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

2023 is an important year for people living with sickle cell disease. Before CRISPR, the only way to treat this lifelong disease was a bone marrow transplant, which is notoriously dangerous and expensive. This month, the FDA approved Vertexs Casgevy, a CRISPR-based therapy to treat sickle cell disease in patients 12 years and older. The landmark approval makes the therapy the first gene-editing therapy to enter the general market.

Casgevy, which also received approval from British regulators for another blood disorder called beta thalassemia, works by giving patients a single infusion of genetically modified stem cells. Clinical study participants taking Casgevy experienced no symptoms associated with sickle cell disease, such as periodic bouts of extreme pain due to blockage of blood flow in blood vessels, for up to a year.

CRISPR, which can modify precise regions of human DNA strands, was once considered a distant 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 has the potential to provide more targeted and effective treatments, Nicole Verdun, director of the Office of Therapeutic Products in the FDA’s Center for Biologics Evaluation and Research, said in a recent press release.

CRISPR-based gene editing can be used to treat a variety of diseases. Scientists can delete, destroy or insert segments of DNA to treat diseases by targeting specific genes or designing new cell therapies. The editing process can be done in vitro (outside the body) like Casgevy, or in vivo (in vivo). Using CRISPR, blood stem cells from patients with sickle cell disease are modified in the laboratory and then reinfused in a single dose infusion as part of a hematopoietic transplant.

Neville Sanjana is a core faculty member at the New York Genome Center and an associate professor in the Department of Biology at NYU, where he runs the Sanjana Laboratory, which develops therapies for complex diseases such as autism and cancer. of gene therapy. Sanjana told Engadget that one of the really fundamental features of CRISPR is its programmability. Sanjana said that while working in Zhang’s lab at the Broad Institute of MIT and Harvard, he helped design the guide RNA that became the blueprint for Vertexs Casgevy. CRISPR screens can be powerful tools for understanding any disease or genetic trait, Sanjana said. He said the biomedical community is currently focused on applying CRISPR-based therapies to treat truly serious genetic diseases.

While this does set a precedent for the first CRISPR-based gene therapy, it may also mean that regulators and the public will view future innovations in the field as less novel, said Katie Hasson, a researcher at the Center for Genetics and Diseases. ) express. Society (CGS) told Engadget. CGS is a public interest and social justice organization dedicated to ensuring that the development and dissemination of gene editing is for the public good. That doesn’t mean that because one drug is approved, all other innovative treatments that follow won’t receive the same amount of scrutiny, Hazen explained.

In addition to treatment, gene editing also has very broad applications in discovering and understanding disease. Scientists can use CRISPR to explore the origins of diseases like cancer and pave the way for treatments and diagnoses of incurable diseases, but that’s not all. Sanjana said scientists still need to conduct a lot of experimental research to realize a practical treatment. When we focus on therapeutic activity at a specific site in the genome, we need to make sure there aren’t any unintended consequences in other parts of the genome.

Still, from a therapeutic perspective, the spotlight will always shine brighter on CRISPR’s spectacular developments. Currently, a new gene-editing method is being developed to target specific cells in a process called cancer crushing of difficult-to-treat brain cancers. Scientists have even discovered a way to engineer bacteria to find tumor cells. However, there are barriers to using CRISPR in clinical practice due to the lack of safe delivery systems for tissues and cells.

Maybe by curing one disease, you might be giving them another disease, especially when you think about cancer. “We call it secondary malignancy,” Sanjana said. While there is good reason to be concerned, CRISPR is not unique to a therapy that opens up pathways for other diseases or cancers. For example, CAR T-cell therapy uses a completely different approach than cell-based gene therapy and does not reflect CRISPR, a life-saving cancer treatment that the FDA found may cause cancer in some cases.

We definitely don’t want any unintended consequences. If you edit some parts of the genome incorrectly, it might not be a big deal, but there are other genes that are critical, Sanjana said. Directly assessing off-target effects, or events in which gene editing mistakenly edits another point on the DNA strand in vivo, is challenging.

The FDA recommends that clinical trial studies investigating the efficacy of gene-editing-based therapies be followed by long-term follow-up for 15 years after the product is administered. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said the agency’s approval of Casgevy followed a rigorous evaluation of scientific and clinical data. For now, Sanjana explains, researchers are focused on improving the precision and accuracy of gene editing, and proper follow-up is definitely worth it. The process now is a careful one.

Hazen believes the 15-year proposal is a good start. I know there’s a big problem in general with pharmaceutical companies actually following up and doing long-term post-marketing studies.

This is where the new approach comes into play. Base editing, a genome editing method derived from CRISPR that makes targeted changes to DNA sequences, has been around since 2016. Drugs using base editors are already making headway in the scientific community. Verve Therapeutics has developed a gene-editing therapy that lowers patients’ cholesterol with just a single infusion. Verve says that at higher doses, the treatment has the potential to reduce proteins associated with bad cholesterol within 2.5 years. Base editing, like CRISPR, has many potential applications in therapy and discovery. For example, base editing can repair genetic mutations that cause blindness in children. Researchers at Weill Cornell Medical College have also found that base editing can help understand which genetic changes affect how patients respond to cancer treatments.

Base editors use CRISPR to bring another functional element to a specific location in the genome. But whether it’s CRISPR cutting or base editing, any time you modify DNA, you’re going to want to know what off-target effects are, and you can bet the FDA wants to know that, too. Sanjana said you need to collect data using standard models such as cell cultures or animal models to show that off-target effects are zero or close to zero.

CRISPR-based therapies have shown great therapeutic potential for diseases beyond sickle cell disease. From blood-based treatments to cancer-targeting edited allogeneic immune cells, a number of human clinical trials are underway or expected to begin next year. Trials of gene-editing therapies targeting certain cells in cancer and autoimmune diseases are expected to begin in 2024.

It won’t be until 2025 that we know more about how Excision BioTherapeutics’ CRISPR-based therapies can treat HIV. The application of gene editing to treat Alzheimer’s disease is still in its early stages, and mice are at the forefront of research. Likewise, researchers at University College London have shown that CRISPR holds promise as a potential treatment for refractory childhood epilepsy. In a recent study, a lab-developed gene-editing therapy was shown to reduce seizures in mice.

But the clinical process of getting CRISPR to work safely and effectively isn’t the only obstacle. The pricing of CRISPR and related therapies overall will be a huge barrier to access. The Innovative Genome Institute (IGI), a research group hoping to advance the ethical use of these gene edits in medicine, estimates that CRISPR-based therapies would cost an average of $500,000 to $2 million per patient. IGI established an affordability working group to address issues of expanding access to these new treatments. Vertex’s treatment for sickle cell disease costs up to $2.2 million per treatment, not including hospital fees. David Altshuler, Chief Scientific Officer at Vertex said MIT Technology Review The hope is to innovate treatments and make them more accessible to patients. “I think that can be accomplished more quickly by finding another way, like a pill that can be distributed more efficiently,” Altshuler said.

CGS Hasson told Engadget that access is a big issue and also a huge equity issue. I think we also want to take a broader look at fairness here. It’s not just a matter of who gets access to drugs once they become available, but how we prioritize equity in the research that leads to these treatments. Hasson explained that the United States already does a poor job of providing equitable health care, which is why it’s important for organizations like CGS to have roundtable discussions about implementing guardrails that value ethical considerations. If you support people’s access to health care, it should also include these cutting-edge treatments.

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