Gene editing is now on the threshold of becoming a mainstream treatment for a host of diseases and genetic treatments are posed to shape the future of health care
CRISPR-Cas9, the tool for editing genes by precisely cutting DNA and letting the body’s natural DNA repair processes take over, deservedly led to Nobel prizes in 2020 for its pioneers, Emmanuelle Charpentier and Jennifer Doudna. Since their breakthroughs in 2012, the technology has moved forward in leaps and bounds, and techniques to manipulate genes that were once the realm of science fiction are becoming very much science “fact.”
The development curve has been so steep that gene editing could soon become a mainstream treatment for a host of conditions—both genetic and nongenetic. In its early days, CRISPR simply made cuts in DNA, whereas today, new sections of DNA—even entire genes—can be created and inserted. The biggest step forward is the development of base editing, developed in 2016 by David Liu, Thomas Dudley Cabot professor of the Natural Sciences and Howard Hughes Medical Institute Investigator at Harvard University’s Department of Chemistry and Chemical Biology. Base editing enables the direct, irreversible conversion of one target DNA base into another in a programmable manner.
Base editors, often likened to a pencil and an eraser, can precisely perform four types of DNA mutations—the “transition” mutations: A to G, G to A, C to T, and T to C—without requiring double-stranded breaks. It brings, however, a risk of “bystander editing,” where nearby, nontarget A or C bases may also be edited.
Three years later, researchers led by Liu came up with prime editing, a new system that avoided double-stranded DNA breaks (DSBs) in the editing process. Prime editing became known as a word processor for genetic code, due to its ability to make virtually any type of local edit without DSBs, with high specificity, and with minimal possibility of bystander editing.
“The major difference between precision genome editing techniques—such as base editing and prime editing—and nuclease-based strategies is that nucleases are not well-suited for specifying the desired outcome of an edit, such as correction of a specific mutation to the wild-type sequence, in most cell types,” Liu explains. “In contrast, base editing and prime editing excel at converting a target sequence into a specified edited sequence.”
“Moreover, because base editing and prime editing do not require DSBs, they typically result in a much lower frequency of uncontrolled insertions and deletions—or indels—and minimize chromosomal abnormalities and other undesired consequences of cutting a chromosome into two or more pieces,” he adds.
March toward the mainstream
It is the precision of base editing and prime editing in directly correcting disease-causing mutations—the “misspellings” in genes—that have brought gene editing to the verge of the mainstream by making it applicable to the vast majority of genetic diseases, where simply turning off a mutated gene isn’t helpful. “Many more patients will be able to benefit from gene editing,” says Prof. Kiran Musunuru, scientific director at the Center for Inherited Cardiovascular Disease at Perelman School of Medicine, University of Pennsylvania. “Another advantage is that they can turn off genes more precisely and safely than the original CRISPR technology.”
This has led to the launch of numerous clinical trials. The first U.S. base editing trial, which was granted investigational new drug (IND) clearance by the Food and Drug Administration (FDA) in late 2021, uses base editing to install naturally occurring mutations in fetal hemoglobin genes as a treatment for sickle-cell disease and β-thalassemia. This was undertaken by Beam Therapeutics, a company founded by Liu.
In China, BRL Medicine is in the midst of a base editing clinical trial for β-thalassemia treatment. In late 2022, the first patients were dosed in an in vivo base editing clinical trial to treat familial hypercholesterolemia by precisely editing the PCSK9 gene, thanks to Verve Therapeutics. Also in 2022, Waseem Qasim from University College, London, treated the first patient in a clinical trial using multiplexed base edited CAR-T cells to treat T-cell leukemia. This involved the infusion of CAR-T cells containing three base edits in CD7, CD52, and the T-cell receptor into patients, with the result that leukemia has since been in remission and undetected. A multiplex base-edited CAR-T strategy is also underway to treat acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), again by Beam Therapeutics, and Qasim’s UCL team is also beginning an AML CAR-T trial.
Gene editing is also the foundation for a new era of xenotransplantation—or heterologous transplant—which involves the transplantation of living cells, tissues, or organs from one species to another. In early 2022, at the University of Maryland Medical Center, a gene-edited pig’s heart was transplanted into a human for the first time in a one-off and highly experimental procedure.
But will these advances bring gene editing firmly into the mainstream? Liu believes the answer is yes. “From the beginning, scientists recognized the immense therapeutic potential of gene editing,” Liu remarks. “The ability to choose not only where to edit in the genome of a living system but also what sequence of letters should be installed within that gene is a powerful and fundamental capability.”
“In addition to correcting disease-causing DNA mutations to treat or even cure genetic diseases, gene editing can be used as an antiviral strategy, to modify immune system cells—CAR-T cells—for some cancer treatments, or as a potential intervention to treat secondary effects of an adverse medical event, such as to repair damaged tissue after a heart attack,” he adds.
Musunuru takes a more cautious view. “I think it will be a while before gene editing is truly mainstream in the sense that lots of patients in communities everywhere will be receiving gene editing treatments, but I do think it’s coming,” says Musunuru, who is the co-founder and senior scientific advisor at Verve. “Gene editing is going to be useful across the entire spectrum of disease, from rare genetic conditions affecting just a few people, to some of the leading causes of death such as cardiovascular disease and cancer.”
