Amblyopia detection: A long climb to market for the Pediatric Vision Scanner

David Hunter Pediatric Vision Scanner

David Hunter, MD, PhD, ophthalmologist-in-chief at Boston Children’s Hospital, is also developer of StrabisPix and BabySee. The Pediatric Vision Scanner received FDA marketing clearance last month.

As a pediatric ophthalmologist, I do my best to assure that every young patient I examine will have a lifetime of perfect sight. The condition that I battle most commonly is amblyopia, or “lazy eye,” in which the eye is healthy but does not develop vision — simply because the brain doesn’t receive proper input when a child’s visual system is “learning” how to see.

When I can diagnose amblyopia early enough, I can treat it with an eye patch or eye drops to block the “good” eye, giving the eye with amblyopia time to catch up. But amblyopia does not fight fairly: about half of affected kids have no visible signs of the condition. As a result, amblyopia silently steals the sight of hundreds of thousands of children — many of whom will never get their vision back because treatment started too late.

It is this problem that inspired me to develop the Pediatric Vision Scanner (PVS). I am also trained as an engineer, and more than 20 years ago, while working with my mentor David Guyton, MD, at Johns Hopkins, we had an idea of how to help pediatricians and school nurses readily identify kids with amblyopia and its companion condition, strabismus (misaligned eyes).

David Hunter Pediatric Vision Scanner amblyopia strabismus

When the eye focuses on a target, the image lines up with a particular area of the retina, the fovea. Knowing that the fovea has certain optical properties, Dr. Guyton wondered whether we could use polarized laser light to scan the retina and find the fovea. If so, this would tell us where the eye was looking.

Our prototype PVS did just that. We scanned both retinas at the same time, and if both eyes weren’t looking directly at a smiley-face target inside the machine at exactly the same time, it indicated a likely problem. In the early 2000s, I moved to Boston Children’s Hospital, where we did the first clinical testing of the PVS.

We were shocked at how well it worked. Kids with normal eyesight were able to pass the test, and the kids with a problem could not. The PVS was able to classify children with 97 percent accuracy — unheard of in the vision screening world.

Indifferent investors

At that point I thought, “Wow, I can just call up a company or a venture capitalist and they’ll see what a great product we have and start producing it and the world will be freed from the burden of amblyopia.”

That did not happen.

The companies and investors we talked to either didn’t believe the PVS could work that well, or they didn’t think a company selling the PVS would be profitable enough to be worth the risk. “Plus,” they all said, “you still need to get through FDA.”

David Hunter with Pediatric Vision Scanner amblyopia strabismusI realized that it was probably going to take years to get the PVS into the world, and that I would need to start my own company whose leadership would have the necessary patience and persistence to see it through. I enlisted Justin Shaka, who had just left Boston Children’s to get his MBA at Carnegie Mellon.

The two of us spun out REBIScan. We licensed the inventions (which had been patented by Boston Children’s and Johns Hopkins) and raised money as best we could with a combination of grants, gifts and small investments from friends, family and Boston Children’s Technology Development Fund. Over the next several years, we were able to build prototypes and loan them out to a few centers to conduct clinical trials.

The trials went incredibly well, again showing accuracy in the 95 percent range — way better than any other screening technology out there. Again I thought, “Okay, now we have proven the technology and we are going to be flooded with investments and start producing the device.”

But the potential large investors continued to sing the same tune: “Call us when you get FDA.”

FDA submission… and resubmission

We had heard horror stories about getting medical devices through the FDA, but we thought we would be different. After all, there were already several (less accurate) vision screeners on the market, and many other scanning laser devices had already cleared the FDA.

But we were not different. The hoops we had to jump through seemed endless. Our paper application to the FDA was thicker than a credit card standing on end. Months later we received a list of dozens of “deficiencies” in our application. These took many more months to work through as we conducted additional studies, gathered additional data and responded to questions. But that just led to more deficiencies, more questions, more studies.

Pediatric Vision Scanner drop test
For safety testing, we literally had to drop the PVS from a height.

Some of the testing we were asked to do made no sense at all. For example, we had shown high reproducibility when we re-tested a child a full year after their original test, and 100 percent consistent results in young adults over eight consecutive tests (two devices x two operators x two tests each). And we showed that the device’s output was 99.7 percent repeatable when tested hundreds of times on an optical bench. But the FDA wanted us to perform repeated testing (three devices, three operators, three tests) on a series of young children — 27 consecutive tests — and still get the same result every time! While most children can sit through one test, or maybe two or three, it takes some concentration to fixate exactly on the smiley face, and we were not aware of any child who could do so 27 consecutive times with consistent results. The FDA’s new requirement was going to be impossible to meet.

