CRISPR 2.0: a new wave of gene editors heads for clinical trials

[bnew]

https://www.nature.com/articles/d41586-023-03797-7

• NEWS
• 07 December 2023

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Landmark approval of the first CRISPR therapy paves the way for treatments based on more efficient and more precise genome editors.

• 
  By
• Heidi Ledford

More versatile genome editors are supplanting the CRISPR-Cas9 editing system (artist’s illustration) for experimental treatments.Credit: Biolution GmbH/Science Photo Library

Less than a month after the world’s first approval of a CRISPR-Cas9 genome-editing therapy, researchers are hoping that the therapy will win its second authorization this week — this time from the United States, with its famously stringent regulators and lucrative health-care market.

The therapy, which UK regulators approved on 16 November, disables a gene as a means of treating a genetic blood disorder called sickle cell disease. A host of other CRISPR-Cas9 therapies that work on the same principle are in clinical trials as treatments for a range of diseases.

As sophisticated as these therapies are, they are only the beginning. “We tend to call these the first generation of genome editing,” says Keith Gottesdiener, chief executive officer of Prime Medicine, a company in Cambridge, Massachusetts, that is developing genome-editing therapies. “They can do some remarkable things, but they’re fairly limited.”

Now, however, there’s a fresh crop of CRISPR-based systems that overcome those limitations. These systems edit DNA with more precision and versatility than the original genome editors could achieve. And they can make changes, such as switching on genes, that the initial tools couldn’t. The regulatory approval of classical CRISPR-Cas9 “sets the stage” for the next generation of genome-editing techniques, says Marianne Carlon, a lung disease specialist at the Laboratory of Respiratory Diseases and Thoracic Surgery at KU Leuven in the Netherlands.

Here, Nature looks at the next generation of CRISPR techniques.

Base editing​

Genome editing offers an opportunity to correct the mutations that cause cystic fibrosis, which affects the lungs and digestive system. But for that, classical CRISPR-Cas9 approaches are of little use: “CRISPR is much better at destroying things than it is at fixing things,” says Gottesdiener.

Instead, Carlon is exploring a cystic-fibrosis treatment that harnesses a method called base editing, which can change individual DNA letters, or bases — converting an A to a G, for example, or a C to a T. Base editing relies on the Cas9 enzyme used in the original CRISPR system to target those changes to the correct spot. But unlike old-fashioned CRISPR-Cas9, base editing does not typically cut both strands of DNA at that spot. Instead, Cas-9 guides other enzymes to the chosen site, where they can go about the work necessary to change the DNA bases.

In the seven years since base editing was first reported, researchers have developed ways to reduce the number of unwanted DNA changes that it produces and shrink the size of its components so that they can be delivered more easily into cells. Base-editing therapies are already being used in early clinical trials, including atreatment for high cholesteroland a form of leukaemia. But the remarkable precision of the technique comes at the cost of inflexibility: it can be used to alter only certain DNA sequences, and cannot insert chunks of DNA into the genome.[/SIZE]

Prime editing​

In 2019, a new CRISPR system called prime editing promised to address those limitations. Prime editing can change individual DNA bases, but can also either insert or delete small stretches of DNA at targeted sites. It is more flexible than base editing in that it can target and correct almost any site in the genome.

But it is also more complicated. “There’s a lot of versatility, but that makes it a bit of a challenge to work with,” says Carlon.

Since 2019, researchers have made prime editing more efficient by designing better enzymes; other enhancements prevent the cell’s natural DNA-repair mechanisms from intervening and introducing errors.

Next year, Prime Medicine plans to seek permission from the US Food and Drug Administration to launch a clinical trial of a prime-editing treatment for chronic granulomatous disease, a genetic immune disorder.

Meanwhile, researchers are pushing the boundaries of the technique, devising ways to insert larger and larger pieces of DNA into targeted sites in the genome. This opens the door to replacing entire genes, says Omar Abudayyeh, a biological engineer at the Massachusetts Institute of Technology in Cambridge — thereby making it easier to develop a therapy to treat genetic disorders, such as cystic fibrosis, that can be caused by many different mutations within a certain gene. Instead of designing therapies to correct each mutation, it might one day be possible to replace the defective copy of the gene with a fresh one.

