For as long as he could remember, Razel Colón had known pain. It tore down his neck and back, shot through his legs and climbed to his feet, often writhing and incapacitating him. He had occasional “acute chest” attacks that suddenly made it difficult to breathe. “It felt like an elephant was sitting on my chest, in a lot of pain,” says Colón. Trips to the emergency room and hospital were the order of the day. “If I were lucky,” he says, “I could stay away for a month.”
Colón, of Hoboken, NJ, is only 19 years old, but the sickle cell anemia that caused these effects has been a constant, albeit undesirable, companion. But he is now telling his story from the perspective of a deceased person a year and a half without this pain. He can do things that were previously out of the question: play basketball, lift weights, swim in cold water. His treatment, says his long-time doctor Stacey Rifkin-Zenenberg, a pediatric hematologist and oncologist at Hackensack University Medical Center, “transformed him from the disease to a carrier”.
Colón’s case marks a point on the curve of a new technology that could forever change our approach to treating diseases like sickle cells. This world, the cutting-edge world of innovative genomic therapies, is once again in the midst of an explosive change – and the designer DNA is the focus of the conversation.
This is daring new territory. Some strategies, such as gene therapy, have been available for some time, including the ability to genetically modify cells to have a therapeutic effect – that is, add a corrected gene into the genome to try to treat a disease. Viruses have traditionally been used to introduce healthy genes into cells, but the last decade has seen profound changes. Several gene therapies have been approved for the treatment of a wide variety of diseases: squamous cell carcinoma of the skin, a rare form of hereditary blindness, melanoma, blood disorders, and so on.
It was this type of treatment that effectively halted Colón’s sickle cell condition as part of the largest ongoing gene therapy study of lentiviruses led by Bluebird Bio. Unpublished interim data from 19 participants in the study, followed for at least six months, with a history of severe vaso-occlusive events (VOEs) or sickle cell crises similar to Colón’s, showed complete resolution of severe VOEs in all patients, according to a company spokesperson. The process is still ongoing and the data is not yet complete, so caution should be exercised, but “the promise is huge,” said the spokesman.
Next generation technology, gene editing, is on an entirely different level. Gene editing enables scientists to precisely target abnormal genes of many organisms (bacteria, plants, animals), cut off the DNA and then remove, replace or add new DNA at the interface. “Imagine you have a car with a flat tire,” says Fyodor Urnov, gene editing expert at the University of California, Berkeley, and the Innovative Genomics Institute. “Gene therapy means taking a fifth wheel and putting it on the car somewhere and hoping it’ll work. The gene editing repairs the apartment. “
The technology received a huge boost with the introduction of a gene editing tool called CRISPR, an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, in 2012. CRISPR technology is easier to use, cheaper, and more efficient than older genome editing methods, as well enables scientists to quickly change DNA sequences to modify gene function. This could have a positive effect on the health of the organism or even reverse the symptoms of illness.
“They are often referred to as ‘molecular scissors,’” says Jennifer Doudna, co-inventor and Nobel Prize winner in chemistry. “Scientists can use CRISPR not only to cut through specific points in the DNA of any organism, but also to provide a template for the repair of the DNA.”
In sickle cell anemia, or SCD, a single mutation in the beta hemoglobin gene results in red blood cells that become sickle-shaped or sickle-shaped. These sickle cells are sticky and clog the arteries, preventing the tissues in the body from receiving adequate oxygen. This can lead to acute debilitating episodes of pain such as Colón experienced and lead to a number of complications: anemia, strokes and organ damage to the lungs, heart, kidney, spleen, etc.
Patients often have poor quality of life due to repeated hospitalizations and transfusions and face the prospect of early death. In regions like Africa and the Middle East, where health care resources are much more limited, many children die from SCD before they are five.
