Advancements in gene therapy and editing are offering the prospect of curing diseases that were once lifelong — and sometimes deadly.
David Vetter was well known across America by the time he passed away in 1984. His story was astounding: He lived in a sterile environment at home — a pressurized, germ-free, plastic enclosure — as scientists sought new treatments for his compromised immune system. The structure led to his nickname, “the bubble boy.”
A fault in David’s DNA impaired his ability to ward off everyday infections, resulting in a disease called severe combined immunodeficiency (SCID). Bone marrow transplants can cure the disease, but the donor must be a close match and, like more than 80% of SCID sufferers, David didn’t have one for most of his life.
Today, researchers are refining new approaches that offer the possibility of curing SCID without an organ donor. These gene-based techniques may one day cure thousands of other genetic afflictions. Through the related disciplines of gene therapy and gene editing, scientists are augmenting or even changing patient DNA in an attempt to cure illnesses that once led to blindness, muscle loss or even death.
“It’s a really new and fast-evolving space, but it’s also one of the more exciting spaces in our coverage universe,” says Capital Group biotechnology analyst Laura Nelson Carney. “It’s the next big horizon of innovation and disruption in medicine.”
The U.S. Food and Drug Administration has already approved some treatments, and researchers are testing many more — including one for David’s version of SCID. The National Institutes of Health published a paper last year that followed eight infants with the condition. While the trial is limited by its small size, the results are promising: All eight of the infants produced their own immune system cells, and three developed antibodies in response to vaccines. Separately, the European Union has approved the gene therapy Strimvelis for SCID; it’s one of the oldest gene therapies and the first to be approved.
Of course, no technology is a panacea, and gene manipulation is no exception. Genetic diseases are complex, and researchers are still figuring out which sicknesses this technology platform can address. While promising, gene-based therapies have little long-term data; only a few have been around long enough to generate five- and 10-year follow-ups. It’s possible that some of these techniques could fade in efficacy over time or carry unforeseen side effects. Additionally, as in traditional medical trials, even intriguing treatments can hit a wall if testing suggests they’re not safe or effective.
Nevertheless, the interrelated fields of gene therapy and editing represent an especially encouraging area of medical exploration, and they highlight the intriguing breakthroughs that clinicians are registering across a variety of fields. Thanks to landmark advances in clinical research and technology, scientists have made enormous progress in such diverse areas as cancer and hemophilia. The treatments under development have the potential to extend lives and improve the quality of daily existence for scores of patients.
“Unlike many traditional medical approaches, these tools can offer actual cures for some conditions,” says Skye Drynan, a Capital Group U.S. biopharmaceutical analyst. “This is a revolutionary step forward in medicine.”
Nelson Carney notes: “Aside from antibiotics, most drugs manage rather than cure disease. Gene therapies are cures.”
To grasp the significance of gene therapy and editing, it’s helpful to keep a few physiological truths in mind. The cells that make up our bodies are veritable factories, pumping out tens of thousands of distinct biochemicals that regulate day-to-day functions. But they require instructions, and that’s where DNA comes in. DNA is like a cookbook for these compounds, with each gene encoding a single chemical recipe.
However, these recipes aren’t set in stone. A cell’s DNA can be damaged during biological processes or by outside factors, such as radiation or viruses. When that damage affects a gene, it may also alter its biochemical recipe, which could result in ineffective or even harmful biochemicals.
Fortunately, most mutations don’t have significant effects and aren’t heritable — meaning they aren’t passed on to children. But mutations that occur in sperm and egg cells are heritable, and mutations that occur very early in a fertilized egg’s development become a core part of the resulting child’s DNA. Someone born with a mutated gene can pass it on to their children.
Negative outcomes associated with mutations are called genetic diseases. They can be caused by a single faulty gene but can also result from the interactions of multiple mutations, some or all of which may be individually harmless.
David’s form of SCID resulted from a flaw in a single gene. Because he didn’t have a working recipe for a specific protein, his body couldn’t create infection-fighting cells. That made him vulnerable to even mild infections — an opportunistic fungus that wouldn’t affect most of us would have grown unhindered in his body. A bone marrow donor’s healthy gene would have produced the missing protein and kick-started David’s immune system. David did eventually get his transplant, but the technology to screen donor tissue was less robust in the ‘80s. The bone marrow introduced a virus into David’s system, and he died months later.
This is where gene therapy and editing can come into play. Though there are clear distinctions between the two, both can augment DNA. The techniques can be accomplished in a number of ways, meaning that these separate approaches to genetic manipulation act more like a set of tools, each with its own advantages.
