First in a two-part series about stem cells.
Aug. 12, 2019 -- Anna Kuehl sat in her home near Los Angeles, feeling grateful as she looked out at the ocean.
"Before, I couldn't see the ships," says the 79-year-old. Now, [even] at night, I can see all the ships, tiny ships, even before my husband, Hans, does."
For years, Kuehl had noticed a slow loss of the vision in her left eye. Gradually, it got worse as a dark, blurry area blocked her central vision. She was diagnosed with age-related macular degeneration (AMD), a vision-robbing condition in which the cells of the macula, part of the retina, weaken.
Slowly, it robbed her of the ability to do everyday activities. "I did the finances in our family,'' she says, "but I couldn't do that anymore." Hiking, one of her passions, became cumbersome. Worse, there is no effective treatment for the type she has, which is known as dry macular degeneration.
Then, in October 2017, she entered an early clinical trial to test a stem cell remedy for macular degeneration. Surgeon Amir H. Kashani, MD, at the University of Southern California in Los Angeles, implanted a stem cell patch -- basically an ultrathin scaffold with cells that would replace ones that had disappeared.
It worked. Kuehl sees better -- she's back to hiking, other everyday activities, and enjoying beating out her spouse on seeing the tiny ships first.
Stem Cells: 30 Years and Counting
Treatments for eye diseases are considered among the most promising for stem cells, which have been under study for more than 3 decades. While proponents say all this groundwork is finally coming to fruition, others call progress slow and plodding.
"We are still far away from the hundreds of diseases that could be eradicated with stem cells," says James Wells, PhD, the chief scientific officer at the Center for Stem Cell and Organoid Medicine at Cincinnati Children's Hospital. "Most of the trials are only dealing with 'Are they safe?''' he says, referring to the first phase of clinical trials that is used only to see if a treatment is safe, not how well it works.
But, he says, one type of stem cell often researched, the induced pluripotent stem cell, was only discovered in 2006. These are adult stem cells reprogrammed to work like embryonic stem cells. Researchers also use embryonic stem cells, derived from embryos and grown in a lab, and adult stem cells from tissues and organs.
"I would say the pace of things has been much faster than I would have predicted," says Andy McMahon, PhD, a W.M. Keck provost and university professor at the University of Southern California.
In comparison, Wells says, prescription drugs often take 15 years to progress from research stages to market.
In fiscal year 2019, the NIH estimates it will fund $1.6 billion in stem cell research.
On its ''clinical dashboard" page, CIRM, California's stem cell agency, lists 56 clinical trials it has funded. CIRM, formerly the California Institute for Regenerative Medicine, was launched after California voters approved Proposition 71 in 2004, providing $3 billion for stem cell research. (Some other states followed suit to fund stem cell research as administrations have gone back and forth about whether federal funding can be used to support research on human embryonic stem cells.)
Those 56 CIRM trials include stem cell research on blood and other cancers, diabetes, HIV and AIDS, and diseases of the eye, neurological system, kidney, heart, and bone. Of the 56, only six are in phase 3, the final before seeking approval. But one of those phase 3 studies has been terminated and another suspended.
On clinicaltrials.gov, a clearinghouse of clinical research studies, 7,381 studies on stem cells are listed, with 751 of those in phase 3.
The Short List
Ask experts about stem cell successes, and many mention the "Bubble Boy" disease treatment, reported earlier in 2019. The treatment is for a rare genetic defect that robs infants of an immune system and can lead to severe infection. The “Bubble Boy” name for the disease reflects how much protection these infants need to avoid an infection. Treatment is crucial to avoid death.
Researchers first obtain blood-forming stem cells from a patient's bone marrow, deliver a normal gene to the cell, then infuse the stem cells back into the patient. The genetically corrected system cells settle in and start producing new blood cells.
Other treatments are not that far along, but among the areas of research cited most often are:
Macular degeneration: The study that Anna Kuehl took part in was a phase 1-2 study. Four patients received the implant. All had stable or improved vision. "What our preliminary results show is that one of the patients read up to about 17 letters more than they did at baseline on the eye chart, or about three lines more," Kashani says. Improving by three lines on an eye chart, as anyone with a vision problem knows, he says, "is huge." These findings suggest there is something happening with the placement of the new implant under the retina to support vision, he says.
