Researchers Are Testing a New Stem Cell Therapy in the Hopes of Saving Millions from Blindness
NIH researchers in Kapil Bharti's lab work toward the development of induced pluripotent stem cells to treat dry age-related macular degeneration.
Of all the infirmities of old age, failing sight is among the cruelest. It can mean the end not only of independence, but of a whole spectrum of joys—from gazing at a sunset or a grandchild's face to reading a novel or watching TV.
The Phase 1 trial will likely run through 2022, followed by a larger Phase 2 trial that could last another two or three years.
The leading cause of vision loss in people over 55 is age-related macular degeneration, or AMD, which afflicts an estimated 11 million Americans. As photoreceptors in the macula (the central part of the retina) die off, patients experience increasingly severe blurring, dimming, distortions, and blank spots in one or both eyes.
The disorder comes in two varieties, "wet" and "dry," both driven by a complex interaction of genetic, environmental, and lifestyle factors. It begins when deposits of cellular debris accumulate beneath the retinal pigment epithelium (RPE)—a layer of cells that nourish and remove waste products from the photoreceptors above them. In wet AMD, this process triggers the growth of abnormal, leaky blood vessels that damage the photoreceptors. In dry AMD, which accounts for 80 to 90 percent of cases, RPE cells atrophy, causing photoreceptors to wither away. Wet AMD can be controlled in about a quarter of patients, usually by injections of medication into the eye. For dry AMD, no effective remedy exists.
Stem Cells: Promise and Perils
Over the past decade, stem cell therapy has been widely touted as a potential treatment for AMD. The idea is to augment a patient's ailing RPE cells with healthy ones grown in the lab. A few small clinical trials have shown promising results. In a study published in 2018, for example, a University of Southern California team cultivated RPE tissue from embryonic stem cells on a plastic matrix and transplanted it into the retinas of four patients with advanced dry AMD. Because the trial was designed to test safety rather than efficacy, lead researcher Amir Kashani told a reporter, "we didn't expect that replacing RPE cells would return a significant amount of vision." Yet acuity improved substantially in one recipient, and the others regained their lost ability to focus on an object.
Therapies based on embryonic stem cells, however, have two serious drawbacks: Using fetal cell lines raises ethical issues, and such treatments require the patient to take immunosuppressant drugs (which can cause health problems of their own) to prevent rejection. That's why some experts favor a different approach—one based on induced pluripotent stem cells (iPSCs). Such cells, first produced in 2006, are made by returning adult cells to an undifferentiated state, and then using chemicals to reprogram them as desired. Treatments grown from a patient's own tissues could sidestep both hurdles associated with embryonic cells.
At least hypothetically. Today, the only stem cell therapies approved by the U.S. Food and Drug Administration (FDA) are umbilical cord-derived products for various blood and immune disorders. Although scientists are probing the use of embryonic stem cells or iPSCs for conditions ranging from diabetes to Parkinson's disease, such applications remain experimental—or fraudulent, as a growing number of patients treated at unlicensed "stem cell clinics" have painfully learned. (Some have gone blind after receiving bogus AMD therapies at those facilities.)
Last December, researchers at the National Eye Institute in Bethesda, Maryland, began enrolling patients with dry AMD in the country's first clinical trial using tissue grown from the patients' own stem cells. Led by biologist Kapil Bharti, the team intends to implant custom-made RPE cells in 12 recipients. If the effort pans out, it could someday save the sight of countless oldsters.
That, however, is what's technically referred to as a very big "if."
The First Steps
Bharti's trial is not the first in the world to use patient-derived iPSCs to treat age-related macular degeneration. In 2013, Japanese researchers implanted such cells into the eyes of a 77-year-old woman with wet AMD; after a year, her vision had stabilized, and she no longer needed injections to keep abnormal blood vessels from forming. A second patient was scheduled for surgery—but the procedure was canceled after the lab-grown RPE cells showed signs of worrisome mutations. That incident illustrates one potential problem with using stem cells: Under some circumstances, the cells or the tissue they form could turn cancerous.
"The knowledge and expertise we're gaining can be applied to many other iPSC-based therapies."
