2023 was a big year for CRISPR-based gene editing but challenges remain

Regulators in the US and the UK approved gene-based therapies for sickle cell disease.

Boston Globe via Getty Images

2023 was an important year for patients with sickle cell disease. Prior to CRISPR, the only cure for the life-long ailment was a bone marrow transplant, which is notoriously dangerous and costly. This month, the FDA approved Vertex’s “Casgevy,” a CRISPR-based therapy for the treatment of sickle cell disease in patients 12 and older. The landmark approval made the therapeutic the first genetically edited therapy to reach the general market.

Casgevy, which also received the greenlight from regulators in the UK for another blood disorder called beta thalassemia, works by being administered in a single-infusion of genetically modified stem cells to a patient. Clinical study participants that took Casgevy were free from symptoms associated with sickle cell disease, like periodic episodes of extreme pain due to blocked blood flow through vessels, for up to a year.

CRISPR, which modifies precise regions of a human’s DNA strands, was once thought to be a far off scientific innovation. Human cells were first modified using CRISPR in clinical trials in China back in 2016. Less than a decade later, these landmark approvals have set the stage for future nods by regulators for other CRISPR-based therapies that can treat things like HIV, cancers and high blood pressure. “Gene therapy holds the promise of delivering more targeted and effective treatments,” Nicole Verdun, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research said in a recent press release.

The Vertex Pharmaceuticals logo is seen, Friday, March 17, 2023, in Boston. (AP Photo/Michael Dwyer)

CRISPR-based gene editing can be designed as a therapeutic for a number of diseases. A scientist can either delete, disrupt or insert segments of DNA to treat conditions by either targeting specific genes or engineering new cell therapies. The editing process can occur ex vivo (outside the body), in the same way Casgevy does, or in vivo (inside the body). Using CRISPR, sickle cell patients’ blood stem cells are modified in a lab before they are re-infused via a single-dose infusion as part of a hematopoietic transplant.

Neville Sanjana, a core faculty member at the New York Genome Center and associate professor in the Department of Biology at New York University, runs the Sanjana lab, which develops gene therapies for complex diseases like autism and cancer. “One of the really fundamental characteristics of CRISPR is its programmability,” Sanjana told Engadget. While working at the Zhang lab at the Broad Institute of MIT and Harvard, Sanjana says he helped design the “guide RNA” that became the blueprint for Vertex’s Casgevy. “CRISPR screens can be powerful tools for understanding any disease or genetic trait,” Sanjana said. Right now, he said biomedical folks are focused on applying CRISPR-based therapies for really serious inheritable diseases.

While it does “set a precedent” to have these first CRISPR-based gene therapies out there, it could also mean that regulators and the general public will regard future innovations in the space as “less novel,” Katie Hasson, a researcher with the Center for Genetics and Society (CGS) told Engadget. The CGS is a public interest and social justice organization that is focused on making sure gene editing is developed and distributed for good. Hasson explained, it doesn't mean that because one got approved that all other innovative therapies to come after it will not get as much scrutiny.

Beyond therapeutics, gene editing has very broad applications for the discovery and understanding of diseases. Scientists can use CRISPR to explore the origins of things like cancer and pave paths for therapeutics and incurable diagnoses, but that's not all there is to it. Scientists still need to conduct “considerable experimental research” when it comes to bringing an actual therapeutic to fruition, Sanjana said. “When we focus on therapeutic activity at a particular site in the genome, we need to make sure that there will not be any unintended consequences in other parts of the genome.”

Still, the spotlight will always shine a brighter light on the flashy developments of CRISPR from a therapeutic standpoint. Currently, a new gene editing method is being developed to target specific cells in a process called “cancer shredding“ for difficult-to-treat brain cancer. Scientists have even discovered a pathway to engineer bacteria to discover tumorous cells. However, there are barriers to using CRISPR in clinical practice due to the lack of “safe delivery systems to target the tissues and cells.”

“Maybe by curing one disease, you might give them a different disease — especially if you think of cancer. We call that a secondary malignancy,” Sanjana said. While there is strong reason for concern, one cure creating a pathway for other diseases or cancers is not unique to CRISPR. For example, CAR T cell therapy, which uses an entirely different approach to cell-based gene therapy and is not reflective of CRISPR, is a lifesaving cancer treatment that the FDA discovered can, in certain situations, cause cancer.

