On July 11, Wills Eye Institute ophthalmologist Carl Regillo delicately placed 100,000 cells beneath the retina of 52-year-old Maurie Hill’s left eye. She was rapidly losing her vision due to Stargardt disease, an inherited macular dystrophy similar to the much more common dry age-related macular degeneration (AMD).
Maurie’s disease was far along, the normally lush forests of photoreceptor cells in the central macula area severely depleted, especially the cones that provide color vision. Would the introduced cells nestle among the ragged remnants of her retinal pigment epithelium (RPE) and take over, restoring the strangled energy supply to her remaining photoreceptors? They should, for the cells placed in Maurie’s eye weren’t ordinary cells. They were derived from human embryonic stem cells (hESCs).
I’ve waited 15 years to see human embryonic stem cells, or their “daughter” cells, make their way through clinical trials. And thanks to Maurie’s sharing her story, I’m witnessing translational medicine.
On September 29, 1997, The Scientist published my first stem cell article, Embryonic Stem Cells Debut to Little Media Attention. Alas, the public was still too enamored with Dolly the cloned sheep to pay much attention to cells that could both spawn specialized cell types and “self-renew,” maintaining a perpetual stream of hard-to-derive cells that could be used to both observe embryonic development and replace abnormal adult tissue. Over the years, public interest seemed to surface only on slow news days. And still the media report that the cells can “turn into” every cell type in the body – ignoring the very quality that defines the cells: the capacity for self-renewal, making more of themselves as their daughters specialize.
Partly because deriving hESCs until just a few years ago required destroying early human embryos, research using less objectionable stem cells accelerated. And while so-called “adult” and induced pluripotent stem cells (iPSCs) don’t require embryos and match patients so that the immune system isn’t provoked, embryonic stem cells remain the “gold standard” for scrutinizing a disease’s beginnings as the ball-of-cells early embryo folds into layers, contorts, develops organs, and grows. For example, hESCs recently glimpsed how the drug thalidomide harms embryos. The second use of hESCs is to generate useful specialized cells, such as sensory neurons to restore hearing. It’s this second application – hESCs as a source of implants – that is the focus of clinical trials for Stargardt disease and dry AMD.
Using hESCs could be incredibly economical. Just one can yield many millions of cells, the characteristics of the cells coaxed by the cocktails that researchers choose. And embryos can be returned to the freezer, unharmed. The RPE cells in Maurie’s eye came from an hESC line derived in 2005 by Robert Lanza and colleagues at Worcester, Mass.-based Advanced Cell Technology, one of five cell lines called NED for “no embryo destroyed.”
NED cells come from a protocol similar to preimplantation genetic diagnosis (PGD), in which one cell of an 8-celled embryo is sampled to screen for genetic disease, and if all is well, the remaining 7-celled embryo is implanted in a uterus. PGD has been around since 1989. The ability to pluck out a cell at this stage without damaging the whole is a characteristic of our branch of the animal kingdom called indeterminate cleavage, for those who recall Zoology 101.
For a time, the first clinical trial to use hESC-derived cells — oligodendrocytes to treat spinal cord injury – was sponsored by Menlo-Park, CA–based Geron Corp. That effort ended in November 2011, due to cost. But eye diseases are perhaps a better first choice, because the retina is naturally shielded from the immune system.
I never expected to befriend one of the first people to be in an hESC clinical trial. But this past June, email friend Irv Arons connected Maurie and me. She and her older sister Cindi would soon be on their way back from the Wills Eye Institute in Philadelphia, where they were being evaluated for the clinical trial to treat Stargardt disease. They’d be at the Albany Amtrak station on their return to Vermont, near my home.
The sisters have become so adept at using their peripheral vision to see around the central abyss in their visual fields that I couldn’t, at first, tell that anything was wrong with them. They were as excited as if they’d just won the lottery.
“Twelve people are participating. When I saw something about the clinical trial a year ago I thought yeah, right. But things just lined up,” Maurie said. She works 12 hours a week blogging for Ai Squared, maker of ZoomText software, and has a young daughter, a husband, and an associate’s degree in electronics and engineering technology.
Cindi agreed. “I was thinking this will never happen. There were too many barriers, too many things had to fall into place.”
The visual loss of Stargardt is slow. “In 3rd grade I‘d read very fast, but by 5th, I knew I should be able to read faster,” Maurie recalled. She struggled, not realizing anything was wrong, and didn’t even have an eye exam until her physical for college. “The doctor saw something and he sent me to an eye specialist who sent me to another eye specialist, but still I had no diagnosis.”