Bharti and his colleagues have gone to great lengths to avoid such outcomes. "Our process is significantly different," he told me in a phone interview. His team begins with patients' blood stem cells, which appear to be more genomically stable than the skin cells that the Japanese group used. After converting the blood cells to RPE stem cells, his team cultures them in a single layer on a biodegradable scaffold, which helps them grow in an orderly manner. "We think this material gives us a big advantage," Bharti says. The team uses a machine-learning algorithm to identify optimal cell structure and ensure quality control.
It takes about six months for a patch of iPSCs to become viable RPE cells. When they're ready, a surgeon uses a specially-designed tool to insert the tiny structure into the retina. Within days, the scaffold melts away, enabling the transplanted RPE cells to integrate fully into their new environment. Bharti's team initially tested their method on rats and pigs with eye damage mimicking AMD. The study, published in January 2019 in Science Translational Medicine, found that at ten weeks, the implanted RPE cells continued to function normally and protected neighboring photoreceptors from further deterioration. No trace of mutagenesis appeared.
Encouraged by these results, Bharti began recruiting human subjects. The Phase 1 trial will likely run through 2022, followed by a larger Phase 2 trial that could last another two or three years. FDA approval would require an even larger Phase 3 trial, with a decision expected sometime between 2025 and 2028—that is, if nothing untoward happens before then. One unknown (among many) is whether implanted cells can thrive indefinitely under the biochemically hostile conditions of an eye with AMD.
"Most people don't have a sense of just how long it takes to get something like this to work, and how many failures—even disasters—there are along the way," says Marco Zarbin, professor and chair of Ophthalmology and visual science at Rutgers New Jersey Medical School and co-editor of the book Cell-Based Therapy for Degenerative Retinal Diseases. "The first kidney transplant was done in 1933. But the first successful kidney transplant was in 1954. That gives you a sense of the time frame. We're really taking the very first steps in this direction."
Looking Ahead
Even if Bharti's method proves safe and effective, there's the question of its practicality. "My sense is that using induced pluripotent stem cells to treat the patient from whom they're derived is a very expensive undertaking," Zarbin observes. "So you'd have to have a very dramatic clinical benefit to justify that cost."
Bharti concedes that the price of iPSC therapy is likely to be high, given that each "dose" is formulated for a single individual, requires months to manufacture, and must be administered via microsurgery. Still, he expects economies of scale and production to emerge with time. "We're working on automating several steps of the process," he explains. "When that kicks in, a technician will be able to make products for 10 or 20 people at once, so the cost will drop proportionately."
Meanwhile, other researchers are pressing ahead with therapies for AMD using embryonic stem cells, which could be mass-produced to treat any patient who needs them. But should that approach eventually win FDA approval, Bharti believes there will still be room for a technique that requires neither fetal cell lines nor immunosuppression.
And not only for eye ailments. "The knowledge and expertise we're gaining can be applied to many other iPSC-based therapies," says the scientist, who is currently consulting with several companies that are developing such treatments. "I'm hopeful that we can leverage these approaches for a wide range of applications, whether it's for vision or across the body."
NEI launches iPS cell therapy trial for dry AMD
n artist rendering of a "smart toilet" that gathers biometric data to monitor a person's health in real time.
It looks like an ordinary toilet but it is anything but. The "smart toilet" is the diagnostic tool of the future, equipped with cameras that take snapshots of the users and their waste, motion sensors to analyze what's inside the urine and stool samples, and software that automatically sends data to a secure, cloud-based system that can be easily accessed by your family doctor.
"It's a way of doing community surveillance. If there is a second wave of infections in the future, we'll know right away."
Using urine "dipstick tests" similar to the home pregnancy strips, the smart toilet can detect certain proteins, immune system biomarkers and blood cells that indicate the presence of such diseases as infections, bladder cancer, and kidney failure.
The rationale behind this invention is that some of the best ways of detecting what's going on in our bodies is by analyzing the substances we excrete every day, our sweat, urine, saliva and yes, our feces. Instead of getting sporadic snapshots from doctor's visits once or twice a year, the smart toilet provides continuous monitoring of our health 24/7, so we can catch the tell-tale molecular signature of illnesses at their earliest and most treatable stages. A brainchild of Stanford University researchers, they're now working to add a COVID-19 detection component to their suite of technologies—corona virus particles can be spotted in stool samples—and hope to have the system available within the year.