Verve, Beam, and beyond
“The original CRISPR technology was rather limited in what it could do, mostly just turning off genes,” notes Musunuru. “There aren’t that many diseases, particularly rare genetic diseases, where turning off genes is helpful. Newer kinds of CRISPR technology are more versatile and greatly open up the range of conditions that can be treated.”
He is currently proving this point through his work at Verve, which is conducting the first human trial of a CRISPR treatment to reduce cholesterol levels. “I’ve been working on CRISPR therapies for hypercholesterolemia and cardiovascular disease since 2013, when CRISPR first came on the scene,” Musunuru explains. “My laboratory performed the key proof-of-concept experiments in mouse models, which paved the way for us to found Verve in 2018 with the goal of taking the therapies to the clinic. The first patient was dosed with one of the treatments in July 2022, which was the first time a base editor was tested in the body of a human patient.”
Atherosclerotic cardiovascular disease is the leading cause of death worldwide, even in low- and middle-income countries, which makes it a vital target for new therapies. “It’s the preeminent global health problem of the 21st century, killing far, far more people in the last three years than COVID-19,” Musunuru remarks. “In a conceptual sense, prevention of cardiovascular disease is straightforward—treat the risk factors and you’ll prevent or treat the disease. In practice, it involves taking chronic therapies for a lifetime, which is challenging to many patients.”
One of the key risk factors is low-density lipoprotein (LDL) cholesterol, which is frequently targeted with medication, principally statins, but Musunuru’s vision is to use gene editing to turn off cholesterol genes permanently. “It would be like taking a statin every day for the rest of your life, but with a single ‘one-and-done’ treatment,” he says. “So far, the gene editing treatments have worked extremely well in mouse models and nonhuman primate models. The first results of the human trial are not expected to be announced for a while yet.”
The first successful CRISPR trials were for blood disorders sickle cell disease and β-thalassemia—conducted by Beam—and patients who received the treatment have seen dramatic health improvements, to the point that many of them have effectively been cured.
Prime Medicine is partnering with Beam on a sickle cell anemia treatment, as one of 18 active preclinical programs covering a broad spectrum of diseases. “Programs are initially focused on treating diseases with a fast and direct path to treatment or that cannot be treated using other gene editing approaches,” notes Liu. “They are currently on track to initiate IND-enabling studies for a chronic granulomatous disease (CGD) therapeutic candidate.”
Other candidates with a potentially fast track to clinical treatment include Fanconi anemia, Wilson’s disease, glycogen storage disease, retinitis pigmentosa, and hearing loss condition Usher syndrome type 3. The company is also investigating treatments for other diseases with high unmet need that are not currently addressable using other gene-editing approaches. Among them are Friedreich’s ataxia, which cause nervous system damage and movement problems; myotonic dystrophy type 1, a multisystem disorder that affects skeletal and smooth muscle; and fragile X syndrome, which prevents the body from making the fragile X mental retardation protein (FMRP) protein that is required for brain development. There has already been some success with clinical trials of CRISPR treatments for transthyretin amyloidosis and hereditary angioedema, and progress in a trial for Leber congenital amaurosis, a genetic form of blindness, as well as hypercholesterolemia, and HIV infection.
“Also, CRISPR is being used to improve the effectiveness of an existing class of therapies, CAR-T immunotherapies for various types of cancer,” Musunuru. “It hasn’t all been good news, though; a recent trial of a CRISPR treatment for Duchenne muscular dystrophy resulted in the death of the single patient who was treated. Developing new therapies is a challenging endeavor.”
Plotting a path to the future
There are many other therapeutic areas that offer great potential. Among them are some of the metabolic disorders that are part of universal newborn screening—potentially devastating diseases where patients need to start treatment as soon as they are born. Musunuru believes these should be quite amenable to gene editing.
Indeed, Musunuru’s group at the University of Pennsylvania and its collaborators at the Children’s Hospital of Philadelphia recently received a $26m grant from the National Institutes of Health (NIH) to develop base editing treatments for three such disorders: phenylketonuria (PKU), tyrosinemia, and mucopolysaccharidosis type 1.
One key issue that hangs over every endeavor in the gene editing world is safety, though that is true of any new experimental therapies. “For patients with terrible diseases where there are no existing treatment options, and they will certainly die soon if they don’t receive the experimental therapy, the benefit clearly outweighs the risk,” says Musunuru. “For something as common as cardiovascular disease, where there are a variety of existing treatments, imperfect as they might be, there will be less tolerance for risk. That means there will need to be larger, longer-running clinical trials to really establish safety.”
“Regulatory bottlenecks need to be addressed now, while we are improving upon our gene editing technologies so that they don’t become the primary reason why patients in need cannot access therapies down the line,” urges Liu. “Most patient communities—even those with the same diagnosis—are genetically diverse. Although the same gene might be affected, mutations often occur in various different locations of the gene. Patients urgently need a generalizable pipeline for drug discovery, development, and scaling of these programmable gene editing technologies.”
If these regulatory barriers can be overcome, the progress of gene editing technologies into the mainstream could happen incredibly quickly. It has already evolved greatly in terms of specificity and applicability in only ten years, and there is an urgent need to develop treatments for some of the conditions it could target. “As long as gene editing clinical trials demonstrate acceptable safety and efficacy profiles, I anticipate that gene editing will become fully integrated into our current health care delivery approaches alongside other therapeutic strategies,” says Liu.
While there is great cause for optimism, there are also important caveats around safety and ethics, but the gene editing genie is out of the bottle, and it will undoubtedly work its magic in many more ways than can currently be imagined.