At age 30, Maurie needed a physical for work, and again made the rounds of referrals. “I could still see pretty well, but some things bothered me: night driving and the lights coming at me and then disappearing, and being unable to recognize faces. I’d have trouble going from light to dark and vice versa.” By age 35, yet another job required a physical, and she went again to retinal specialists, but by this time she’d lost enough visual function to meet the diagnostic criteria for Stargardt. With every month, she could see less.
Meanwhile, Cindi’s vision was going downhill. “I went to my doctor, and I said ‘my sister has this, do I have it too?’ He ran out to open his textbook to see what it was, and said ‘yes, I think you have it,” Cindi said. She taught special ed for 14 years before she had to leave, no longer able to do the visual tasks required for her job, even with the adaptive technology that had helped for a decade.
The sisters have four other siblings. True to Mendel’s first law for single-gene inheritance, their older brother has Stargardt too, although his case is so mild that until recently he could read normal-sized print, although slowly and with great eyestrain.
In May 2009, the family went to the National Eye Institute to confirm Maurie’s 1995 diagnosis, which had been based on clinical findings. But genetic test results indicated that the family didn’t have a mutation in the ABCA4 gene, as 40% of those diagnosed with Stargardt do, or any other mutation. “That was a little disappointing, since we knew the mutation would have to be known to do gene therapy,” recalled Maurie.
But what about stem cell therapy?
Maurie read (by zooming her text and using her peripheral vision) a news release from Advanced Cell Technology announcing that their researchers had derived RPE cells from hESCs. The first two applications would be dry age-related macular degeneration and Stargardt disease. Mice and rats had responded well.
So Maurie called her siblings, and her brother called ACT immediately, but got nowhere. The timing just wasn’t right.
By late 2010, FDA had approved ACTs testing the RPE cells for safety, and clinicaltrials.gov officially announced the upcoming experiments in late April 2011. Four cohorts of three Stargardt patients each would receive escalating doses, starting with 50,000 RPE cells. The AMD trial would proceed in parallel.
Results came very quickly, published online in January 2012’s Lancet. And the news was good. The cells hadn’t harmed the first two patients, a woman in her 70s with AMD and a 51-year-old woman with Stargardt, both treated at the Jules Stein Eye Institute in Los Angeles.
A fear of using embryonic stem cells is that they can give rise to teratomas, which are bizarre tumors festooned with bits of specialized tissue such as teeth and hair. If an ES cell lurked among the RPE cells put into a patient’s eye, a teratoma might sprout. But since this hadn’t happened by three months, and neither woman had inflammation or immune rejection, the therapy passed the first safety hurdle. (A year out, the 9 patients treated so far report more vibrant color vision and improved visual acuity. The first woman treated, for example, could detect only hand-waving before the procedure, but can now read three lines on an eye chart.)
After the sisters heard the two LA patients on NPR January 23, Maurie called the clinical trial director at the nearest participating center, the Wills Eye Institute. When she finally got through, she learned that the center would consider only local patients, so they’d be easier to follow. But a month later, her local eye doctor urged her not to give up.
So Maurie called back, and finally the timing was right. “The research coordinator answered and was flowing with information.” Elated, Maurie sent her medical records right away – she had fortuitously just had a colonoscopy (cancer is grounds for exclusion due to the teratomas), mammogram, Pap smear, cholesterol test, and more.
Dr. Regillo liked Maurie’s test results. She was the ideal clinical trial participant – healthy except for the condition under study, a rarity. When Maurie got the good news, she asked if she could bring Cindi along. Both sisters agreed to foot the Amtrak bills. They told me about the visit when I met them in the Albany train station. Maurie was in; Cindi is still being evaluated.
The big day came in just a month. On July 11, Maurie and Cindi arrived a little before noon, greeted by video cameras. Every step of the procedure had been meticulously choreographed and practiced, with trial runs to identify the time with the lightest traffic on a midsummer Wednesday between New Jersey, where the precious cells were on ice, and Philadelphia.
The cells arrived in a red cooler, the clock ticking down the 3 hours they could survive. Testing for viability and contamination took 30 minutes, and then the procedure itself took just 3 minutes.
Maurie hadn’t expected to be awake and aware as the descendants of human embryonic stem cells flooded her eye, although she’d chosen local anesthesia. “I actually saw the needle come in the inside of my eye! Dr. Regillo said, ‘Can you see that?” I said I clearly saw the needle coming in from the left, and he said, ‘Yup!’ I could see the fluid coming out and forming a little puddle. It was the coolest thing. And everyone was so excited that I saw it!”
And so Maurie Hill joins the brave and selfless individuals who have volunteered to participate in clinical trials, who make new treatments possible for many. But Maurie’s going one huge step farther: she’s blogging about her progress.
To be continued …