"We can connect the toilet system to cell phones so we'll know the results within 30 minutes," says Seung-min Park, a lead investigator on the research team that devised this technology and a senior research scientist at the Stanford University School of Medicine. "The beauty of this technology is that it can continuously monitor even after this pandemic is over. It's a way of doing community surveillance. If there is a second wave of infections in the future, we'll know right away."
Experts believe that the COVID-19 pandemic will accelerate the widespread acceptance of in-home diagnostic tools such as this. "Shock events" like pandemics can be catalysts for sweeping changes in society, history shows us. The Black Death marked the end of feudalism and ushered in the Renaissance while the aftershocks of the Great Depression and two world wars in the 20th century led to the social safety net of the New Deal and NATO and the European Union. COVID-19 could fundamentally alter the way we deliver healthcare, abandoning the outdated 20th century brick and mortar fee-for-service model in favor of digital medicine. At-home diagnostics may be the leading edge of this seismic shift and the pandemic could accelerate the product innovations that allow for home-based medical screening.
"That's the silver lining to this devastation," says Dr. Leslie Saxon, executive director of the USC Center for Body Computing at the Keck School of Medicine in Los Angeles. As an interventional cardiologist, Saxon has spent her career devising and refining the implantable and wearable wireless devices that are used to treat and diagnose heart conditions and prevent sudden death. "This will open up innovation—research has been stymied by a lack of imagination and marriage to an antiquated model," she adds. "There are already signs this is happening—relaxing state laws about licensure, allowing physicians to deliver health care in non-traditional ways. That's a real sea change and will completely democratize medical information and diagnostic testing."
Ironically, diagnostics have long been a step-child of modern medicine, even though accurate and timely diagnostics play a crucial role in disease prevention, detection and management. "The delivery of health care has proceeded for decades with a blind spot: diagnostic errors—inaccurate or delayed diagnoses—persist throughout all settings of care and continue to harm an unacceptable number of patients," according to a 2015 National Academy of Medicine report. That same report found as many as one out of five adverse events in the hospital result from these errors and they contribute to 10 percent of all patient deaths.
The pandemic should alter the diagnostic landscape. We already have a wealth of wearable and implantable devices, like glucose sensors to monitor blood sugar levels for diabetics, Apple's smart watch, electrocardiogram devices that can detect heart arrythmias, and heart pacemakers.
The Food and Drug Administration is working closely with in-home test developers to make accurate COVID-19 diagnostic tools readily available and has so far greenlighted three at-home collection test kits. Two, LabCorp's and Everlywell's, use nasal swabs to take samples. The third one is a spit test, using saliva samples, that was devised by a Rutgers University laboratory in partnership with Spectrum Solutions and Accurate Diagnostic Labs.
The only way to safely reopen is through large scale testing, but hospitals and doctors' offices are no longer the safest places.
In fact, DIY diagnostic company Everlywell, an Austin, Texas- based digital health company, already offers more than 30 at-home kits for everything from fertility to food sensitivity tests. Typically, consumers collect a saliva or finger-prick blood sample, dispatch it in a pre-paid shipping envelope to a laboratory, and a physician will review the results and send a report to consumers' smartphones.
Thanks to advances in technology, samples taken at home can now be preserved long enough to arrive intact at diagnostic laboratories. The key is showing the agency "transport and shipping don't change or interfere with the integrity of the samples," says Dr. Frank Ong, Everlywell's chief medical and scientific officer.
Ong is keenly aware of the importance of saturation testing because of the lessons learned by colleagues fighting the SARS pandemic in his family's native Taiwan in 2003. "In the beginning, doctors didn't know what they were dealing with and didn't protect themselves adequately," he says. "But over two years, they learned the hard way that there needs to be enough testing, contact tracing of those who have been exposed, and isolation of people who test positive. The value of at-home testing is that it can be done on the kind of broad basis that needs to happen for our country to get back to work."
Because of the pandemic, new policies have removed some of the barriers that impeded the widespread adoption of home-based diagnostics and telemedicine. Physicians can now practice across state lines, get reimbursed for telemedicine visits and use FaceTime to communicate with their patients, which had long been considered taboo because of privacy issues. Doctors and patients are becoming more comfortable and realizing the convenience and benefits of being able to do these things virtually.
Added to this, the only way to safely reopen for business without triggering a second and perhaps even more deadly wave of sickness is through large-scale testing, but hospitals and doctors' offices are no longer the safest places. "We don't want people sitting in a waiting room who later find out they're positive, and potentially infected everyone, including doctors and nurses," says Dr. Kavita Patel, a physician in Washington, DC who served as a policy director in the Obama White House.
