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
The large genetic studies underlying certain disease risk tests have primarily been done in populations of European ancestry, limiting their accuracy.
Earlier this year, California-based Ambry Genetics announced that it was discontinuing a test meant to estimate a person's risk of developing prostate or breast cancer. The test looks for variations in a person's DNA that are known to be associated with these cancers.
Known as a polygenic risk score, this type of test adds up the effects of variants in many genes — often in the dozens or hundreds — and calculates a person's risk of developing a particular health condition compared to other people. In this way, polygenic risk scores are different from traditional genetic tests that look for mutations in single genes, such as BRCA1 and BRCA2, which raise the risk of breast cancer.
Traditional genetic tests look for mutations that are relatively rare in the general population but have a large impact on a person's disease risk, like BRCA1 and BRCA2. By contrast, polygenic risk scores scan for more common genetic variants that, on their own, have a small effect on risk. Added together, however, they can raise a person's risk for developing disease.
These scores could become a part of routine healthcare in the next few years. Researchers are developing polygenic risk scores for cancer, heart, disease, diabetes and even depression. Before they can be rolled out widely, they'll have to overcome a key limitation: racial bias.
"The issue with these polygenic risk scores is that the scientific studies which they're based on have primarily been done in individuals of European ancestry," says Sara Riordan, president of the National Society of Genetics Counselors. These scores are calculated by comparing the genetic data of people with and without a particular disease. To make these scores accurate, researchers need genetic data from tens or hundreds of thousands of people.
Myriad's old test would have shown that a Black woman had twice as high of a risk for breast cancer compared to the average woman even if she was at low or average risk.
A 2018 analysis found that 78% of participants included in such large genetic studies, known as genome-wide association studies, were of European descent. That's a problem, because certain disease-associated genetic variants don't appear equally across different racial and ethnic groups. For example, a particular variant in the TTR gene, known as V1221, occurs more frequently in people of African descent. In recent years, the variant has been found in 3 to 4 percent of individuals of African ancestry in the United States. Mutations in this gene can cause protein to build up in the heart, leading to a higher risk of heart failure. A polygenic risk score for heart disease based on genetic data from mostly white people likely wouldn't give accurate risk information to African Americans.
Accuracy in genetic testing matters because such polygenic risk scores could help patients and their doctors make better decisions about their healthcare.
For instance, if a polygenic risk score determines that a woman is at higher-than-average risk of breast cancer, her doctor might recommend more frequent mammograms — X-rays that take a picture of the breast. Or, if a risk score reveals that a patient is more predisposed to heart attack, a doctor might prescribe preventive statins, a type of cholesterol-lowering drug.
"Let's be clear, these are not diagnostic tools," says Alicia Martin, a population and statistical geneticist at the Broad Institute of MIT and Harvard. "We can't use a polygenic score to say you will or will not get breast cancer or have a heart attack."
But combining a patient's polygenic risk score with other factors that affect disease risk — like age, weight, medication use or smoking status — may provide a better sense of how likely they are to develop a specific health condition than considering any one risk factor one its own. The accuracy of polygenic risk scores becomes even more important when considering that these scores may be used to guide medication prescription or help patients make decisions about preventive surgery, such as a mastectomy.
In a study published in September, researchers used results from large genetics studies of people with European ancestry and data from the UK Biobank to calculate polygenic risk scores for breast and prostate cancer for people with African, East Asian, European and South Asian ancestry. They found that they could identify individuals at higher risk of breast and prostate cancer when they scaled the risk scores within each group, but the authors say this is only a temporary solution. Recruiting more diverse participants for genetics studies will lead to better cancer detection and prevent, they conclude.
Recent efforts to do just that are expected to make these scores more accurate in the future. Until then, some genetics companies are struggling to overcome the European bias in their tests.
Acknowledging the limitations of its polygenic risk score, Ambry Genetics said in April that it would stop offering the test until it could be recalibrated. The company launched the test, known as AmbryScore, in 2018.
