Stem cells and gene therapy were supposed to revolutionize biomedicine around the turn of the millennium and provide relief for desperate patients with incurable diseases. But for many, progress has been frustratingly slow. We still cannot, for example, regenerate damaged organs like a salamander regrows its tail, and genome engineering is more complicated than cutting and pasting letters in a word document.
"There are a number of things that make [the eye] ideal for new experimental therapies which are not true necessarily in other organs."
For blind people, however, the future of medicine is one step closer to reality. In December, the FDA approved the first gene therapy for an inherited disease—a mutation in the gene RPE65 that causes a rare form of blindness. Several clinical trials also show promise for treating various forms of retinal degeneration using stem cells.
"It's not surprising that the first gene therapy that was approved by the FDA was a therapy in the eye," says Bruce Conklin, a senior investigator at the San Francisco-based Gladstone Institutes, a nonprofit life science research organization, and a professor in the Medical Genetics and Molecular Pharmacology department at the University of California, San Francisco. "There are a number of things that make it ideal for new experimental therapies which are not true necessarily in other organs."
Physicians can easily see into the eye to check if a procedure worked or if it's causing problems. "The imaging technology within the eye is really unprecedented. You can't do this in someone's spinal cord or someone's brain cells or immune system," says Conklin, who is also deputy director of the Innovative Genomics Institute.
There's also a built-in control: researchers can test an intervention on one eye first. What's more, if something goes wrong, the risk of mortality is low, especially when compared to experimenting on the heart or brain. Most types of blindness are currently incurable, so the risk-to-reward ratio for patients is high. If a problem arises with the treatment their eyesight could get worse, but if they do nothing their vision will likely decline anyway. And if the treatment works, they may be able to see for the first time in years.
An additional appeal for testing gene therapy in the eye is the low risk for off-target effects, in which genome edits could result in unintended changes to other genes or in other cell types. There are a number of genes that are solely expressed in the eye and not in any other part of the body. Manipulating those genes will only affect cells in the eye, so concerns about the impact on other organs are minimal.
Ninety-three percent of patients who received the injection had improved vision just one month after treatment.
RPE65 is one such gene. It creates an enzyme that helps the eye convert light into an electrical signal that travels back to the brain. Patients with the mutation don't produce the enzyme, so visual signals are not processed. However, the retinal cells in the eye remain healthy for years; if you can restore the missing enzyme you can restore vision.
The newly approved therapy, developed by Spark Therapeutics, uses a modified virus to deliver RPE65 into the eye. A retinal surgeon injects the virus, which has been specially engineered to remove its disease-causing genes and instead carry the correct RPE65 gene, into the retina. There, it is sucked up by retinal pigment epithelial (RPE) cells. The RPE cells are a particularly good target for injection because their job is to eat up and recycle rogue particles. Once inside the cell, the virus slips into the nucleus and releases the DNA. The RPE65 gene then goes to work, using the cell's normal machinery to produce the needed enzyme.
In the most recent clinical trial, 93 percent of patients who received the injection—who range in age from 4 to 44—had improved vision just one month after treatment. So far, the benefits have lasted at least two years.
"It's an exciting time for this class of diseases, where these people have really not had treatments," says Spark president and co-founder, Katherine High. "[Gene therapy] affords the possibility of treatment for diseases that heretofore other classes of therapeutics really have not been able to help."
Another benefit of the eye is its immune privilege. In order to let light in, the eye must remain transparent. As a result, its immune system is dampened so that it won't become inflamed if outside particles get in. This means the eye is much less likely to reject cell transplants, so patients do not need to take immunosuppressant drugs.
One study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells in the eye.
Henry Klassen, an assistant professor at UC Irvine, is taking advantage of the eye's immune privilege to transplant retinal progenitor cells into the eye to treat retinitis pigmentosa, an inherited disease affecting about 1 in 4000 people that eventually causes the retina to degenerate. The disease can stem from dozens of different genetic mutations, but the result is the same: RPE cells die off over the course of a few decades, leaving the patient blind by middle age. It is currently incurable.
Retinal progenitor cells are baby retinal cells that develop naturally from stem cells and will turn into one of several types of adult retinal cells. When transplanted into a patient's eye, the progenitor cells don't replace the lost retinal cells, but they do secrete proteins and enzymes essential for eye health.
"At the stage we get the retinal tissue it's immature," says Klassen. "They still have some flexibility in terms of which mature cells they can turn into. It's that inherent flexibility that gives them a lot of power when they're put in the context of a diseased retina."
Klassen's spin-off company, jCyte, sponsored the clinical trial with support from the California Institute for Regenerative Medicine. The results from the initial study haven't been published yet, but Klassen says he considers it a success. JCyte is now embarking on a phase two trial to assess improvements in vision after the treatment, which will wrap up in 2021.