In-home testing avoids the risks of direct exposure to the virus for both patients and health care professionals, who can dispense with cumbersome protective gear to take samples, and also enables people without reliable transportation or child-care to learn their status. "At home testing can be a critical component of our country's overall testing strategy," says Dr. Shantanu Nundy, chief medical officer at Accolade Health and on the faculty of the Milken Institute School of Public Health at George Washington University. "Once we're back at work, we need to be much more targeted, and have much more access to data and controlling those outbreaks as tightly as possible. The best way to do that is by leapfrogging clinics and being able to deliver tests at home for people who are disenfranchised by the current system."
In the not-too-distant future, in-home diagnostics could be a key component of precision medicine, which is customized care tailored specifically to each patient's individual needs. Like Stanford's smart toilet prototype, these ongoing surveillance tools will gather health data, ranging from exposures to toxins and pollutions in the environment to biochemical activity, like rising blood pressure, signs of inflammation, failing kidneys or tiny cancerous tumors, and provide continuous real-time information.
"These can be deeply personalized and enabled by smart phones, sensors and artificial intelligence," says USC's Leslie Saxon. "We'll be seeing the floodgates opening to patients accessing medical services through the same devices that they access other things, and leveraging these tools for our health and to fine tune disease management in a model of care that is digitally enabled."
[Editor's Note: This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]
Kids' immune systems come into contact with so many antigens every day that extra cleaning and disinfecting won't harm them, experts say.
Cleaning has taken on a whole new meaning in Frank Mosco's household during the COVID-19 pandemic. There's a protocol for everything he and his two teenage daughters do.
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic.
"We wipe down every package that comes into the house and the items inside," says Mosco, a technologist and social justice activist in Hastings-on-Hudson, N.Y. "If it's a fruit or vegetable, I use vinegar and water, or water and soap. Then we throw out the boxes, clean up the table, and wash our hands." Only then do they put items away.
As the novel coronavirus continues to pose an invisible threat, parents of infants to adolescents are pondering how vigorously and frequently to clean and disinfect surfaces at home and apply hand sanitizer in public. They also fret over whether there can be too much of a good thing: Will making everything as seemingly germ-free as possible reduce immunity down the road?
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic. Every family should assess their particular risks. Factors to consider include pre-existing medical conditions, the number of people living in the same home, and whether anyone works in a hospital or other virus-prone environment, says Kari Debbink, assistant professor of biology at Bowie State University in Bowie, Maryland.
Constantly cleaning everything in sight isn't necessary, she explains, because coronavirus tends to spread mainly via immediate contact with respiratory droplets—catching it from surfaces is a less-likely scenario. The longer the virus stays on a surface, the less contagious it becomes.
Some parents worry that their children's growing bodies may become accustomed to an environment that is "too clean." Debbink, a virologist, offers a salient reminder: "The immune system comes into contact with many, many different antigens every day, and it is 'trained' from birth onwards to respond to pathogens. Doing a little more cleansing and disinfecting during the pandemic will not weaken the immune system."
Other experts agree. "There should be no negative outcome to properly washing your hands more frequently," says Stacey Schultz-Cherry, an infectious diseases specialist at St. Jude Children's Research Hospital in Memphis, Tennessee. "Even with enhanced disinfection, kids are still getting exposed to immune-boosting microbes from playing outside, having pets, etc."
"There's no reason why hand sanitizer would weaken anyone's immune system of any age."
Applying hand sanitizer consisting of at least 60 percent alcohol helps clean hands while outdoors, says Angela Rasmussen, associate research scientist and a virologist at Columbia University's Mailman School of Public Health in New York. "There's no reason why hand sanitizer would weaken anyone's immune system of any age," she adds, and recommends moisturizer so hands don't dry out from frequent use. Meanwhile, "cleaning and disinfecting at home also don't have an impact on antiviral immunity, in kids or adults."
With the coronavirus foremost in parents' minds, Patricia Garcia, a pediatric hospitalist, has fielded many questions about how thoroughly they should wipe, rub, scrub, or mop. As medical director of Connecticut Children's Healthy Homes Program in Hartford, which takes aim at toxins and other housing hazards, she reassures them with this mantra: "You're never going to get it perfectly sterilized, and that's okay."
