A major CRISPR breakthrough came last May.

Researchers at Penn Medicine and the Children’s Hospital of Philadelphia developed a personalized base-editing treatment in just 6 months. The treatment was made just for “ KJ,” an infant with a rare metabolic disease called carbamoyl phosphate synthetase 1 deficiency, affecting his ability to break down ammonia. 

“He’s the only patient in the world that we know of who has that specific variant that causes his specific disease, and we were able to make a bespoke therapy for him that, to all appearances, helped him,” said Kiran Musunuru, MD, PhD, professor of translational research at the University of Pennsylvania, Philadelphia, and lead author on the study.

KJ’s rapid, bespoke treatment also raised hopes for more gene-editing therapies targeting rare and ultrarare diseases — a possibility that faces significant roadblocks. The biotech market is “in a down cycle right now,” forcing companies to scale back once extensive drug pipelines, Musunuru said.

Indeed, more than a decade after the discovery of CRISPR-Cas9 unleashed a frenzy of research and hype, gene editing has arrived at a fraught moment. Investors are retreating, and some of the most successful companies have cut staff. Promised treatments for rare diseases have yet to materialize.

In spite of that, researchers across the board have seen some fascinating developments.

The State of the Science

Two CRISPR medicines for inherited forms of high cholesterol are in phase-1b clinical trials. Developed by Verve Therapeutics (recently acquired by Eli Lilly), the drugs are designed to permanently switch off specific genes in the liver, providing a “one and done” treatment, Musunuru said. In the trial, Verve-102, which also treats premature coronary artery disease, reduced low-density lipoprotein cholesterol by an average of 53% and up to 69% at higher doses. Verve-201, which targets a gene regulating cholesterol and triglycerides, is being evaluated for safety.

Another therapy in a phase 1/2 trial targets alpha-1 antitrypsin deficiency, an inherited disorder of the lungs and liver without a cure. Developed by Beam Therapeutics, it corrects a disease-causing mutation, rather than switching it off. While it’s too early to determine if participants are clinically improved, there are “clear signs” of normal proteins being made in their bodies, Musunuru said.

“This is the first example you can point to where there has been direct correction of a disease-causing mutation in the body of a patient,” Musunuru said. “That’s really exciting, because it opens the door to being able to treat genetic disorders by addressing the root cause.”

The medicines rely on base editing, also known as CRISPR 2.0. Clinical trials of base editing therapies for sickle cell disease and acute lymphoblastic leukemia are also underway. The original CRISPR severs both strands of DNA, sometimes resulting in random gene additions or deletions where the strands are fused back together. Base editors are less error-prone; they nick one strand instead of severing both. An enzyme attached to Cas9 triggers a chemical reaction to flip DNA bases, converting adenine (A) to g uanine (G) or cytosine (C) to thymine (T).

“I never would have thought that, 10 years later, so many people would be using base editors, that it would have been used in multiple people, and saved multiple people’s lives,” said Alexis Komor, PhD, who developed the technology at Harvard University, Cambridge, Massachusetts, in 2016. 

But base editing isn’t perfect. Sometimes, a C gets replaced by an A or a G, for example. Komor, now an associate professor of chemistry and biochemistry at the University of California, San Diego, has been trying to figure out why. Researchers in her lab used a green fluorescent protein gene, which glows when the base editor works. They also applied a CRISPR inhibition screen, to knock down different genes involved in DNA repair. Combined, the tools revealed how a DNA ligase (Lig3) can interfere with editing and how a dual-protein (MutS-alpha protein complex) assists. The findings, published last May in Nature Communications, may help discourage errors and pave the way for safer, more effective therapeutics. 

“We could potentially hunt down certain cell types, where we’ll get really efficient and very clean C-to-T editing from the base editor,” Komor said.

CRISPR-Based Technologies on the Rise

Emerging CRISPR-based tools, such as prime editing, have also made headway this year. Like base editing, the technique nicks one strand of DNA. But if base editing is a typewriter, prime editing more closely resembles a word processor, Musunuru said. Prime editors can add or remove short sequences of genetic code, squeezing in a letter or trimming a few that shouldn’t be there. Last May, Prime Medicine, a biotech company focused on the technology, reported promising results from the first-ever clinical trial of a prime-editing therapeutic candidate.

Two patients’ cells were treated ex vivo for chronic granulomatous disease, a rare inherited condition affecting the immune system.

“In this case, the variant was not a simple misspelling. A couple of letters were missing. So it wasn’t something you can easily fix with a base editor,” Musunuru said. “By all appearances, it worked really well at treating the disease.”