Another study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells (iPSC) in the eye. iPSC are created by reprogramming a patient's own skin cells into stem cells, circumventing any controversy around embryonic stem cell sources. In the trial, led by Masayo Takahashi at RIKEN, the scientists transplant retinal pigment epithelial cells created from iPSC into the retinas of patients with age-related macular degeneration. The first woman to receive the treatment is doing well, and her vision is stable. However, the second patient suffered a swollen retina as a result of the surgery. Despite this recent setback, Takahashi said last week that the trial would continue.
Although recent studies have provided patients with renewed hope, the field has not been without mishap. Most notably, an article in the New England Journal of Medicine last March described three patients who experienced severe side effects after receiving stem cell injections from a Florida clinic to treat age-related macular degeneration. Following the initial article, other reports came out about similar botched treatments. Lawsuits have been filed against US Stem Cell, the clinic that conducted the procedure, and the FDA sent them a warning letter with a long list of infractions.
"One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials."
Ajay Kuriyan, an ophthalmologist and retinal specialist at the University of Rochester who wrote the paper, says that because details about the Florida trial are scarce, it's hard to say why the treatment caused the adverse reaction. His guess is that the stem cells were poorly prepared and not up to clinical standards.
Klassen agrees that small clinics like US Stem Cell do not offer the same caliber of therapy as larger clinical trials. "It's not the same cells and it's not the same technique and it's not the same supervision and it's not under FDA auspices. It's just not the same thing," he says. "Unfortunately, to the patient it might sound the same, and that's the tragedy for me."
For patients who are interested in joining a trial, Kuriyan listed a few things to watch out for. "One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials," he says. "Another big red flag is doing the procedure in both eyes" at the same time. Third, if the only treatment offered is cell therapy. "These clinics tend to be sort of stand-alone clinics, and that's not very common for an actual big research study of this scale."
Despite the recent scandal, Klassen hopes that the success of his trial and others will continue to push the field forward. "It just takes so many decades to move this stuff along, even when you're trying to simplify it as much as possible," he says. "With all the heavy lifting that's been done, I hope the world's got the patience to get this through."
On the morning of April 12, 1955, newsrooms across the United States inked headlines onto newsprint: the Salk Polio vaccine was "safe, effective, and potent." This was long-awaited news. Americans had limped through decades of fear, unaware of what caused polio or how to cure it, faced with the disease's terrifying, visible power to paralyze and kill, particularly children.
The announcement of the polio vaccine was celebrated with noisy jubilation: church bells rang, factory whistles sounded, people wept in the streets. Within weeks, mass inoculation began as the nation put its faith in a vaccine that would end polio.
Today, most of us are blissfully ignorant of child polio deaths, making it easier to believe that we have not personally benefited from the development of vaccines. According to Dr. Steven Pinker, cognitive psychologist and author of the bestselling book Enlightenment Now, we've become blasé to the gifts of science. "The default expectation is not that disease is part of life and science is a godsend, but that health is the default, and any disease is some outrage," he says.
The Rise and Fall of Public Trust<p>When the polio vaccine was released in 1955, "we were nearing an all-time high point in public trust," says Matt Baum, Harvard Kennedy School professor and lead author of <a href="http://www.kateto.net/covid19/COVID19%20CONSORTIUM%20REPORT%2013%20TRUST%20SEP%202020.pdf" target="_blank" rel="noopener noreferrer"><u>several</u></a> <a href="https://shorensteincenter.org/wp-content/uploads/2020/09/COVID19-CONSORTIUM-REPORT-14-MISINFO-SEP-2020.pdf" target="_blank" rel="noopener noreferrer"><u>reports</u></a> measuring public trust and vaccine confidence. Baum explains that the U.S. was experiencing a post-war boom following the Allied triumph in WWII, a popular Roosevelt presidency, and the rapid innovation that elevated the country to an international superpower.</p><p> The 1950s witnessed the emergence of nuclear technology, a space program, and unprecedented medical breakthroughs, adds Emily Brunson, Texas State University anthropologist and co-chair of the Working Group on Readying Populations for COVID-19 Vaccine. "Antibiotics were a game changer," she states. While before, people got sick with pneumonia for a month, suddenly they had access to pills that accelerated recovery. </p><p>During this period, science seemed to hold all the answers; people embraced the idea that we could "come to know the world with an absolute truth," Brunson explains. Doctors were portrayed as unquestioned gods, so Americans were primed to trust experts who told them the polio vaccine was safe. </p>