"After careful consideration, we have decided to discontinue AmbryScore to help reduce disparities in access to genetic testing and to stay aligned with current guidelines," the company said in an email to customers. "Due to limited data across ethnic populations, most polygenic risk scores, including AmbryScore, have not been validated for use in patients of diverse backgrounds." (The company did not make a spokesperson available for an interview for this story.)
In September 2020, the National Comprehensive Cancer Network updated its guidelines to advise against the use of polygenic risk scores in routine patient care because of "significant limitations in interpretation." The nonprofit, which represents 31 major cancer cancers across the United States, said such scores could continue to be used experimentally in clinical trials, however.
Holly Pederson, director of Medical Breast Services at the Cleveland Clinic, says the realization that polygenic risk scores may not be accurate for all races and ethnicities is relatively recent. Pederson worked with Salt Lake City-based Myriad Genetics, a leading provider of genetic tests, to improve the accuracy of its polygenic risk score for breast cancer.
The company announced in August that it had recalibrated the test, called RiskScore, for women of all ancestries. Previously, Myriad did not offer its polygenic risk score to women who self-reported any ancestry other than sole European or Ashkenazi ancestry.
"Black women, while they have a similar rate of breast cancer to white women, if not lower, had twice as high of a polygenic risk score because the development and validation of the model was done in white populations," Pederson said of the old test. In other words, Myriad's old test would have shown that a Black woman had twice as high of a risk for breast cancer compared to the average woman even if she was at low or average risk.
To develop and validate the new score, Pederson and other researchers assessed data from more than 275,000 women, including more than 31,000 African American women and nearly 50,000 women of East Asian descent. They looked at 56 different genetic variants associated with ancestry and 93 associated with breast cancer. Interestingly, they found that at least 95% of the breast cancer variants were similar amongst the different ancestries.
The company says the resulting test is now more accurate for all women across the board, but Pederson cautions that it's still slightly less accurate for Black women.
"It's not only the lack of data from Black women that leads to inaccuracies and a lack of validation in these types of risk models, it's also the pure genomic diversity of Africa," she says, noting that Africa is the most genetically diverse continent on the planet. "We just need more data, not only in American Black women but in African women to really further characterize that continent."
Martin says it's problematic that such scores are most accurate for white people because they could further exacerbate health disparities in traditionally underserved groups, such as Black Americans. "If we were to set up really representative massive genetic studies, we would do a much better job at predicting genetic risk for everybody," she says.
Earlier this year, the National Institutes of Health awarded $38 million to researchers to improve the accuracy of polygenic risk scores in diverse populations. Researchers will create new genome datasets and pool information from existing ones in an effort to diversify the data that polygenic scores rely on. They plan to make these datasets available to other scientists to use.
"By having adequate representation, we can ensure that the results of a genetic test are widely applicable," Riordan says.
New Podcast: George Church on Woolly Mammoths, Organ Transplants, and Covid Vaccines
Dr. George Church, a leading pioneer of gene editing, updates our listeners on several of his noteworthy projects.
The "Making Sense of Science" podcast features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This monthly podcast is hosted by journalist Kira Peikoff, founding editor of the award-winning science outlet Leaps.org.
This month, our guest is notable genetics pioneer Dr. George Church of Harvard Medical School. Dr. Church has remarkably bold visions for how innovation in science can fundamentally transform the future of humanity and our planet. His current moonshot projects include: de-extincting some of the woolly mammoth's genes to create a hybrid Asian elephant with the cold-tolerance traits of the woolly mammoth, so that this animal can re-populate the Arctic and help stave off climate change; reversing chronic diseases of aging through gene therapy, which he and colleagues are now testing in dogs; and transplanting genetically engineered pig organs to humans to eliminate the tragically long waiting lists for organs. Hear Dr. Church discuss all this and more on our latest episode.
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Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.