Gene-editing drugs are moving from the laboratory to the clinic at lightning speed. peppermint

Patrick Doherty was walking his dog up a steep hill in County Donegal, Ireland, on an autumn day in 2020 when he noticed she was unusually short of breath. The final diagnosis was devastating: amyloidosis, a rare genetic disease that caused a build-up of the protein, amyloid, in her organs and tissues. The prognosis was even worse: it caused him pain for years until he eventually died. However, in the face of such a terrible fate, Mr. Doherty had luck on his side. He was able to join a trial of a new medical therapy and, with just one injection, was apparently cured. Now, he continues to take his dog up that steep hill in County Donegal every week.

The treatment involved editing Mr Doherty’s genes using CRISPR-Cas9, a technology that has moved from the laboratory to the clinic at lightning speed. Scientists have already used gene editing to improve the vision of people with a hereditary condition that causes blindness. They also seem to be able to treat sickle cell disease with it and restore hearing in deaf mice. This new class of drugs will accelerate the fight against heart disease and cancer in the coming year. A new generation of more precise and efficient gene-editing tools is also under testing.

cut and run

CRISPR-Cas9 works like a pair of molecular scissors that cut DNA at a precise location. A piece of RNA (a single-stranded version of DNA) attached to the drug guides the cutting enzyme, Cas9. Once the DNA is cut, the cell’s natural repair systems come into play. Gene-editing drugs take control of those natural cellular systems and replace the existing (problematic) section of code with a new (correct) sequence.

The pace of innovation has been impressive. CRISPR-Cas9 was discovered in the laboratory in 2012 and just three years later Egenesis, a biotech firm in Cambridge, Massachusetts, used it to edit pig embryos to create organs more suitable for transplant into humans. By 2016 CRISPR-Cas9 therapy was approved for testing in cancer patients, although on immune cells that were removed from the body, these cells were edited to help fight cancer better , and then was returned.

Next year, Vertex and Crispr Therapeutics, pharmaceutical companies based in Boston, Massachusetts and Zug, Switzerland, said they will co-develop a treatment called CTX001, a treatment for two disorders: sickle cell disease and beta thalassemia. Both are caused by genetic defects in the instructions for making hemoglobin, a protein that helps red blood cells carry oxygen.

CTX001, known today as CasGevi (xagamagglutinin autotemcel), hit the market in November 2023, priced at $2.2 million for a one-time treatment. It involves collecting blood stem cells from a patient, editing a gene within them to restart the production of a type of hemoglobin that is normally only produced when a baby is in the womb, and using those stem cells. Involves re-injecting. The patient is then able to produce enough healthy red blood cells to treat the symptoms of their blood disorders.

As cool as it is, CRISPR-Cas9 has limitations. The RNA guide molecule can sometimes be imprecise, leading to unintended cuts in the patient’s DNA. Furthermore, because the tool breaks both strands in the DNA helix, subsequent repair may also result in unwanted insertions or deletions. Damage to genetic information like this can eventually lead to cancer or disrupt cellular function in other ways.

Thus work is going on to update the technology. CRISPR-Cas9 nickases, for example, are enzymes that cut only one strand of the DNA double helix. To make genetic changes, nickases need to be used in pairs, meaning less risk of off-target effects. It is unlikely that an edit would incorrectly connect both surnames to the same segment of DNA. Another method, “base editing”, can chemically change one letter of a DNA sequence to another without the need for cutting.

Some of these technologies already exist in the clinic. In 2022, a patient suffering from familial hypercholesterolemia was given an infusion of a base-editing treatment as part of a trial. This disorder, which affects one in 250 people, results in reduced clearance of bad cholesterol from the blood. The treatment, Verve-101, made by Verve Therapeutics, turns off the PCSK9 gene in the liver by making a single letter change (from A to G) in the DNA.

Beam Therapeutics, based in Cambridge, Massachusetts, is using base editing to create treatments for a number of conditions. These include making four DNA-letter changes to immune cells so they are better able to attack leukemia, as well as a product that works for the same diseases as CasGevi. The company believes its base-editing drug will work better than CRISPR-Cas9 and provide higher levels of hemoglobin. Data from early trials of the base-editing technology in patients is expected in the second half of this year.

At the clinical frontier is “prime editing”, which uses Cas9 nickase with a specially designed RNA guide that not only locates the correct region of DNA, but also contains a template of the desired change. An enzyme called reverse transcriptase is also attached to the CRISPR protein. It reads the RNA template and synthesizes the correct DNA sequence at the location of the nicked site, yielding a precisely edited gene.

In April, Harvard University molecular biologist David Liu posted on X that the first trial using prime editing in a patient had been approved, just four and a half years after his lab published the first paper on the technology. Prime Medicine, a biotech firm in Cambridge, Massachusetts, has already begun clinical trials of its drug PM359 to treat chronic granulomatous disease – a life-threatening condition that affects the blood’s ability to destroy infection.

Being able to alter large pieces of the genome, as is the case with prime editing, makes it possible to treat diseases where errors extend over long distances, such as Huntington’s disease. But it could also help navigate the tricky economics of treating rare diseases. Instead of creating a drug that treats a single mutation in a gene, it would be possible to cure multiple types of mutations with one improvement. The flexibility of the technology means that, in theory, prime editing can correct about 90% of disease-causing genetic variations.

Technological progress in gene-editing tools has not stopped. Yet another method, known as “bridge RNA”, details of which were published in Nature in June, uses a form of guide RNA that recognizes two parts of the DNA – the target site and The new gene that has to be inserted. This new technology allows large sections of DNA to be added, removed or reversed.

All of these new technologies will face technical and security hurdles in the coming years. A big question is how to deliver the treatments to the right places in the body. Blood cells, cancer, retina and liver are all easy to access and edit. The brain and lungs are more difficult. One solution to the delivery problem, proposed by Era Therapeutics of Cambridge, Massachusetts, is a nanoparticle with a capsid, a protein shell. Based on human proteins, these nanoparticles can be targeted to different tissues while also not provoking a strong response from the body’s immune system.

But perhaps the biggest challenge will be economic. So far, the new generation of genomic drugs have been prohibitively expensive — a shot of the hemophilia B gene-therapy HemGenix costs $3.5 million, about a million dollars more than CasGevi. Companies believe they can charge high prices not only because of the cost of developing and manufacturing the drugs, but also because they potentially provide lifelong benefits (although the durability of these treatments remains to be proven).

There are several reasons to think that costs may decline over time. Treating diseases that affect large patient groups, such as heart disease, will help reduce costs. Ultimately, many believe that gene-editing tools will evolve into “platforms”, where the core technology remains unchanged and only the specific instructions are changed to alter genes for new diseases. This will reduce the need for clinical trials for every new drug. However, until this happens, companies may be forced to abandon even promising treatments due to market conditions. Yet gene editing is advancing so rapidly that it seems only a question of when, not when, these new drugs will overcome their difficulties.

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