One autumn day in 2020, Patrick Doherty was walking his dog up a steep mountain in County Donegal, Ireland when he noticed he was unexpectedly running out of breath. The diagnosis he received was terrifying: amyloidosis, a rare genetic disease that caused a protein called amyloid to accumulate in his organs and tissues. The prognosis was grim, with the disease expected to cause him years of suffering until it eventually took his life. However, Mr. Doherty found himself fortunate when he was given the opportunity to participate in a trial for a new medical therapy. With a single injection, he was seemingly cured of the disease. Today, he continues to take his dog on weekly walks up that same steep mountain in County Donegal.
The treatment that Mr. Doherty received involved the use of CRISPR-Cas9, a cutting-edge technology that has swiftly transitioned from the laboratory to clinical settings. Scientists have successfully utilized gene editing to enhance the vision of individuals with an inherited form of blindness. They have also shown promising results in curing sickle-cell disease and restoring hearing in deaf mice. In the upcoming year, this new class of medicines is expected to advance even further, addressing conditions such as cardiovascular disease and cancer. Additionally, a new generation of more precise and efficient gene-editing tools is currently undergoing trials.
CRISPR-Cas9 functions as a pair of molecular scissors that can cut DNA at specific locations. By attaching a piece of RNA to the medicine, the cutting enzyme, Cas9, is guided to the precise location for editing. Once the DNA is cut, the cell’s natural repair mechanisms take over, allowing the gene-editing medicine to replace problematic genetic sequences with corrected ones.
The pace of innovation in gene editing has been remarkable. Within just three years of its discovery in 2012, eGenesis, a biotech company in Cambridge, Massachusetts, used CRISPR-Cas9 to edit pig embryos for the purpose of creating organs suitable for human transplantation. By 2016, a CRISPR-Cas9 therapy was being tested on cancer patients, specifically on immune cells that were removed from the body, edited to enhance their ability to combat cancer, and then reintroduced to the patient.
In subsequent years, pharmaceutical companies Vertex and Crispr Therapeutics announced their collaboration on developing a treatment called CTX001 for sickle-cell disease and beta thalassemia. These disorders stem from genetic mutations affecting the production of hemoglobin, a protein crucial for oxygen transport by red blood cells. The treatment, now known as Casgevy, was released in November 2023 at a price of $2.2 million for a one-time procedure. It involves extracting blood stem cells from the patient, editing a specific gene within these cells to initiate the production of fetal hemoglobin (normally produced only in the womb), and then reintroducing the modified stem cells. This approach enables the patient to generate adequate healthy red blood cells to alleviate the symptoms of their blood disorders.
Despite the success of CRISPR-Cas9, it does have its limitations. The RNA guide molecule can occasionally be imprecise, leading to unintended DNA cuts. Additionally, because the tool breaks both strands of the DNA helix, the repair process may result in undesired insertions or deletions. Such alterations to genetic information could potentially lead to cancer or disrupt cellular functions in other ways.
To address these limitations, advancements in gene-editing technology are being pursued. For instance, CRISPR-Cas9 nickases have been developed, which cut only one strand of the DNA double helix, reducing the risk of off-target effects. Another approach, known as “base editing,” enables the chemical modification of a single DNA letter into another without the need for DNA cuts.
Some of these techniques have already entered clinical trials. In 2022, a patient with familial hypercholesterolemia received an infusion of a base-editing therapy as part of a trial. This disorder, affecting one in 250 individuals, leads to impaired clearance of LDL cholesterol from the bloodstream. The treatment, VERVE-101 by Verve Therapeutics, targets the PCSK9 gene in the liver by making a single-letter alteration in the DNA sequence.
Beam Therapeutics, based in Cambridge, Massachusetts, is employing base editing to develop treatments for various conditions, including enhancing immune cells’ ability to combat leukemia by making four DNA-letter changes. The company also aims to address the same diseases as Casgevy. Their base-editing drug is anticipated to outperform CRISPR-Cas9, delivering higher levels of hemoglobin. Early trials of the base-editing technology in patients are expected in the latter half of this year.
At the forefront of clinical applications is “prime editing,” which utilizes a Cas9 nickase along with a specially designed RNA guide containing a template for the desired genetic modification. An enzyme called reverse transcriptase, attached to the CRISPR protein, reads the RNA template and synthesizes the correct DNA sequence at the targeted site, enabling precise gene editing.
In April, molecular biologist David Liu of Harvard University announced that the first trial using prime editing in a patient had been approved. Only four and a half years after his lab published the initial paper on the technology, Prime Medicine, a biotech company in Cambridge, Massachusetts, has commenced clinical trials of their drug PM359 for treating chronic granulomatous disease, a severe condition affecting the body’s ability to combat infections.
The capability to modify larger segments of the genome, as seen with prime editing, opens up possibilities for treating diseases with extended genetic abnormalities, such as Huntington’s disease. This approach could also offer economic benefits in treating rare diseases. Rather than developing treatments for individual gene mutations, prime editing could address multiple mutations with a single correction. The flexibility of this technology suggests that prime editing could potentially correct almost 90% of genetic variations that cause disease.
The advancements in gene-editing tools continue to progress rapidly. Another method, known as “bridge RNA,” was detailed in a publication in Nature in June. This technique involves a guide RNA that recognizes two DNA regions—the target site and the new gene to be inserted. By utilizing this method, large DNA segments can be added, removed, or inverted.
While these technologies show great promise, they also face challenges related to technical and safety considerations. A significant issue is the delivery of therapies to specific locations in the body. While certain areas like blood cells, cancers, the retina, and liver are easily accessible for editing, the brain and lungs present greater challenges. A proposed solution by Aera Therapeutics involves the use of capsids, nanoparticles with protein shells that can target different tissues without eliciting a strong immune response.
Perhaps the most substantial hurdle that gene-editing technologies face is the economic aspect. The new generation of genomic medicines has come with exorbitant price tags—such as the $3.5 million cost of a shot of Hemgenix, a gene therapy for hemophilia B, which is approximately a million dollars more expensive than Casgevy. While companies justify these high prices based on the costs of research, development, and production, as well as the potential long-term benefits of the treatments (whose durability is still under evaluation), there is a need to address affordability.
There is optimism that costs may decrease over time, particularly with the treatment of diseases affecting larger patient populations like heart disease, which could help offset expenses. Many anticipate that gene-editing tools will evolve into versatile “platforms,” where the core technology remains constant, and only the specific instructions for gene modifications are adjusted for different diseases. This approach could reduce the necessity for extensive clinical trials for each new drug. However, until this transition occurs, companies may encounter challenges in bringing promising treatments to market due to economic factors. Despite these hurdles, the rapid progress in gene editing suggests that these innovative medicines will likely overcome their obstacles in the near future.