The Shift in How We Consume Information<p>In the 1950s, the media created an informational consensus. The fundamental ideas the public consumed about the state of the world were unified. "People argued about the best solutions, but didn't fundamentally disagree on the factual baseline," says Baum. Indeed, the messaging around the polio vaccine was centralized and consistent, led by President Roosevelt's successful <a href="https://files.eric.ed.gov/fulltext/EJ978264.pdf" target="_blank" rel="noopener noreferrer"><u>March of Dimes crusade</u></a>. People of lower socioeconomic status with limited access to this information were <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1551508/?page=3" target="_blank" rel="noopener noreferrer"><u>less likely to have confidence</u></a> in the vaccine, but most people consumed <a href="https://www.c-span.org/video/?506891-1/a-special-report-polio" target="_blank" rel="noopener noreferrer"><u>media that assured them</u></a> of the vaccine's safety and <a href="https://www.cbsnews.com/news/the-salk-polio-vaccine-greatest-public-health-experiment-in-history/" target="_blank" rel="noopener noreferrer"><u>mobilized them</u></a> to receive it. </p><p>Today, the information we consume is no longer centralized—in fact, just the opposite. "When you take that away, it's hard for people to know what to trust and what not to trust," Baum explains. We've witnessed an increase in polarization and the technology that makes it easier to give people what they want to hear, reinforcing the human tendencies to vilify the other side and reinforce our preexisting ideas. When information is engineered to further an agenda, each choice and risk calculation made while navigating the COVID-19 pandemic <a href="https://www.nytimes.com/2020/12/19/opinion/sunday/coronavirus-science.html?referringSource=articleShare" target="_blank" rel="noopener noreferrer"><u>is deeply politicized</u></a>. </p><p>This polarization maps onto a rise in socioeconomic inequality and economic uncertainty. These factors, associated with a sense of lost control, prime people to embrace misinformation, explains Baum, especially when the situation is difficult to comprehend. "The beauty of conspiratorial thinking is that it provides answers to all these questions," he says. Today's insidious fragmentation of news media accelerates the circulation of mis- and disinformation, reaching more people faster, regardless of veracity or motivation. In the case of vaccines, skepticism around their origin, safety, and motivation is intensified. </p><p>Alongside the rise in polarization, Pinker says "the emotional tone of the news has gone downward since the 1940s, and journalists consider it a professional responsibility to cover the negative." Relentless focus on everything that goes wrong further erodes public trust and paints a picture of the world getting worse. "Life saved is not a news story," says Pinker, but perhaps it should be, he continues. "If people were more aware of how much better life was generally, they might be more receptive to improvements that will continue to make life better. These improvements don't happen by themselves."</p>
The Future Depends on Vaccine Confidence<p>So far, the U.S. has been unable to mitigate the catastrophic effects of the pandemic through social distancing, testing, and contact tracing. President Trump has <a href="https://www.washingtonpost.com/politics/bob-woodward-rage-book-trump/2020/09/09/0368fe3c-efd2-11ea-b4bc-3a2098fc73d4_story.html" target="_blank" rel="noopener noreferrer"><u>downplayed the effects and threat of the virus</u></a>, <a href="https://www.washingtonpost.com/outlook/2020/07/14/cdc-directors-trump-politics/" target="_blank" rel="noopener noreferrer"><u>censored experts and scientists</u></a>, <a href="https://www.theatlantic.com/science/archive/2020/06/america-giving-up-on-pandemic/612796/" target="_blank" rel="noopener noreferrer"><u>given up on containing the spread</u></a>, and <a href="https://www.nytimes.com/2020/09/16/world/covid-coronavirus.html" target="_blank" rel="noopener noreferrer"><u>mobilized his base to protest masks</u></a>. The Trump Administration failed to devise a national plan, so our national plan has defaulted to hoping for the <a href="https://www.politico.com/news/2020/08/26/nation-of-miracles-pence-coronavirus-vaccine-rnc-402949" target="_blank" rel="noopener noreferrer"><u>"miracle" of a vaccine</u></a>. And they are "something of a miracle," Pinker says, describing vaccines as "the most benevolent invention in the history of our species." In record-breaking time, three vaccines have arrived. But their impact will be weakened unless we achieve mass vaccination. As Brunson notes, "The technology isn't the fix; it's people taking the technology."</p><p> Significant challenges remain, including facilitating widespread access and supporting on-the-ground efforts to allay concerns and build trust with <a href="https://www.newyorker.com/news/daily-comment/african-american-resistance-to-the-covid-19-vaccine-reflects-a-broader-problem" target="_blank" rel="noopener noreferrer"><u>specific populations with historic reasons for distrust</u></a>, says Brunson. Baum predicts continuing delays as well as deaths from other causes that will be linked to the vaccine. </p><p> Still, there's every reason for hope. The new administration "has its eyes wide open to these challenges. These are the kind of problems that are amenable to policy solutions if we have the will," Baum says. He forecasts widespread vaccination by late summer and a bounce back from the economic damage, a "Good News Story" that will bolster vaccine acceptance in the future. And Pinker reminds us that science, medicine, and public health have greatly extended our lives in the last few decades, a trend that can only continue if we're willing to roll up our sleeves. </p>
Imagine this scenario: you get an annoying cough and a bit of a fever. When you wake up the next morning you lose your sense of taste and smell. That sounds familiar, so you head to a doctor's office for a Covid test, which comes back positive.
Your next step? An anti-Covid nasal spray of course, a "trickster drug" that will clear the once-dangerous and deadly virus out of the body. The drug works by tricking the coronavirus with decoy receptors that appear to be just like those on the surface of our own cells. The virus latches onto the drug's molecules "thinking" it is breaking into human cells, but instead it flushes out of your system before it can cause any serious damage.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
Biochemist David Baker, pictured in his lab at the University of Washington.