Maybe the science is finally catching up with BioViva CEO Elizabeth Parrish.
Gene therapy has come a long way since it was first used on humans 33 years ago. Since 2000, incremental progress has expanded the use of ex vivo gene therapy (where cells are harvested from a person, genetically modified, and then infused back into the person’s bloodstream). And in vivo gene therapy, which involves injecting genes directly into the body, has proven safe and effective in a number of clinical trials. It is becoming available as a treatment to a wider range of circumstances. One realm in which in vivo gene therapy has really taken off is in treating diseases of the retina, including macular degeneration. Such cases involve injection of therapies into the eye, which sounds unpleasant, but the strategy has been wildly successful—curing blindness for many people.
The progress has also led to some spectacular successes, finding permanent cures for many young people of a range of recessive inherited diseases, from hemophilia to hereditary blindness and hereditary immune conditions like severe combined immunodeficiency (sometimes called “bubble boy disease”).
As a therapeutic approach, however, gene therapy suffers somewhat from the undue weight of exuberant expectations. For years people have speculated about applications going beyond restoration of lost body function and into biological enhancement, such as longevity. Some now categorize gene therapy as belonging to the realm of transhumanism—the use of medical and surgical interventions to enhance the body, or give it extra capabilities, as opposed to treating things that go wrong.
All this still seems like science fiction, and indeed, the current process that moves ideas through basic research, safety testing, and clinical trials is sometimes torturously long. Even for therapies devised to work directly against top causes of death, like coronary artery disease and cancer, taking a drug from the laboratory through clinical trials and FDA approval can take approximately ten years on average.
But this reality has not stopped one particular biotech CEO from being a human test subject in gene therapy research aimed at extending lifespan, and especially healthspan, the number of healthy years lived. A recipient of four therapies in vivo, administered over the course of two trips outside the United States, one in 2015, another in 2020, Elizabeth Parrish, CEO of BioViva, is the only known human to have received such therapy with longevity as the clinical goal.
In 2015, Parrish’s gene therapies consisted of receiving extra copies of the gene telomerase reverse transcriptase (TERT), which produces a protein that lengthens the tips of chromosomes and may keep cells younger, and the gene FST, which makes the enzyme follistatin and may preserve or increase muscle mass. She has received two other genes thought to be important for slowing aging.
All four genes are thought to be important for longevity because they address fundamental molecular processes linked to age-related pathologies, like muscle wasting and shortening of the tips of chromosomes, which leads to deterioration of cell function. Studies of long-lived animals and families with exceptional longevity show extra copies or excessive activity among these genes compared with their activity in typical humans. Furthermore, the idea to utilize such approaches in humans is supported by laboratory studies with rodents and C. elegans worms. However, there are no clinical trials involving gene therapy in humans to extend their lifespans and healthspans. There is only Liz.
Her therapies were administered at an offshore clinic in 2015 and in 2020, but on both trips Parrish needed to receive each gene as a separate injection. More than one gene could not be combined, because the vector—the entity used to enclose the genetic payload for its trip through the bloodstream to target cells—was an adeno-associated virus (AAV). This viral vector is thought to be safer than certain other vectors used in earlier gene therapy work, because it delivers genes as “episomes”—DNA that enters the cell nucleus and functions, but does not integrate into the cell’s chromosomes—and because it produces less of an immune reaction than earlier used vectors. It only has the payload capacity for one gene at a time, however, and they have to be fairly small genes.
“The ability to safely deliver the payload as an episome—and a relatively large episome at that—is encouraging, and if replicated in humans may be a significant advance.”
But a study published this past May in PNAS has demonstrated that another common virus, called cytomegalovirus (CMV), works well as a vector for TERT and for FST, at least in mice. It can carry a much larger genetic payload. Together with the finding that the cytomegalovirus-packaged gene therapies, delivered by injection or intranasally, increased the lifespan of the mice by 41 percent without increasing the cancer risk, the finding is extremely encouraging.
“We’re particularly interested in the CMV vector because its immunogenicity is low like AAV, and it delivers the genetic payload as an episome rather than merging it with the recipient’s chromosomes—but also because of the much larger genetic payload that CMV can carry,” says Parrish. Her company, BioViva, was not involved in the study, but she emphasized how it could impact gene therapy. Each of her own four different gene therapies required its own AAV vector. That’s important, because despite its relative safety, AAVs may still be toxic if given in a high enough dose, which could be a concern for someone receiving numerous genes in one session. “Using CMV instead, we’d be able to deliver an overall lower vector dose because more genes can be packed into each vector.”