Kashani is hoping to begin another phase 2 study in 2020 to evaluate patients with less advanced macular degeneration.
Kidney transplant: Patients who receive a kidney transplant must take immunosuppressive drugs to prevent organ rejection for life. The medications have risks, such as becoming toxic and increasing a patient's risk of infection, heart disease, cancer, and diabetes. Now, researchers are infusing stem cells and immune cells from the organ donor into the patient who received the donor kidney. The hope is to stop the need for the immunosuppressive drugs.
The research is now in phase 3, with an estimated enrollment of 75. Researchers want to show that the approach is safe and effective, and see if it ends the need for the immunosuppressive drugs. The study is due to be completed in January 2022.
Diabetes: Other researchers are working on using embryonic stem cell therapy to treat type 1 diabetes, which happens when the immune system destroys the beta cells in the pancreas that make insulin. Researchers have found a way to turn human embryonic stem cells into ones known as pancreatic progenitor cells. These can then mature into insulin-making beta cells.
The research is in phases 1 and 2, to test the safety of putting a device containing the progenitor cells into 69 people with type 1 diabetes. The completion of the study, with participants in San Diego, CA, and Edmonton, Canada, is set for January 2021.
Parkinson's disease: Twenty patients with Parkinson's disease received stem cells taken from the bone marrow of a healthy adult. Research suggests that chronic brain inflammation plays a role in the progress of the neurological disease, causing problems with movement and balance. Study researcher Mya Schiess, MD, a professor of neurology at McGovern Medical School at UTHealth in Houston, says the stem cells are believed to have regenerative effects and tamp down the inflammation.
All four doses tested were well-tolerated and safe, Schiess says. "We found the greatest effect with the highest dose." At the 12-week follow-up, all 20 patients had better movement scores and still did at the 6-month mark. She is hoping to get funding and approval for a phase 2 study later this year.
Stem Cells: Not Just Disease Cures
"Most people are familiar with the approach of taking stem cells and putting them back in [to treat or cure]," says USC's McMahon. Another aspect is to take stem cells, simulate disease models in a dish, and then test drugs on the models to see which ones might work, he says.
These approaches won't just potentially find and evaluate new drugs, he says, but find a drug that treats a person’s disease, taking into account different forms of disorders.
Obstacles and Controversies
Controversy about the source of stem cells for research is ongoing. In early June, the U.S. Department of Health and Human Services did not renew a fetal tissue research contract with the University of California San Francisco involving human fetal tissue from elective abortions to develop testing protocols, and also announced measures to limit future research involving such tissue.
The origin of stem cells for research depends on the purpose, McMahon says. Normal adult stem cells from specific tissues, such as the liver, are used, as well as induced pluripotent cells and, to a lesser degree, embryonic stem cells.
Embryonic stem cell lines that supply enough for much research can be developed from a single embryo. Most of the work now underway is with existing stem cell lines. There’s no real effort to generate new embryonic stem cells, McMahon says.
Meanwhile, the number of stem cell clinics -- now at about 700 -- continues to grow. The clinics offer unproven treatments that have little research behind them, according to a report in The Journal of the American Medical Association (JAMA). In June, a federal judge ordered two Florida stem cell clinics shut down after the FDA asked for a permanent injunction against the clinics because their fat tissue-derived stem cell treatments are not proven or approved.
"The future has to be really rosy," USC's McMahon says of stem cell applications. He predicts stem cell research will spawn different types of medicine, including not only disease treatments, but finding drugs that work better for individual patients.
In an extensive review of stem cell research, experts writing in Nature Cell Biology conclude that almost 30 years of research were needed to move forward.
Kuehl, the macular degeneration patient, also has the condition in her right eye. If it worsens to the same point as her left eye, she says she would not hesitate to sign up once again for the treatment.
The age-related macular degeneration study co-author, Mark Humayun MD, PhD, co-director of the USC Roski Eye Institute, is the founder of Regenerative Patch Technologies LLC, which holds the license to produce the retinal implant.