To quell some of these concerns, in March the U.S. Environmental Protection Agency (EPA) released a list of products for household use. None of these products have been specifically tested against SARS-CoV-2, the novel coronavirus that causes COVID-19. But the agency expects these products to be effective because they have demonstrated efficacy against a different human coronavirus similar to SARS-CoV-2 or an even harder-to-kill virus.
Many products on the list contain isopropyl alcohol or hydrogen peroxide. "When using an EPA-registered disinfectant," the agency's website instructs, "follow the label directions for safe, effective use. Make sure to follow the contact time, which is the amount of time the surface should be visibly wet."
Bear in mind that not all cleaners actually disinfect, cautions Alan Woolf, a pediatrician at Boston Children's Hospital who directs its environmental health center and is a professor at Harvard Medical School. Some cleaners remove visible dirt, grease, and grime, but they don't kill viruses. Disinfectants by their nature inactivate both bacteria and viruses. "That's an important distinction," Woolf says.
Frequently touched surfaces—for instance, doorknobs, light switches, toilet-flushing levers, and countertops—should not only be cleaned, but also disinfected at least daily during a pandemic if someone in the household is sick. The objects one touches upon coming home are the ones most likely to become contaminated with viruses, experts say.
Before bringing items inside, "it might be good to clear off a counter space where they will be placed," says Debbink, the biology professor and virologist. "This way, they come into contact with as few items and surfaces as possible."
If space permits, another option would be to set aside nonperishable items. "I've heard of some families putting things in a 'mud room' and closing the door for 48 hours, some leaving things in their garage or car trunk," says Stephanie Holm, co-director of the Western States Pediatric Environmental Health Specialty Unit at the University of California, San Francisco. "Letting new purchases sit for 48 hours undisturbed would greatly reduce the number of viable viruses present."
Cleaning surfaces is recommended before disinfecting them. Holm suggests using unscented soap and microfiber cloths instead of paper towels, which can transmit bacteria and viruses from one area to another.
Soap has the power to eradicate viruses with at least 20 seconds of contact time. It attacks the coronavirus's protective coat, explains infectious diseases specialist Schultz-Cherry. "If you destroy the coat, the virus is no longer infectious. Influenza virus is also very sensitive to soap."
"The most important thing that parents should do for children's immune systems is make sure they are up to date on all their vaccines."
For cribs, toys, and other mouth-contact surfaces, sanitizing with soap and water, not disinfectants, is advisable, says pediatrician Woolf. Fresh fruits and vegetables also can be cleaned with soap, removing dirt and pesticide residue, he adds.
"Some parents are nervous about using disinfectant on toys, which is understandable, considering many toys end up in children's mouths, so soap and water can be an alternative," says pediatrician Garcia, who recommends using hot water.
While some toys can go in the washing machine and dryer or dishwasher, others need to be cleaned by hand, with dish soap or a delicate detergent, as indicated on their labels. But toys with electrical components cannot be submerged in water, in which case consulting the EPA's list of disinfectants may be a parent's best option, she says.
Labels on the back of cleaning and disinfecting products also contain specific instructions. Not allowing a liquid to sit on a surface for the recommended time results in exposure to chemicals without even accomplishing the intended purpose of disinfection. For most household bleach-containing agents, the advisable "dwell time" is 10 minutes. "Many people don't realize this," says Holm, the environmental health specialist who also trained as a physician.
Beware of combining any type of cleaners or disinfectants that aren't already premixed. Doing so can release harmful gases into the air, she cautions.
During the pandemic, Mosco and his daughters have been very conscientious about decontaminating whatever comes through their doors. Mosco says he doesn't believe the family is overusing cleaning and disinfecting products. Although he's fastidious, he says, "a completely sterile environment is not the goal."
His mother, who was a nurse, instilled in him that exposure to some bacteria is a good thing. In turn, he "always encouraged his kids to play with animals, and to have fun in sand and dirt, with plenty of sunlight to keep their immune systems strong."
Even though a vaccine for coronavirus currently doesn't exist, parents can take some comfort in the best weapon available today to protect kids from deadly pathogens: "The most important thing that parents should do for children's immune systems," says virologist Rasmussen, "is make sure they are up to date on all their vaccines."