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
A company uses AI to fight muscle loss and unhealthy aging
In December 2022, a company called BioAge Labs published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people.
There’s a growing need to slow down the aging process. The world’s population is getting older and, according to one estimate, 80 million Americans will be 65 or older by 2040. As we age, the risk of many chronic diseases goes up, from cancer to heart disease to Alzheimer’s.
BioAge Labs, a company based in California, is using genetic data to help people stay healthy for longer. CEO Kristen Fortney was inspired by the genetics of people who live long lives and resist many age-related diseases. In 2015, she started BioAge to study them and develop drug therapies based on the company’s learnings.
The team works with special biobanks that have been collecting blood samples and health data from individuals for up to 45 years. Using artificial intelligence, BioAge is able to find the distinctive molecular features that distinguish those who have healthy longevity from those who don’t.
In December 2022, BioAge published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people. Much of the research on aging has been in worms and mice, but BioAge is focused on human data, Fortney says. “This boosts our chances of developing drugs that will be safe and effective in human patients.”
How it works
With assistance from AI, BioAge measures more than 100,000 molecules in each blood sample, looking at proteins, RNA and metabolites, or small molecules that are produced through chemical processes. The company uses many techniques to identify these molecules, some of which convert the molecules into charged atoms and then separating them according to their weight and charge. The resulting data is very complex, with many thousands of data points from patients being followed over the decades.
BioAge validates its targets by examining whether a pathway going awry is actually linked to the development of diseases, based on the company’s analysis of biobank health records and blood samples. The team uses AI and machine learning to identify these pathways, and the key proteins in the unhealthy pathways become their main drug targets. “The approach taken by BioAge is an excellent example of how we can harness the power of big data and advances in AI technology to identify new drugs and therapeutic targets,” says Lorna Harries, a professor of molecular genetics at the University of Exeter Medical School.
Martin Borch Jensen is the founder of Gordian Biotechnology, a company focused on using gene therapy to treat aging. He says BioAge’s use of AI allows them to speed up the process of finding promising drug candidates. However, it remains a challenge to separate pathologies from aspects of the natural aging process that aren’t necessarily bad. “Some of the changes are likely protective responses to things going wrong,” Jensen says. “Their data doesn’t…distinguish that so they’ll need to validate and be clever.”
Developing a drug for muscle loss
BioAge decided to focus on muscular atrophy because it affects many elderly people, making it difficult to perform everyday activities and increasing the risk of falls. Using the biobank samples, the team modeled different pathways that looked like they could improve muscle health. They found that people who had faster walking speeds, better grip strength and lived longer had higher levels of a protein called apelin.
Apelin is a peptide, or a small protein, that circulates in the blood. It is involved in the process by which exercise increases and preserves muscle mass. BioAge wondered if they could prevent muscular atrophy by increasing the amount of signaling in the apelin pathway. Instead of the long process of designing a drug, they decided to repurpose an existing drug made by another biotech company. This company, called Amgen, had explored the drug as a way to treat heart failure. It didn’t end up working for that purpose, but BioAge took note that the drug did seem to activate the apelin pathway.
BioAge tested its new, repurposed drug, BGE-105, and, in a phase 1 clinical trial, it protected subjects from getting muscular atrophy compared to a placebo group that didn’t receive the drug. Healthy volunteers over age 65 received infusions of the drug during 10 days spent in bed, as if they were on bed rest while recovering from an illness or injury; the elderly are especially vulnerable to muscle loss in this situation. The 11 people taking BGE-105 showed a 100 percent improvement in thigh circumference compared to 10 people taking the placebo. Ultrasound observations also revealed that the group taking the durg had enhanced muscle quality and a 73 percent increase in muscle thickness. One volunteer taking BGE-105 did have muscle loss compared to the the placebo group.
Heather Whitson, the director of the Duke University Centre for the study of aging and human development, says that, overall, the results are encouraging. “The clinical findings so far support the premise that AI can help us sort through enormous amounts of data and identify the most promising points for beneficial interventions.”
More studies are needed to find out which patients benefit the most and whether there are side effects. “I think further studies will answer more questions,” Whitson says, noting that BGE-105 was designed to enhance only one aspect of physiology associated with exercise, muscle strength. But exercise itself has many other benefits on mood, sleep, bones and glucose metabolism. “We don’t know whether BGE-105 will impact these other outcomes,” she says.