“We definitely don't want any unintended consequences. There are bits of the genome that if you edit them by mistake, it's probably no big deal but then there are other genes that are vitally important,” Sanjana said. Direct assessment of “off-target effects” or events in which a gene edit incorrectly edits another point on a DNA strand in vivo is challenging.

The FDA recommends that after a clinical trials’ period of investigatory study looking at the efficacy of a gene editing-based therapy, there needs to be a 15-year long term follow up after product administration. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said that the agency’s approval of Casgevy follows “rigorous evaluations of the scientific and clinical data.” Right now, researchers are focused on improving the precision and accuracy of gene editing and having the proper follow up is absolutely well merited, Sanjana explained. “The process right now is a careful one.”

Hasson believes that the 15-year recommendation is a good start. “I know that there is a big problem overall with pharmaceutical companies actually following through and doing those long term post-market studies.”

That’s where new approaches come into play. Base editing, a CRISPR-derived genome editing method that makes targeted changes to DNA sequences, has been around since 2016. Drugs that use base editing have already made headway in the scientific community. Verve Therapeutics developed a gene edited therapy that can lower cholesterol in patients with a single infusion. At higher doses, Verve said the treatment has the potential to reduce proteins associated with bad cholesterol for 2.5 years. Base editing, like CRISPR, has many potential applications for treatment and discovery. For example, base editing could repair a gene mutation that causes childhood blindness. Researchers at Weill Cornell Medicine also found base editing could help understand what genetic changes influence a patient’s response to cancer therapies.

Base editors use CRISPR to bring another functional element to a specific place in the genome. “But it doesn't matter whether it's CRISPR cutting or base editing… any time you're modifying DNA…you would want to know what the off target effects are and you can bet that the FDA wants to know that too. You're going to need to collect data using standard models like cell culture, or animal models to show there are zero or near zero off-target impacts,” Sanjana said.

CRISPR-based therapies already show high therapeutic potential for conditions beyond sickle cell disease. From blood based treatments, to edited allogeneic immune cells for cancers, there are a number of human clinical trials underway or expected to start next year. Trials for gene-edited therapies that target certain cells for cancer and autoimmune diseases are expected to begin in 2024.

Boston, MA - December 5: The lobby at Crispr Therapeutics. (Photo by Jonathan Wiggs/The Boston Globe via Getty Images)
Boston Globe via Getty Images

It won't be until 2025 before we get a better understanding of how Excision BioTherapeutics’ CRISPR-based therapy works to treat HIV. The application of gene editing as a therapeutic for Alzhiemer’s is still in the early stages, with mice at the forefront of research. Similarly, University College London researchers proved that CRISPR has promise as a potential therapeutic for treatment-resistant forms of childhood epilepsy. In a recent study, a gene edited therapy developed in the lab was shown to reduce seizures in mice.

But the clinical process of getting CRISPR to safely and effectively work as it's intended isn’t the only hurdle. The pricing of CRISPR and related therapies in general will be a huge barrier to access. The Innovative Genomics Institute (IGI), a research group that hopes to advance ethical use of these gene editing in medicine, estimates that the average CRISPR-based therapy can cost between $500,000 and $2 million per patient. The IGI has built out an “Affordability Task Force” to tackle the issue of expanding access to these novel therapies. Vertex’s sickle cell treatment costs a cool $2.2 million per treatment, before hospital costs. David Altshuler, the chief scientific officer at Vertex, told MIT Tech Review that wants to innovate the delivery of the therapeutic and make it more accessible to patients. “I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively,” Altshuler said.

“Access is a huge issue and it's a huge equity issue,” the CGS’ Hasson told Engadget. “I think we would also like to look at equity here even more broadly. It's not just about who gets access to the medication once it comes on the market but really how can we prioritize equity in the research that's leading to these treatments.” The US already does a poor job of providing equitable healthcare access as it is, Hasson explained, which is why it's important for organizations like CGS to pose roundtable discussions about implementing guardrails that value ethical considerations. “If you support people having access to healthcare, it should encompass these cutting edge treatments as well.”

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