Therapies that use epigenetic editing are also underway. The CRISPR-based technique can be used to upregulate or downregulate genes, modifying their expression without changing the genetic sequence. Chemical changes in DNA, such as methylation patterns, and environmental and diet factors that expose cells to stress can alter gene expression. These epigenetic factors are linked to many genetic diseases, said Lei (Stanley) Qi, PhD, associate professor of bioengineering at Stanford Medicine, Stanford, California. 

“All the cells in our body share the same code, yet they are very different cells with different functions, and that is epigenetics,” Qi said. “Epigenetic editing [is] only just emerging, but I’m super excited to see how it can change the therapeutic field.” 

A type of neuromuscular dystrophy called facioscapulohumeral muscular dystrophy has epigenetic roots. Abnormal DNA methylation turns on a gene that is toxic to muscle cells and causes muscle degeneration. Qi’s startup, Epicrispr Biotechnologies, developed a CRISPR-based therapy to permanently “epigenetically silence” that gene (DUX4 in skeletal muscle). A first-in-human clinical trial began in 2025, and the first patient received a dose of the drug in September.

The first generation of CRISPR, Cas9, is difficult to deliver into the body because of its size. Qi’s team engineered a much smaller version with a deactivated nuclease, which prevents it from cutting DNA. This “very compact” nuclease-dead Cas9 carries an epigenetic molecule that causes demethylation. A guide RNA directs the Cas9 to the abnormal DUX4 gene, permanently silencing it. The drug is delivered intravenously inside a viral vector already clinically approved for Duchenne muscular disease.

“We target the toxic gene, we silence that [gene] in myocytes, and we are delivering it one time to rescue all the muscular function,” Qi said.

CRISPR is also being used in diagnostics. Two CRISPR-based tests for SARS-CoV-2 received FDA emergency authorization during the COVID pandemic. Other diagnostics use CRISPR enzymes to identify multiple pathogens and disease variants from one biological sample. For example, a tool called mCARMEN detects SARS-CoV-2 and “a suite of other related respiratory diseases,” said Cameron A. Myhrvold, PhD, assistant professor at Princeton University, Princeton, New Jersey, who developed the technology in 2022. (The FDA showed interest in the test but ultimately declined to pursue it because Myhrvold’s lab lacked the ability to operate at scale, he said.)

Myhrvold’s recent collaboration with the Massachusetts Institute of Technology, Cambridge, researchers, bbCARMEN, identified SARS-CoV-2, respiratory syncytial virus, influenza A and B, and other pathogens from a panel of nine viruses. It also correctly identified 46 positive COVID cases out of a group of 47 specimens (97.9% sensitivity), according to a September 2025 study in Nature Biomedical Engineering. Myhrvold is also developing CRISPR-based diagnostics to find drug-resistant mutations, especially those causing tuberculosis. Tools that can detect numerous different mutations are “critical, because we need to know which mutation is present and if it’s giving you resistance to one drug or another drug, or maybe multiple drugs even,” he said.

Pushing CRISPR Therapies Forward Despite the ‘Down Cycle’

Researchers are under pressure to pursue treatments for more common diseases that offer a greater return on investment. Gene replacement therapies are still probably another 5-10 years away, he said.

But Musunuru is hopeful for a regulatory solution modeled on KJ’s treatment. The FDA was “very receptive” to his proposal last summer to fast-track a treatment for phenylketonuria (PKU), a rare disease caused by variants in the PAH gene. Musunuru’s lab is developing a base-editing therapy to correct six of the most recurrent variants that can cause PKU. They’ve shown in mouse models and in vitro that the same base editor can correct the six variants, with only the guide RNA changing. Under the proposal, they’d do all the usual studies for one variant, followed by cellular studies of the other five variants, followed by an umbrella clinical trial of patients with PKU caused by any of the six variants.

If the treatments worked, Musunuru envisions a drug labeled for any patient with PKU caused by any PAH variant, including potential treatments for patients with unique variants. Eventually, the label could come to include any of the six genes involved in urea cycle disorders, or even any disease that affects the liver, regardless of the gene. Making a single drug applicable to patients across many diseases improves its commercial viability, he said. 

Ideally, with regulatory intervention, geneticists like Musunuru could design and produce bespoke gene-editing therapies within “a matter of weeks instead of 6 months,” he said. “In my view, we can’t wait. There are very sick patients, like KJ, who we can help. We proved it; even if we have to make one drug at a time, we can do it.”

Musunuru reported being a co-founder of Verve Therapeutics, which was recently acquired by Eli Lilly. Musunuru also reported having a sponsored research agreement with Beam Therapeutics.