CRISPR: From Discovery To Clinic—And Charting A Path Forward

Demaris Mills is president at Integrated DNA Technologies, a global genomics solutions provider.

In the world of biopharmaceutical innovation, 2024 will be remembered as CRISPR’s breakout year. In the spring, five patients with sickle cell disease began treatment with Casgevy, the first FDA-approved CRISPR-Cas9 gene editing treatment. The therapy—which involves removing blood stem cells from patients, editing them and then reinfusing them—can take up to a year for patients to complete. It’s groundbreaking nonetheless because the one-time CRISPR process reduces the activity of a gene that contributes to the painful blood disorder, and in so doing, it offers patients the chance of a normal life.

As we begin a new year, it’s a good time to look forward to the next phase of CRISPR innovation. There are an estimated 300 CRISPR therapies in the development pipeline to treat diseases such as diabetes, HIV/AIDS and cancer. Most of these treatments are in the earliest stages of development. To speed the delivery of novel CRISPR therapies to the patients who need them, developers are working hard to drive improvements in gene editing that will be essential for streamlining production and treatment processes. I’m excited to see how these efforts advance in 2025.

Editing Genes In The Body

One way researchers are working to improve gene editing is by developing in vivo CRISPR therapies, which involve delivering editing tools directly into the body. Casgevy is an ex vivo CRISPR process, meaning the gene editing happens after blood stem cells are removed from the body. To precondition the body to accept the cells, patients are given high doses of chemotherapy to kill the faulty cells before the new cells can be infused. Similar to bone marrow transplantation, this process is long and uncomfortable for patients, who often experience side effects such as hair loss, nausea and muscle pain.

In vivo CRISPR would ease the treatment for patients by eliminating the need for preconditioning, and it would make CRISPR more efficient, potentially lowering costs for both developers and health systems.

There are some promising in vivo CRISPR approaches in the pipeline, including Intellia Therapeutics’ treatment for transthyretin (ATTR) amyloidosis with cardiomyopathy, which is currently in phase 3 trials. It’s designed to inactivate the faulty TTR gene, reducing the production of the misfolded protein that causes the disease. If it proves to be safe and effective, it could be a one-time treatment alternative to antisense oligonucleotide drugs, which are effective in knocking down expression of the TTR gene but have to be administered to patients on a regular basis for life.

Improving Safety And Delivery

Another priority in the CRISPR field is improving the safety of gene editing. The first generation of gene editing technology makes double-stranded breaks in DNA, which raises the risk of dangerous off-target edits. Some next-generation CRISPR systems that are in development don’t require double-stranded breaks. For example, advances have been made in base editors, which use a mutated Cas9 nuclease to target DNA sequences without creating DNA breaks.

In 2023, a research team from St. Jude Children’s Research Hospital and the Broad Institute of MIT and Harvard showed proof-of-concept for prime editing in animal models of sickle cell disease. And earlier this year, the FDA gave the green light to a clinical trial of a prime editor for chronic granulomatous disease. I’m confident that more next-generation CRISPR technologies will move closer to the clinic in 2025.

CRISPR innovators are also perfecting new methods for delivering editing tools into the body. Packaging CRISPR in viruses is a popular method, but it can raise the risk of immune reactions and off-target editing. Concerns about viruses integrating into normal genes and disrupting them have raised the demand for nonviral approaches. Some CRISPR approaches use lipid nanoparticles (LNPs), which are most effective for targeting gene editing to cells in the liver.

Delivering CRISPR to tissues and organs beyond the liver is significantly more challenging, but success could broaden the scope of diseases that can be treated with CRISPR. The ability to target CRISPR to lung epithelial cells could result in new treatments for cystic fibrosis. And if researchers can figure out how to deliver CRISPR to brain cells, that could yield new approaches to treating a wide range of neurodegenerative diseases. Research in this area is still in the early stages, but results have been promising so far. One study published in October described a potential method for delivering genome editors in LNP-based ribonucleoprotein (RNP) complexes. The method was effective in editing both liver and lung cells in mice, reported a research team led by CRISPR pioneer Jennifer Doudna of UC Berkeley.

Looking To 2025

No doubt 2025 will usher in many more advances in CRISPR therapies, thanks to the FDA’s new Platform Technology Designation Program, which will allow innovators to have an easier path to market. This program will allow CRISPR developers to establish gene-editing platforms and apply for FDA approval for them. Then they’ll be able to take a gene-editing system developed for one disease and easily tailor it to other diseases, without having to repeat preclinical safety testing.

To take advantage of this program, CRISPR developers should prepare detailed documentation as early as possible in the development process to show that an innovation qualifies as a platform. According to the FDA’s guidance, a platform is a "well-understood and reproducible technology,” including a molecular structure, nucleic acid sequence or delivery method. Therapeutic components may also qualify as platforms if they meet certain criteria laid out in the FDA’s guidance. FDA officials acknowledged last year that the agency’s approach to defining platforms in gene editing will evolve over time, in collaboration with the biopharmaceutical industry.

That’s why it’s important for CRISPR developers to engage the FDA early on to ensure their platforms meet the criteria. The advent of CRISPR platforms promises to streamline the development and regulatory approval for future gene-editing therapies, bringing new cures to patients faster than ever before.

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