If gene therapy intervention to counteract aging strikes you as overly optimistic or premature, keep in mind that researchers are also eying the new study from the standpoint of diseases that are not necessarily all related to aging.
“As a clinical geneticist, I’m less concerned about changing the overall human lifespan than the healthspan—how we might keep people healthier for longer,” notes Shane McKee, a consultant in genetic and genomic medicine at Northern Ireland Regional Genetics Center in Belfast City Hospital, who was not involved in the study. “This CMV method, with its high genetic payload capacity, has therapeutic potential against so many medical conditions, without some of the risks of CRISPR and other gene therapy techniques.”
CRISPR editing of DNA often makes headlines—as well as sci-fi TV shows—because it allows us to alter the chromosomal DNA itself with high precision. However, McKee notes that “off-target” effects of CRISPR may run the risk of knocking out important genes, and potentially causing problems in those cells. Until there are better targeting methods, there is some concern that CRISPR might disrupt chromosomal sequences, leading to dangers similar to those that came up in the early days of gene therapies when it was delivered in retrovirus vectors. “The ability to safely deliver the payload as an episome—and a relatively large episome at that—is encouraging, and if replicated in humans may be a significant advance,” says McKee.
The future is about safety
Certainly it’s possible that beckoning, novel approaches, like therapies encoded in mRNA carried within microscopic lipid particles (like the mRNA in the COVID-19 vaccines of Pfizer-BioNTech and Moderna) or CRISPR gene editing administered in vivo, may eventually render traditional gene therapy obsolete, even when delivered by the currently promising-looking CMV vectors. But all technologies must remain available for clinical application, as the story of gene therapy has not always gone smoothly, especially with regard to vectors.
Early on, researchers relied on retroviruses as vectors—such as in the first human gene therapy in 1989, when researchers modified immune cells known as lymphocytes outside the body, then infused them to render cancer cells more vulnerable to a drug, delivering the genetic payload directly into the host’s chromosomes. Research progressed from there to adenoviruses, whose payload did get delivered as an episome, so that was an improvement, but adenoviruses proved extremely immunogenic. Such hyper-stimulation of the host’s immune system led to the tragic and heroic death of Jesse Gelsinger in 1999. Suffering from a hereditary deficiency that caused ammonia to accumulate in his body, the 20-year-old Gelsinger volunteered for a clinical study at the University of Pennsylvania, not because he couldn’t live indefinitely without the treatment, but to help children with more severe forms of his disease.
The advent of the less immunogenic AAV in place of adenoviruses several years later thus represented a major step forward, leading to Parrish’s ability to weigh potential benefits against the risks in her case. This new mouse study using CMV now opens a new chapter.
“It is remarkable that, by providing copies of two genes (TERT and FST), they see marked improvement in their experimental mice, and their results suggest that complex disorders (like type 2 diabetes and muscular dystrophy) could someday be routinely treated using these viral vectors and gene therapy,” says Maia Larios Sanz, associate professor and chair of biology at the University of St. Thomas in Houston, who also was not involved in the new research. “The study sets the foundation for further work that can help cement the use of these viral delivery systems to ease many of the maladies that affect humanity, especially as our bodies decline with age.”
Medicine is coming to recognize that aging itself is a disease.
Also worth noting is that gene therapy with an otherwise pernicious virus like CMV constitutes yet another example of a negative phenomenon in medicine being transformed into a beneficial technique. Botulinum toxin comes from Clostridium botulinum bacteria, one of the major causes of foodborne illness. It’s what makes those bacteria so deadly. But the same toxin, known therapeutically as Botox, is an effective treatment for various neuromuscular conditions like strabismus (crossed eyes), facial spasm, cervical dystonia, muscle spasticity (and yes, also for cosmetic treatments to get rid of wrinkles). Like the bacterium from which Botox derives, CMV is also a cause of disease. Along with being the second most common cause of mononucleosis (a different virus called Epstein Barr is the first), CMV infections are a major threat to immunocompromised people.
Despite the flashiness of the longevity study in which she herself is a guinea pig, Parrish sees herself as a pragmatist. Medicine is coming to recognize that aging itself is a disease, and we may be inching ever closer to the day when treatments to prevent aging and the diseases of aging are considered routine, like childhood vaccinations, and not exotic experiments of dubious social value. Eight billion people on Earth could benefit from gene therapies, she says. That’s her motivation.
“Forty-one million people will die this year of aging,” notes Parrish, not counting elderly people dying of cases of COVID-19 made more severe on account of their old age. “That comes out to 63 percent of human deaths.”
