Advancing CRISPR Technology

As the first clinical trial results trickle in, researchers look ahead to more sophisticated medical applications for genome editing / Nat...

As the first clinical trial results trickle in, researchers look ahead to more sophisticated medical applications for genome editing / Nature.

The prospect of using the popular genome-editing tool CRISPR to treat a host of diseases is moving closer to reality.  The potential of CRISPR-Cas9, a revolutionary genome-editing tool, to treat various diseases in humans is rapidly becoming a reality. 

Throughout 2019, medical applications of CRISPR-Cas9 witnessed significant milestones, with initial results emerging from clinical trials and the launch of more ambitious studies. Researchers are now setting their sights on more sophisticated applications that could pave the way for treating a wide array of diseases, from blood disorders to hereditary blindness.

Despite the promising outcomes observed in early clinical trials, caution remains paramount. The field is still in its infancy, and the safety and efficacy of CRISPR-Cas9 in clinical settings are yet to be conclusively established. "There's been a lot of appropriate caution in applying this to treating people," notes Edward Stadtmauer, an oncologist at the University of Pennsylvania.

CRISPR-Cas9, initially discovered only seven years ago, has rapidly evolved from a microbial defense system to a tool capable of rewriting human genes. The clinical trials underway explore its potential in treating various diseases, such as cancer, HIV, and blood disorders. However, conclusive results regarding safety and effectiveness are still pending due to the limited number of participants and the early stage of these trials.

Signs of progress

Two notable trials, focused on gene-edited blood cells for treating HIV and certain forms of cancer, showed promising signs in terms of cell engraftment but lacked clear medical benefits. Despite encouraging progress, researchers acknowledge the need for further refinement. For instance, a study attempting to use CRISPR to disable a protein crucial for HIV entry revealed that only 5% of transplanted cells were edited, falling short of achieving a curative effect.

Nevertheless, there are indications of success in treating genetic disorders such as sickle-cell anemia and β-thalassemia using CRISPR technology. Early results suggest a potential alleviation of symptoms, providing hope for effective therapeutic applications in the future. These developments highlight the ongoing transition from editing cells in a controlled environment to exploring the challenges of delivering gene-editing machinery to specific locations within the human body.

A landmark moment in this journey is the trial launched by Editas Medicine and Allergan, aiming to treat Leber congenital amaurosis 10, a genetic disorder causing blindness. This trial marks the first attempt at CRISPR-Cas9 gene editing inside the body, bypassing the need to guide tools through the bloodstream. Researchers are injecting a virus carrying the CRISPR genome-editing machinery directly into the eye, and early results are anticipated this year.

The current reliance on viruses for transporting genome-editing machinery poses challenges, such as potential immune responses and limitations in the amount of DNA they can carry. Researchers are actively exploring alternatives, with Intellia Therapeutics developing fatty nanoparticles in collaboration with Novartis to protect and deliver genome-editing molecules. This approach could provide a pathway to more efficient and versatile genome editing.

While current technologies being tested represent significant strides, researchers emphasize the need for continued innovation. They envision an ideal future where gene-editing tools are not constrained by viruses or size limitations. As the field advances, the focus remains on addressing challenges, refining techniques, and eventually designing more effective and precise drugs. The transformative potential of gene editing is evident, and the momentum toward a future with widespread applications of CRISPR technology remains unstoppable.

Shrink to fit

What's more, some gene-editing tools are currently too large to fit inside commonly used gene therapy viruses, says chemical biologist Andrew Anzalone at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. These include the souped-up CRISPR systems called prime editors that were first reported in late 20192 and might prove to be more precise and controllable than CRISPR–Cas9. Intellia is looking for a way around the viruses. 

The company has partnered with Swiss pharmaceutical giant Novartis to develop fatty nanoparticles that can protect genome-editing molecules as they travel through the bloodstream, but also pass through the membranes of target cells. These particles tend to accumulate in the liver, and researchers are working to develop particles that infiltrate other tissues, such as muscle or the brain. 

But for now, Intellia will focus on liver diseases, says Leonard, and plans to launch its first trial of the technology this year. “It’s crawl before you walk, so to speak,” he says. None of the technologies currently being tested is what researchers envision for the long-term applications of genome editing, says Gersbach. “The approaches that people are taking are the things that we can do today,” he says, “but not what we would do if we could design the ideal drug.”

Leonard says that when he meets with investors, they often demand to know what medical advances will be made in the next six months. “We do our best to describe that, but I always end it by saying, ‘Can you imagine a future without gene editing?’” he says. “I have yet to meet the person who says, ‘yes’.”

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