“If you look at a car engine, there’s more than one component at work there,” Drynan says. “If you take one single thing, you’re going to miss how everything is intertwined.”
In gene therapy, DNA isn’t changed. A functional gene is added to the patient’s cells, where it can help produce useful biochemicals. The gene is delivered through a “vector” — often a virus that scientists have hijacked. Instead of making patients sick, the virus adds the helpful gene to cells.
The technique has some limitations. It can only add a gene to a patient’s cells; it doesn’t alter or remove a harmful gene. And researchers aren’t sure if this change is permanent. For example, many of our cells divide and multiply, and new genes might not be copied as part of that process. In that case, the cure could be diluted or even erased over time. Hearteningly, few studies have shown gene therapy effects fading: The first SCID patients treated during the Strimvelis trials are still cured nearly 20 years later. However, that’s an outlier, as very few trials are more than a couple of years old. Robust, long-term data is needed to answer the question.
Gene editing goes a step further by allowing scientists to alter DNA. While editing can be used directly on patient cells, it’s also used in a wide variety of other techniques. Vectors, for example, are often created with gene editing. Several tools, including CRISPR technology, can be used to insert, remove or replace pieces of DNA or even whole genes. That added flexibility opens the door to treating a wider variety of diseases.
Editing has some downsides. Every time a cell is altered, there’s a risk of damaging its DNA. Additionally, some forms of this procedure introduce editing tools into the cell, where they can’t be retrieved, so they could possibly continue to affect the DNA. It’s an open question how much of a risk these challenges pose, and it’s something researchers are striving to better understand.
Still, several extremely promising real-world applications are already in use. In CAR-T cell therapy, scientists use gene editing to modify T cells — specialized “killer cells” that attack foreign bodies — to hunt down and eliminate blood cancers. The key to this technology resides on the surfaces of the tumor cells, which feature a suite of proteins that don’t exist in healthy cells. Scientists can change the T cells so they can sense and latch onto those proteins, allowing them to see and attack the cancer as though it were an infection.
“The CAR-T cells are more able to selectively and aggressively target and destroy tumor cells,” Drynan says. “They’re like bounty hunters searching for one particular person.”
The first of these cell therapies, Kymriah, was approved to fight acute lymphoblastic leukemia in 2017.
While several genetic therapies have been approved by the FDA and many more are being tested, researchers have catalogued thousands of genetic disorders. In other words, there’s plenty of room to expand this technology.
For example, FDA-approved gene therapies so far treat only diseases caused by a single faulty gene. However, many genetic conditions result from the subtle interactions of several mutations and are much more difficult to address. Breaking through that roadblock could yield huge dividends. Diabetes and cardiovascular disease both have genetic components, for example, and most cancers are the result of successive mutations. Although every disease is unique and will require its own treatment — and thus its own dedicated research — genetic treatments hold the potential to address or even cure many common conditions.
And there’s plenty of room to mature on cost. Right now, these techniques require a lot of specialized labor, expensive machines and long-term research. As a result, they have a high price tag. Zolgensma, a gene therapy for spinal muscular atrophy (SMA), which progressively weakens muscle tissue and at its most severe is lethal in infants, costs a record $2.15 million per dose. However, there’s another gene therapy that might top Zolgensma’s price: Valrox, a treatment for hemophilia that the FDA is reviewing. It might run as much as $3 million a dose.
Right now, insurers are likely to pick up the tab. SMA is a rare disease, so even big insurers aren’t likely to encounter more than a couple claims a year. They’re more concerned with the overall bottom line than the price per patient, Nelson Carney says, so the cost is less shocking than it may look. And if Valrox is approved and proves long-lasting, it could be less expensive than lifetime treatment, so there’s a possibility that it will save money despite its high price. However, when a treatment of this kind is required by hundreds or thousands of patients annually, insurers will be unable to cover it. This is where advances in the manufacturing process could boost the field; some diseases are just not economically feasible to research right now. Lower costs will increase the number of sensible research targets, and that’s good for everyone — patients, researchers and businesses.
There are many avenues for research, including possible “off the shelf” treatments that won’t conflict with patient immune systems, or much more efficient delivery systems that could better treat some diseases. The field is wide open right now. The explosion of powerful data processing and gene-editing tools have positioned researchers to make great strides toward treatments that were dreams just five years ago.
The above article originally appeared in the Spring 2020 issue of Quarterly Insights magazine.