology is still lacking, and we need to be cautious in evaluating the safety of CRISPR gene editing technology
.

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

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

2018 Nian 6 Yue 12 Ri, Nature Medicine  journal published back to back two papers [ 4 , 5 ], pointed out that CRISPR-Cas9 gene editing can activate p53 -induced DNA damage, which means that the normal p53 gene inhibits the CRISPR-Cas9 gene editing , That is, the p53 gene of the successfully edited cells is likely to be defective, and the risk of cell canceration is increased.
If the cells edited by the CRISPR/Cas9 gene are used for treatment, there will be a potential carcinogenic risk
.

2018 Nian 6 Yue 12 Ri, Nature Medicine  journal published back to back two papers [ 4 , 5 ], pointed out that CRISPR-Cas9 gene editing can activate p53 -induced DNA damage, which means that the normal p53 gene inhibits the CRISPR-Cas9 gene editing , That is, the p53 gene of the successfully edited cells is likely to be defective, and the risk of cell canceration is increased.
If the cells edited by the CRISPR/Cas9 gene are used for treatment, there will be a potential carcinogenic risk
.

2018 Nian 8 Yue 8 Ri, Nature  's paper pointed out [ 6 ], CRISPR / Cas9 frequent large number of base deletion (kilobases of the order) fertilized eggs of mice after gene editing appear
.

2018 Nian 8 Yue 8 Ri, Nature  's paper pointed out [ 6 ], CRISPR / Cas9 frequent large number of base deletion (kilobases of the order) fertilized eggs of mice after gene editing appear
.

2019 Nian 1 Yue 28 Ri, Nature Medicine  paper by the noted [ 7 ], the pre-existing body against Cas9 protein of the immune response, although this is not a security issue, but will affect the CRISPR efficacy of gene editing
.

2019 Nian 1 Yue 28 Ri, Nature Medicine  paper by the noted [ 7 ], the pre-existing body against Cas9 protein of the immune response, although this is not a security issue, but affects the immune CRISPR efficacy of gene editing
.

This  Nature Genetics  paper pointed out that the DNA double-strand break introduced during the CRISPR-Cas9 gene editing process may cause chromosome fragmentation.
This is a very destructive form of genome rearrangement that may further lead to the oncogenic fusion protein.
Occurrence or dysregulation of specific gene expression .

This  Nature Genetics  paper pointed out that the DNA double-strand break introduced during the CRISPR-Cas9 gene editing process may cause chromosome fragmentation.
This is a very destructive form of genome rearrangement that may further lead to the oncogenic fusion protein.
Occurrence or dysregulation of specific gene expression .

 

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

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

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

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

At present, there are very few people receiving CRISPR-Cas9 therapy in the world .
With the popularization of CRISPR therapy, the problem of genotoxicity leading to serious adverse events is likely to follow
.
Of course, these studies are not to slow down the development of CRISPR , but to let people know and value the new potential risks of CRISPR gene editing
.

At present, there are very few people receiving CRISPR-Cas9 therapy in the world .
With the popularization of CRISPR therapy, the problem of genotoxicity leading to serious adverse events is likely to follow
.
Of course, these studies are not to slow down the development of CRISPR , but to let people know and value the new potential risks of CRISPR gene editing
.

Concluding remarks

Concluding remarks

The most basic requirement of gene editing in clinical application is accuracy and safety
.
As a genetic manipulation involving the DNA level, the side effects of gene editing can undoubtedly cause terrible harm to patients.
Therefore, it is necessary to be cautious when using gene editing technology into clinical use
.

The most basic requirement of gene editing in clinical application is accuracy and safety
.
As a genetic manipulation involving the DNA level, the side effects of gene editing can undoubtedly cause terrible harm to patients.
Therefore, it is necessary to be cautious when using gene editing technology into clinical use
.

In terms of accuracy, since the birth of CRISPR gene editing technology, off-target effects have always been worrying.
Off-target effects are usually caused by the wrong cutting of DNA .
In addition to improving the accuracy of CRISPR system targeting, the development of DNA cutting activity is lost.
the dCas9 , and does not rely on DNA double-strand breaks single base editor is also important that direction
.

In terms of accuracy, since the birth of CRISPR gene editing technology, off-target effects have always been worrying.
Off-target effects are usually caused by the wrong cutting of DNA .
In addition to improving the accuracy of CRISPR system targeting, the development of DNA cutting activity is lost.
the dCas9 , and does not rely on DNA double-strand breaks single base editor is also important that direction
.

For safety, the human body 's immunogenic reaction to the Cas9 protein of bacterial origin, DNA damage caused by CRISPR-Cas9 activation of p53 , the loss of large chromosomal fragments, and the enrichment of p53 inactivation mutations, etc.
, are all A huge obstacle to the application of CRISPR in the human body .

For safety, the human body 's immunogenic reaction to the Cas9 protein of bacterial origin, DNA damage caused by CRISPR-Cas9 activation of p53 , the loss of large chromosomal fragments, and the enrichment of p53 inactivation mutations, etc.
, are all A huge obstacle to the application of CRISPR in the human body .

In recent years, clinical trials of CRISPR gene editing have been carried out one after another, and some clinical trials have also shown good results
.
This shows that there are no insurmountable obstacles to the application of CRISPR gene editing in the human body.
What we need to do is to solve these discovered problems and work hard to develop a safe and effective clinical application program for human gene editing
.

In recent years, clinical trials of CRISPR gene editing have been carried out one after another, and some clinical trials have also shown good results
.
This shows that there are no insurmountable obstacles to the application of CRISPR gene editing in the human body.
What we need to do is to solve these discovered problems and work hard to develop a safe and effective clinical application program for human gene editing
.

Reference materials:

Reference materials:

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