The future
BioAge is planning phase 2 trials for muscular atrophy in patients with obesity and those who have been hospitalized in an intensive care unit. Using the data from biobanks, they’ve also developed another drug, BGE-100, to treat chronic inflammation in the brain, a condition that can worsen with age and contributes to neurodegenerative diseases. The team is currently testing the drug in animals to assess its effects and find the right dose.
BioAge envisions that its drugs will have broader implications for health than treating any one specific disease. “Ultimately, we hope to pioneer a paradigm shift in healthcare, from treatment to prevention, by targeting the root causes of aging itself,” Fortney says. “We foresee a future where healthy longevity is within reach for all.”
How old fishing nets turn into chairs, car mats and Prada bags
A company called Aquafil is turning the fibers from fishing nets and old carpets into new threads for chairs, car mats, bikinis and Prada bags.
Discarded nylon fishing nets in the oceans are among the most harmful forms of plastic pollution. Every year, about 640,000 tons of fishing gear are left in our oceans and other water bodies to turn into death traps for marine life. London-based non-profit World Animal Protection estimates that entanglement in this “ghost gear” kills at least 136,000 seals, sea lions and large whales every year. Experts are challenged to estimate how many birds, turtles, fish and other species meet the same fate because the numbers are so high.
Since 2009, Giulio Bonazzi, the son of a small textile producer in northern Italy, has been working on a solution: an efficient recycling process for nylon. As CEO and chairman of a company called Aquafil, Bonazzi is turning the fibers from fishing nets – and old carpets – into new threads for car mats, Adidas bikinis, environmentally friendly carpets and Prada bags.
For Bonazzi, shifting to recycled nylon was a question of survival for the family business. His parents founded a textile company in 1959 in a garage in Verona, Italy. Fifteen years later, they started Aquafil to produce nylon for making raincoats, an enterprise that led to factories on three continents. But before the turn of the century, cheap products from Asia flooded the market and destroyed Europe’s textile production. When Bonazzi had finished his business studies and prepared to take over the family company, he wondered how he could produce nylon, which is usually produced from petrochemicals, in a way that was both successful and ecologically sustainable.
The question led him on an intellectual journey as he read influential books by activists such as world-renowned marine biologist Sylvia Earle and got to know Michael Braungart, who helped develop the Cradle-to-Cradle ethos of a circular economy. But the challenges of applying these ideologies to his family business were steep. Although fishing nets have become a mainstay of environmental fashion ads—and giants like Dupont and BASF have made breakthroughs in recycling nylon—no one had been able to scale up these efforts.
For ten years, Bonazzi tinkered with ideas for a proprietary recycling process. “It’s incredibly difficult because these products are not made to be recycled,” Bonazzi says. One complication is the variety of materials used in older carpets. “They are made to be beautiful, to last, to be useful. We vastly underestimated the difficulty when we started.”
Soon it became clear to Bonazzi that he needed to change the entire production process. He found a way to disintegrate old fibers with heat and pull new strings from the discarded fishing nets and carpets. In 2022, his company Aquafil produced more than 45,000 tons of Econyl, which is 100% recycled nylon, from discarded waste.
More than half of Aquafil’s recyclate is from used goods. According to the company, the recycling saves 90 percent of the CO2 emissions compared to the production of conventional nylon. That amounts to saving 57,100 tons of CO2 equivalents for every 10,000 tons of Econyl produced.
Bonazzi collects fishing nets from all over the world, including Norway and Chile—which have the world’s largest salmon productions—in addition to the Mediterranean, Turkey, India, Japan, Thailand, the Philippines, Pakistan, and New Zealand. He counts the government leadership of Seychelles as his most recent client; the island has prohibited ships from throwing away their fishing nets, creating the demand for a reliable recycler. With nearly 3,000 employees, Aquafil operates almost 40 collection and production sites in a dozen countries, including four collection sites for old carpets in the U.S., located in California and Arizona.
First, the dirty nets are gathered, washed and dried. Bonazzi explains that nets often have been treated with antifouling agents such as copper oxide. “We recycle the coating separately,” he says via Zoom from his home near Verona. “Copper oxide is a useful substance, why throw it away?”
