Few technologies are revolutionizing biomedical research in recent years more than the use of CRISPR-Cas9 based gene editing, but there is still more to learn to unlock its full potential to treat diseases. This technology allows scientists to make edits to DNA in cells with remarkable precision – removing specifically targeted sections of DNA and potentially replacing them with different targeted sections of DNA. In ALS, CRISPR-Cas9 has helped scientists develop new ways to conduct research in cellular and animal models of the disease.

How CRISPR Works

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, a term describing a process involved in the immune response of bacteria. This process, in simplified terms, allows bacteria to “remember” certain genetic patterns in the DNA of viruses that they have previously been infected with. If they encounter this virus again, they release a protein called “CRISPR-Cas9” (Cas9 stands for “CRISPR Associated Protein 9) which can cut these specific strands of DNA from the viruses’ DNA, neutralizing them, and preventing reinfection.

In 2012, a group of scientists published their findings that this CRISPR-Cas9 protein could be “programmed” to edit the genomes of cells, removing specific DNA segments from their genetic code. Using this method, scientists can remove a particular segment of DNA or an entire gene from a cell’s genetic code. They can also take advantage of the cell’s natural DNA repair processes to replace the removed genetic material with a customized DNA sequence. This can have many uses, including finding potential targets in drug development or understanding the biology of a specific gene or repairing a damaging genetic mutation.

While methods for editing the genomes of organisms have existed for decades, CRISPR-based gene editing technology has provided researchers with the ability to make changes with increased precision, accuracy, and efficiency. This discovery earned the 2020 Nobel Prize and has come to be considered one of the most significant discoveries in the history of biology.

Uses of CRISPR

CRISPR technology has been used in many industries – from creating genetically engineered crops to pest control. However, its largest impact has been on the biomedical research space. One area where CRISPR has been very impactful is in the creation of disease models. Disease models allow researchers to test drugs for safety and efficacy before they are moved into human trials. These models, including human cells and animals such as mice or fish, are an essential part of the preclinical development of treatments for many diseases, including amyotrophic lateral sclerosis (ALS).

CRISPR-based gene editing has allowed researchers to create these “transgenic” models of disease – – organisms whose genomes have been engineered to include mutations associated with certain diseases ­– more efficiently. By using CRISPR to create better models of a disease, we are able to gain more valuable data from our drug testing.

There has also been a great deal of research into treatments for a variety of diseases that utilize CRISPR gene-editing technology. Nearly all of these are “ex-vivo” treatments, meaning that they involve removing cells from the body, editing their genetic code, and then reintroducing them. This technique has been used to develop immunotherapies for cancer, several of which are currently in clinical trials. While no CRISPR-based treatments are currently on the market, in 2023 two treatments using a similar ex-vivo technique to treat sickle-cell disease have been submitted to the FDA for approval.

CRISPR Limitations and Ethical Concerns

While CRISPR-based gene editing may have many potential roles in treating diseases, it does have some limitations. The previously mentioned treatments involve removing cells from the body before they are edited. This is because currently CRISPR technology is generally only able to safely edit cells in a dish – not those inside a living organism. While it is possible that CRISPR could be used to create fully genetically modified organisms, currently these genome edits must take place in an embryo. 

The consequences of introducing CRISPR into the human body are poorly understood, but, with current CRISPR technology, there are many potential risks. 

  • Unlike a dish of human cells, a human body contains many kinds of cells – blood cells, muscle cells, immune cells, motor neurons, and more. These cells are all surrounded by other cells and tissues. There is currently no predictable way to control where a CRISPR-based treatment would reach, meaning it could possibly affect unintended cells, or even miss its intended target entirely. Also, it is currently challenging to deliver CRISPR to specific cell types where it might be needed, like those within the central nervous system.
  • While scientists often utilize modified viruses to introduce the genetic code for the CRISPR and Cas9 proteins into cell models it is unknown how the human immune system might respond to this therapeutic approach. 
  • CRISPR gene edits are also not always 100% accurate in every cell – meaning a CRISPR-based treatment could potentially cause additional genetic damage even while removing or changing a harmful mutation.

One other potential way for CRISPR to be used to treat diseases would involve editing the genetic code of a fertilized human embryo before it is implanted during in-vitro fertilization (IVF). It is a relatively common practice to use genetic testing to select embryos without certain genetic mutations during IVF, particularly if the parents have a known genetic disease that runs in their family. However, editing individual embryos – and thus creating a genetically modified human being – raises ethical concerns and is illegal in many countries.

CRISPR and ALS

CRISPR gene editing technology already has a significant role in ALS research. Researchers at the ALS Therapy Development Institute (ALS TDI) have used CRISPR-edited cells to learn more about the processes behind the disease. Every day, our scientists use models that have been genetically modified with these techniques. 

Due to the complications and risks associated with editing genes in the body, CRISPR has not yet been used to try to directly modify the disease in people with ALS, but there are now groups studying this approach to treat ALS.

At the ALS TDI, we know that it will take many treatments to end ALS. That’s why every day we’re working to identify effective treatments for the disease – using cutting edge research approaches, including CRISPR-based research techniques. As the Drug Discovery Engine for ALS, it is our mission to continue this work until there are effective treatments for the disease.

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