“Then you’d have a drug that’s applicable to every single patient for that disease,” he says. “Everybody’s working on different flavours of ways to do this.”

Epigenome editing​

As well as altering the sequence of a gene itself, CRISPR systems can change how genes are expressed by altering the ‘epigenome’, including the array of chemical modifications to DNA that can affect gene activity.

Technologies targeting the epigenome have not moved as quickly as base editing. In part, that’s because scientists assumed that epigenome edits would be erased during cell division, says Derek Jantz, chief scientific officer of Tune Therapeutics in Durham, North Carolina. “That’s a common misconception,” he says. “But epigenetics is very long-lasting.”

In May, scientists at Tune presented data showing that they could shut down a gene called PCSK9, which regulates cholesterol, in non-human primates without altering the bases in the DNA itself. Instead, they used a method that added chemical tags called methyl groups that are attached to the DNA and that regulate the activity of the gene. The effects have persisted for at least 11 months, says Jantz.

A long-lasting effect could give epigenome editing an advantage over some RNA-based medicines that must be readministered every few weeks or months. And the fact that the treatment doesn’t involve changing DNA relieves safety concerns that regulators have about CRISPR-Cas9 treatments, Jantz says.

The finding is also an example of how an improved understanding of the epigenome could push these treatments forwards, says Lei Stanley Qi, a synthetic biologist at Stanford University in California, and tackle diseases that other forms of CRISPR editing cannot. Tune, for example, hopes to use epigenome editing to treat hepatitis B virus infections, by silencing the viral DNA that can lurk in cells even after antiviral treatments.

Although such applications are a far cry from the CRISPR-Cas9 editing used in the first approved CRISPR medicine, the regulators’ approvals help to establish CRISPR-based editing as a viable way of treating disease, says Qi. That, in turn, could bolster interest in epigenome editing. “That approval is a huge deal,” he says. “After that, I guess we’ll enter a fast track.”

doi: https://doi.org/10.1038/d41586-023-03797-7

 

[bnew]

I received the new gene-editing drug for sickle cell disease. It changed my life.

As a patient enrolled in a clinical trial for Vertex’s new exa-cel treatment, I was among the first to experience CRISPR’s transformative effects.

www.technologyreview.com

I received the new gene-editing drug for sickle cell disease. It changed my life.​

As a patient enrolled in a clinical trial for Vertex’s new exa-cel treatment, I was among the first to experience CRISPR’s transformative effects.

By

• Jimi Olaghere archive page

December 4, 2023

MATT ODOM

On a picturesque fall day a few years ago, I opened the mailbox and took out an envelope as thick as a Bible that would change my life. The package was from Vertex Pharmaceuticals, and it contained a consent form to participate in a clinical trial for a new gene-editing drug to treat sickle cell disease.

A week prior, my wife and I had talked on the phone with Haydar Frangoul, an oncologist and hematologist in Nashville, Tennessee, and the lead researcher of the trial. He gave us an overview of what the trial entailed and how the early participants were faring. Before we knew it, my wife and I were flying to the study site in Nashville to enroll me and begin treatment. At the time, she was pregnant with our first child.

I’d lived with sickle cell my whole life—experiencing chronic pain, organ damage, and hopelessness. To me, this opportunity meant finally taking control of my life and having the opportunity to be a present father.

The drug I received, called exa-cel, could soon become the first CRISPR-based treatment to win approval from the US Food and Drug Administration, following the UK’s approval in mid-November. I’m one of only a few dozen patients who have ever taken it. In late October, I testified in favor of approval to the FDA’s advisory group as it met to evaluate the evidence. The agency will make its decision about exa-cel no later than December 8.

Related Story​

The first CRISPR cure might kickstart the next big patent battle


Vertex Pharmaceuticals plans to sell a gene-editing treatment for sickle-cell disease. A patent on CRISPR could stand in the way.

I’m very aware of how privileged I am to have been an early recipient and to reap the benefits of this groundbreaking new treatment. People with sickle cell disease don’t produce healthy hemoglobin, a protein that red blood cells use to transport oxygen in the body. As a result, they develop misshapen red blood cells that can block blood vessels, causing intense bouts of pain and sometimes organ failure. They often die decades younger than those without the disease.