Still, only a small percentage of Aquafil’s products are made from nets fished out of the ocean, so your new bikini may not have saved a strangled baby dolphin. “Generally, nylon recycling is a good idea,” says Christian Schiller, the CEO of Cirplus, the largest global marketplace for recyclates and plastic waste. “But contrary to what consumers think, people rarely go out to the ocean to collect ghost nets. Most are old, discarded nets collected on land. There’s nothing wrong with this, but I find it a tad misleading to label the final products as made from ‘ocean plastic,’ prompting consumers to think they’re helping to clean the oceans by buying these products.”
Aquafil gets most of its nets from aqua farms. Surprisingly, one of Aquafil’s biggest problems is finding enough waste. “I know, it’s hard to believe because waste is everywhere,” Bonazzi says. “But we need to find it in reliable quantity and quality.” He has invested millions in establishing reliable logistics to source the fishing nets. Then the nets get shredded into granules that can be turned into car mats for the new Hyundai Ioniq 5 or a Gucci swimsuit.
The process works similarly with carpets. In the U.S. alone, 3.5 billion pounds of carpet are discarded in landfills every year, and less than 3 percent are currently recycled. Aquafil has built a recycling plant in Phoenix to help divert 12,500 tons of carpets from the landfill every year. The carpets are shredded and deconstructed into three components: fillers such as calcium carbonate will be reused in the cement industry, synthetic fibers like polypropylene can be used for engineering plastics, and nylon. Only the pelletized nylon gets shipped back to Europe for the production of Econyl. “We ship only what’s necessary,” Bonazzi says. Nearly 50 percent of his nylon in Italy and Slovenia is produced from recyclate, and he hopes to increase the percentage to two-thirds in the next two years.
His clients include Interface, the leading world pioneer for sustainable flooring, and many other carpet producers plus more than 2500 fashion labels, including Gucci, Prada, Patagonia, Louis Vuitton, Adidas and Stella McCartney. “Stella McCartney just introduced a parka that’s made 100 percent from Econyl,” Bonazzi says. “We’re also in a lot of sportswear because Nylon is a good fabric for swimwear and for yoga clothes.” Next, he’s looking into sunglasses and chairs made with Econyl - for instance, the flexible ergonomic noho chair, designed by New Zealand company Formway.
“When I look at a landfill, I see a gold mine," Bonazzi says.
“Bonazzi decided many years ago to invest in the production of recycled nylon though industry giants halted similar plans after losing large investments,” says Anika Herrmann, vice president of the German Greentech-competitor Camm Solutions, which creates bio-based polymers from cane sugar and other ag waste. “We need role models like Bonazzi who create sustainable solutions with courage and a pioneering spirit. Like Aquafil, we count on strategic partnerships to enable fast upscaling along the entire production chain.”
Bonazzi’s recycled nylon is still five to 10 percent more expensive than conventionally produced material. However, brands are increasingly bending to the pressure of eco-conscious consumers who demand sustainable fashion. What helped Bonazzi was the recent rise of oil prices and the pressure on industries to reduce their carbon footprint. Now Bonazzi says, “When I look at a landfill, I see a gold mine.”
Ideally, the manufacturers take the products back when the client is done with it, and because the nylon can theoretically be reused nearly infinitely, the chair or bikini could be made into another chair or bikini. “But honestly,” Bonazzi half-jokes, “if someone returns a McCartney parka to me, I’ll just resell it because it’s so expensive.”
The next step: Bonazzi wants to reshape the entire nylon industry by pivoting from post-consumer nylon to plant-based nylon. In 2017, he began producing “nylon-6,” together with Genomatica in San Diego. The process uses sugar instead of petroleum. “The idea is to make the very same molecule from sugar, not from oil,” he says. The demonstration plant in Ljubljana, Slovenia, has already produced several hundred tons of nylon, and Genomatica is collaborating with Lululemon to produce plant-based yoga wear.
Bonazzi acknowledges that his company needs a few more years before the technology is ready to meet his ultimate goal, producing only recyclable products with no petrochemicals, low emissions and zero waste on an industrial scale. “Recycling is not enough,” he says. “You also need to produce the primary material in a sustainable way, with a low carbon footprint.”