Every single one of us is the product of a genetic lottery.The Human Genome Project estimates that
humans have between 20,000 and 25,000 genes that determine our individual traits, with two copies of every gene, one inherited from each parent.And if you happen to be born with a genetic mutation that leads to an incurable chronic disease, fairness doesn’t factor into how you feel, what your symptoms are, or whether your physical limitations are great or small.The fixed power of your genetic blueprint has indelibly shaped your future.
Until now, perhaps.
What if you could get a one-shot dose of medicine that could repair the problematic, mutated gene that’s creating the disease, leaving you symptom-free? As sci-fi, pie-in-the-sky as this sounds, this is exactly what scientists are working to achieve through buzzed-about advancements in gene editing—a new technology that modifies genes in the DNA.By fixing mutations, certain genetic disorders can be eradicated in the here and now, if not yet among future generations, which (at this point, anyway) will still be susceptible to inheriting mutated genes and the illnesses that come with them.
But for people living and coping on the regular with symptoms like
pain crises, it’s welcome news.
The concept was first introduced in the late 1990s, with various iterations.Then, in 2009, CRISPR (short for clustered regularly interspaced short palindromic repeats) arrived, breaking from the pack because it’s “simpler, faster, cheaper, and more accurate than older genome editing methods,” according to the National Human Genome Research Institute.
But what is CRISPR, exactly? It’s a gene editing therapy with two components, explains
Matthew Porteus, M.D., Ph.D., a professor of pediatrics and stem cell transplantation at Stanford Medical School in Stanford, CA.One component is called the guideRNA (gRNA).It works like a carrier pigeon to identify where in the gene the other component, called the Cas9 nuclease protein, should make a cut, delivering the medication.“Then the cell repairs the break and either knocks out or fixes the gene,” Dr.
Porteus says.This leap forward in how to make cuts in our genetic code to repair it can be attributed to two scientists who won the Nobel Prize in chemistry in 2012 for developing CRISPR’s groundbreaking DNA “scissors.”
Genetic code-splicing technology can happen in vivo, meaning the editing takes place inside the human body, or in vitro, when immune cells or stem cells are extracted from people and then returned, once the errant gene is modified in the lab.
The implications of gene editing for a wide range of chronic conditions, then, are both exciting and potentially life-changing.Here’s where the research is at, right now, in treating specific disorders with gene editing with the aim of eliminating them in the near future.
An Effective (Expensive) Cure for Sickle Cell Disease
In December, the U.S.Food and Drug Administration (FDA) approved the first-ever treatment using CRISPR.It’s for
[sickle cell disease](/condition/sickle-cell-anemia/game-changing-gene-therapies-for-sickle-cell-disease) (SCD), an inherited, painful, and life-threatening blood disorder that causes red blood cells to take on a sickle-shape that limits blood and oxygen flow throughout the body.
The condition is caused by a single mutated gene and affects about 100,000 Americans, a disproportionate percentage of whom are Black, occurring in one out of every 365 Black or African American births.), according to the U.S.
Centers for Disease Control and Prevention (CDC).
People with SCD make red blood cells with faulty hemoglobin, which is what causes all that misshapen sickling, explains
Bruce Sullenger, Ph.D., a professor of surgery, pharmacology and cell biology in Durham, NC.
To treat the disease, stem cells are removed from a person’s bone marrow, collected from their blood.Next, they are edited in the lab and then infused back into the bloodstream, where they return to and repopulate the patient’s bone marrow.
“The therapy, Exa-cel, is delivered by CRISPR, and is designed to modify a certain DNA gene in the stem cells” says Dr.Sullenger.“The edited cells produce another form of hemoglobin known as fetal hemoglobin, restoring normal red blood cell function.” In other words, CRISPR delivers a new set of genetic instructions for red blood cells to make healthy hemoglobin going forward—effectively curing the disease in that patient.
As exciting as this is, it’s not known when CRISPR therapy for SCD will be available to the average person.A single treatment currently costs
$2.2 million dollars, according to American Family Physician, and comes with a recovery protocol that requires a four-to six-month hospital stay.
A Lead on Lowering High Cholesterol
There is now evidence that gene editing can reduce high, low-density lipoprotein cholesterol (LDL, or “bad” cholesterol), one of the major risk factors for
[heart disease](/category/heart-disease), in people with a genetic predisposition for the disease.(It’s possible the approach could work in people whose [high cholesterol](/condition/high-cholesterol) is driven by lifestyle choices alone, experts say, but most doctors would advise a change of diet and additional exercise, among other possible interventions, before considering this invasive technique.) High LDL can lead to plaque building up in the arteries that deliver blood flow to your heart, causing them to become narrow or blocked—and increasing risk for both [stroke](/condition/stroke) and [heart attack](/condition/heart-attack), per the CDC.
Preliminary results from a small
study of 10 people with familial hypercholesterolemia%20is%20a,disease%20at%20a%20younger%20age.), a genetic condition that causes extremely high cholesterol, found that inactivating a gene in the liver called PCSK9 that plays a role in producing LDL can significantly reduce bad cholesterol levels.
CRISPR delivers a single-course in vivo medicine called Verve 101 that targets PCSK9’s dysfunction, according to
Verve Therapeutics, who makes the drug.