After I received exa-cel, I started to experience things I had only dreamt of: boundless energy and the ability to recover by merely sleeping. My physical symptoms—including a yellowish tint in my eyes caused by the rapid breakdown of malfunctioning red blood cells—virtually disappeared overnight. Most significantly, I gained the confidence that sickle cell disease won’t take me away from my family, and a sense of control over my own destiny.

Today, several other gene therapies to treat sickle cell disease are in the pipeline from biotech startups such as Bluebird Bio, Editas Medicine, and Beam Therapeutics as well as big pharma companies including Pfizer and Novartis—all to treat the worst-suffering among an estimated US patient population of about 100,000, most of whom are Black Americans.

But many people who need these treatments may never receive them. Even though I benefited greatly from gene editing, I worry that not enough others will have that opportunity. And though I’m grateful for my treatment, I see real barriers to making these life-changing medicines available to more people.

A grueling process​

I feel very fortunate to have received exa-cel, but undergoing the treatment itself was an intense, monthslong journey. Doctors extracted stem cells from my own bone marrow and used CRISPR to edit them so that they would produce healthy hemoglobin. Then they injected those edited stem cells back into me.

It was an arduous process, from collecting the stem cells, to conditioning my body to receive the edited cells, to the eventual transplant. The collection process alone can take up to eight hours. For each collection, I sat next to an apheresis machine that vigorously separated my red blood cells from my stem cells, leaving me weakened. In my case, I needed blood transfusions after every collection—and I needed four collections to finally amass enough stem cells for the medical team to edit.

The conditioning regimen that prepared my body to receive the edited cells was a whole different challenge. I underwent weeks of chemotherapy to clear out old, faulty stem cells from my body and make room for the newly edited ones. That meant dealing with nausea, weakness, hair loss, debilitating mouth sores, and the risk of exacerbating the underlying condition.

MATT ODOM

My transplant day was in September 2020. In a matter of minutes, a doctor transferred the edited stem cells into me using three small syringes filled with clear fluid. Of course, the care team did a lot to try and make it a special day, but for me that moment was honestly deflating.

However, the days and months since have been enriching. I’ve escaped from the clutch of fear that comes from thinking every occasion could be my last. Noise and laughter from my 2-year-old twin daughters and 4-year-old son echo through my home, and I’ve gained immense confidence from achieving my goal of being a father.

It’s clear to me from my experience that this treatment is not made for everyone, though. To receive exa-cel, I spent a total of 17 weeks in the hospital. Not everyone will want to subject themselves to such a grueling process or be able to take time away from family obligations or work. And my treatment was free as part of the trial—if approved, exa-cel could cost millions of dollars per patient.

Another potential barrier is that some people become enmeshed with their chronic disease. In many ways, your disease becomes part of your identity and way of life. The community of people with sickle cell disease—we call ourselves warriors—is a source of strength and support for many. Even the promise of a better life from a novel technology may not be strong enough to break that bond.

From few, to many​

Other challenges are society-wide. In advancing new treatments, the US medical industrial complex has too often left a trail of systemic racism and unethical medical practices in its wake. As a result, many Black Americans mistrust the medical system, which could further suppress turnout for new gene therapies.

Related Story​

Three people were gene-edited in an effort to cure their HIV. The result is unknown.



CRISPR is being used in an experimental effort to eliminate the virus that causes AIDS.

Global accessibility has also not been a priority for most of the companies developing these new treatments, which I feel is a mistake. Some have cited the lack of health-care infrastructure in sub-Saharan Africa, which houses about 80% of all sickle cell disease cases globally. But that just sounds to me like a convenient excuse.

The options for treating sickle cell disease are very limited. Denying access to such a powerful and transformative treatment based on someone’s ability to pay, or where they happen to live, strikes me as unethical. I believe patients and health-care providers everywhere deserve to know that the treatment will be available to those who need it.

Conducting gene therapy research and clinical trials in African populations could allow for a more comprehensive understanding of the genetic diversity of sickle cell disease. This knowledge may even contribute to the development of more effective and tailored therapies—not only for Africans, but also for people of African descent living in other regions.

Even as a direct beneficiary of gene therapy, I often struggle with not knowing the full consequences of my actions. I fundamentally, at a cellular level, changed who I am. Where do we draw the line at playing God? And how do we make the benefits of a God-like technology such as this more widely available?

Jimi Olaghere is a patient advocate and tech entrepreneur.