CRISPR is accelerating the pace at which genetic engineering is advancing the treatment of such diseases. Matthew Porteus, a gene editing pioneer, founder of CRISPR Therapeutics and professor of pediatrics at the Stanford School of Medicine, says researchers are currently using two primary gene editing strategies to cure sickle cell patients. One guy uses CRISPR to essentially flip a genomic switch and turn on healthy fetal hemoglobin production that was turned off early in life. The advantage? The fetal hemoglobin does not sickle.
A second gene editing strategy, gene correction, directly fixes the mutation in a faulty gene that has caused a disease. In the case of sickle cells, the correction allows the body to easily produce normal hemoglobin. Researchers logged an amazing amount of work to get to this point.
Although advances have been made in the approval of several new drugs to relieve the symptoms of SCD, they are not curative. Bone marrow transplants (stem cells) are the only cure option, but finding healthy donors can be a challenge. Enter the genomic therapies that Theodore Friedmann of the University of California, San Diego, first proposed for genetic disorders in 1972, and which took a step towards reality that same year with the production of recombinant DNA by Paul Berg at Stanford University. In the 1980s, scientists showed how DNA can be transported within cells, and by 2003 the entire human genome was deciphered.
There have been setbacks, and even as gene editing systems came on the market at the beginning of the new century, they remained challenging and time consuming to use. Then came CRISPR, which made its way into the clinical arena, potentially changing not only the treatment but also the prevention of disease. The technology is already being used by scientists researching cancer, lymphoma, AIDS, cystic fibrosis, and more, for diagnostics including the detection of SARS-CoV-2, and even in agricultural engineering efforts to produce larger tomatoes, non-browning apples, and longer-lasting mushrooms .
In real time, there is hope that genetic editing will offer a cure for a very common and debilitating hereditary disease, the sickle cell. Several experts I spoke to suggested for the first time that a cure for SCD might be in sight.
That’s an amazing thought. In practice, the ability to cut out malfunctioning genes and replace them with normally functioning ones can help mitigate the worst effects of a wide variety of diseases. When the 2020 Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuelle Charpentier for their invention of this technology, the Secretary General of the Royal Swedish Academy of Sciences Goran K. Hansson said clearly, “This year’s prize is about rewriting” the code of life.”
And scientists are already working on a more precise, next-generation CRISPR technology. Base editors, who correct single-letter DNA mutations without severing the DNA double helix, have recently shown that they can treat sickle cell disease in mice. And then there are “Prime Editors” that can replace even larger DNA snafus.
It’s all pretty remarkable – and it’s early days. “The field of genomic therapies for hemoglobinopathies is not a zero-sum game,” says Urnov. “I am convinced that there will ultimately be several approved drugs. There will be multiple approvals for gene therapy and there will be multiple approvals for gene editing. “
Many questions remain to be considered, including the moral implications of how far a concept like gene editing could go, as well as cost, safety, and accessibility (experts say current treatments are valued at $ 2 million). Says Doudna, “A real healing means treatment for all who need it. That’s why we’re working hard on the next generation of therapies to cut costs and make them more accessible. “ And since gene editing is not perfect: “The long-term safety of all genetically modified therapies must be carefully examined,” says Porteus.
In the coming months, a consortium from the University of California (UC San Francisco, UC Berkeley and UCLA) will conduct the first open-label, Phase I-II human study with non-viral CRISPR technology developed at the Innovative Genomics Institute. Scientists hope to alleviate the suffering of those taking part in sickle cell studies by replacing their faulty beta globin gene – which causes the disease – with a corrected one and directly fixing the mutation in their blood stem cells.
“The more mutations that are corrected and replicated in healthy red blood cells, the more likely it is to be cured,” says Mark Walters, director of studies and professor of pediatrics at UC San Francisco. “Sickle cell anemia is cured by genomic therapies.” That is the ultimate benefit of technology, after all – and it can become a reality as we learn more about the area.
This is an opinion and analysis article; the views of the views Author or authors are not necessarily those of Scientific American.