“The study is showing sustained LDL reduction up to six months across 10 patients,” says
Nishant Shah, M.D., a cardiologist at Duke University Medical Center and Duke Clinical Research Institute in Durham, NC, who was not involved in the study.
Dr.Shah says the “one-and-done” aspect of gene editing treatment is a “major breakthrough for cardiovascular disease.In the current chronic care model, patients need to be on medications for life,” he adds.
“Needless to say, this can be burdensome, so we see inconsistent adherence patterns as life progresses.”
According to
the latest statistics from the American Heart Association, elevated LDL was responsible for more than 3.7 million deaths worldwide in 2021, in large part, says Dr.Shah, from poor medication adherence.But for the people who are genetically predisposed for developing high cholesterol and [heart disease](/condition/heart-disease), regardless of how well they follow their medication plans or adopt healthy diets, “this could be a game-changer,” he adds.
Even so, gene editing for inherited high LDL likely won’t be available any time soon.“The FDA can need up to 14 years before these therapies are approved for use.Long-term safety and efficacy need to be established.However, early results show promise,” notes Dr.Shah.
A Potential Cure for Cardiomyopathies?
[Cardiomyopathy](/condition/cardiomyopathy) is an umbrella term for any disorder that causes a structural abnormality of the heart, resulting in poor function.“ [Coronary artery disease](/condition/coronary-artery-disease-cad) is the most common cause, but cardiomyopathies can also be caused by inherited genetic mutations,” says Dr.
Shah.“And that’s where gene editing can help.By targeting that mutation, you can hopefully either treat or prevent the cardiomyopathy,” he explains.
For example, the cardiomyopathy
[ATTR amyloidosis](/condition/transthyretin-cardiac-amyloidosis) (transthyretin amyloidosis) is a life-threatening, heart-damaging disease caused by the production of too much TTR protein.
“There are currently investigational studies in small groups of people using CRISPR to deliver a single dose of the treatment NTLA-2001 in vivo to knock out the gene responsible for producing the TTR protein,” says Dr.
Shah.One early clinical trial being conducted with six people with hereditary amyloidosis reduced the amount of the protein TTR by 52% after 28 days; those given a higher dose of the serum showed a reduction of 87%.
“That’s huge,” says Dr.Shah.“By inhibiting the abnormal gene that leads to the disease we may be able to not only prevent progression of the disease, but we may also have the potential to prevent the disease from manifesting in the first place.”
But again, even though promising research is being conducted on people right now, it will likely take years before this approach to end inherited cardiomyopathies could become a reality.
Hereditary Angioedema Flares Reduced by 95%
In February of this year, successful
interim results from a 10-person study using CRISPR to treat the rare and painful genetic illness hereditary angioedema were published in the New England Journal of Medicine.
“Hereditary angioedema is a disease that comes with recurrent flares [throughout the body] of severe swelling that are spontaneous, unpredictable, and lifelong,” says Dr.
Porteus.The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway.
“This [gene editing] treatment is able to knock out the kallikrein B1 gene (KLKB1) that causes those flares,” he explains.
The
https://www.nejm.org/doi/full/10.1056/NEJMoa2309149 uses a single-dose therapy called NTLA-2002, which is made by Intellia Therapeutics (the same maker of the cardiomyopathy drug NTLA-2001).All 10 people who were studied showed a 95% reduction in their monthly attack rate, and nine out of 10 remained totally attack-free following the 16-week initial observation period through the latest follow-up.Results of the next research phase are expected to be released this year.
Base Editing and Beyond
Although we are many years away from treating most diseases using gene editing, research led by scientists like Drs.Sullenger and Porteus continue to get us closer, mostly by coming up with ways to sharpen CRISPR’s precision, making it more apt to hit its target gene.Because the current approach is not without risk.
“Gene editing runs the risk of missing its mark and zeroing in on an off-target gene, which can result in the alteration of the unintended part of the genome,” explains Dr.Sullenger.
A new version called
base editing (so named because the process works as the DNA base pair level), is proving more precise.
For now, the majority of gene editing research on most hereditary diseases such as type 1
diabetes, cystic fibrosis, Huntington’s disease, and inherited blindness, to name a few, is still being done on animals.And Dr.Porteus cautions against over-zeal.“There is a very large translational gap between a small study that shows promise in less than a dozen humans and a proven process in large, diverse populations when it comes to finding cures for disease,” he notes.
“Another key caveat for CRISPR gene editing’s success is that we have to understand the genetic basis for a disease in order for it to have an impact.And for most chronic diseases, a clear genetic determinant is not understood,” says Dr.Porteus.Meaning, gene editing can only be as successful as the current science is in identifying which particular gene leads to which specific disorder.
And, he adds, part of gene editing’s potential success will depend on how it makes its way from the lab to actual people with chronic conditions.“The issues of cost and complexity remain.
Until those issues are resolved, the accessibility of this therapy to all patients who might benefit will remain a challenge,” says Dr.Porteus.
Still, “for the first time, we’re seeing real possibilities for curing many genetic diseases by treating them at their source via gene editing,” says Dr.Sullenger.“It’s exciting as we continue to optimize the editing machinery.”
[Holly St.
Lifer, Health Writer:](/author/holly-st-lifer) [Arefa Cassoobhoy, M.D., M.P.H., Internal Medicine Physician :](/author/arefa-cassoobhoy)
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