To appeal, we created a video of repeated testing in a single child. It clearly showed the difficulty: She was all smiles on the first test, but by the fourth test she was sighing in boredom and by the 10th test she simply refused to look at the machine. Nonetheless, we were told that the repeated testing was required.

The process of appealing and negotiating took months to work out. When things seemed the most dire, I had to remind myself, “The FDA is here to protect us from snake oil salesmen.” And that proving safety and effectiveness would help pediatricians make an informed choice to use the PVS and, in the long term, benefit the kids receiving the test.

More than once during this trying 35-month period, we came close to running out of money. But just as the till was running empty, another supportive investor was willing to step in and write a check to keep us going.

Finally, on June 8, 2016, I got a text from Justin Shaka, now CEO of REBIScan. We could now market the PVS!

FDA clearance Pediatric Vision ScannerThe long climb to market

David Hunter Pediatric Vision ScannerI like to cycle, and I remember a day when I was climbing a hill, heading for a landmark. The hill was enormous. I climbed and climbed, keeping the top in sight, and with sweat and effort and persistence I at last reached the top. And what was just over the crest of the hill? Not the landmark — another hill, this one even higher.

That is sort of where we are now. With FDA clearance behind us, we still need to raise enough investor funds to build a mass-produced version of the PVS. As we enter discussions with potential investors, even with FDA approval, we expect some will want more clinical results, or signed purchase orders, or evidence that we are making a profit before they will invest. In the medical device field, with so many hazards to be negotiated, only a very few visionary investors are willing to accept those risks to move the field forward.

So the long climb to market continues. But every time I see another child with vision loss whose amblyopia has been missed, I gain the strength to work and sweat and push — until every child is screened by the PVS at every well visit, and until every child with amblyopia is caught in time to receive sight-saving treatment.



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Another use for mTOR inhibitors: Preserving vanishing bones in Gorham-Stout syndrome

Gorham Stout rapamycin sirolimus
In Gorham-Stout, lymphatic vessels gone amok eat away at bone. Sirolimus appears to reverse this process.

The mTOR pathway is fundamental to nearly every cell in the body. It drives processes related to cell growth, protein production and metabolism, influencing everything from neurocognition to tumor growth. Because of this broad role, indications for drugs targeting the mTOR pathway are also remarkably broad.

Alexander Malloy, 14, is one of the first patients to benefit from a new use: curbing rapid bone loss in patients with a rare “vanishing bone disease,” or Gorham-Stout syndrome. It was discovered when Alex, who had mild scoliosis, started getting worse. To his parents’ shock, an MRI scan showed he was missing bones in his spine.

Gorham-Stout is actually the result of a rare vascular anomaly.

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Where science connects with care: A Q&A with Leonard Zon

Leonard Zon in the lab

Leonard Zon, MD, is founder and director of the Stem Cell Research Program at Boston Children’s Hospital and an investigator with the Howard Hughes Medical Institute and the Harvard Stem Cell Institute. His laboratory research focuses on stem cell therapies for patients with cancer and blood disorders, using a high-throughput, automated system for screening potential drugs in zebrafish. Zon was cofounder of Scholar Rock and Fate Therapeutics and founder and past president of the International Society for Stem Cell Research.

Your hospital just received a #1 ranking from U.S. News & World Report. What does this mean relative to your role there?

I’ve been at Boston Children’s Hospital for 25 years, and it’s really satisfying to be at the premier institution for clinical care. And we’re very lucky to have one of the premier stem cell programs in the world. I have a strong sense that my impact on society is as a physician-scientist, bringing basic discoveries to the clinic. We’re able to have a huge impact on finding new diagnoses and new therapies for our children.

What inspires you to do your job every day?

As a hematologist I take care of patients who have devastating diseases – a variety of blood diseases and cancer. When I see these children, I’m always wondering, could there be ways to treating them that haven’t been thought of before? Successfully treating a child gives them an entire lifetime of health.

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Hunting rare cancers to ground

rare cancers
(UGREEN 3S / Shutterstock)

As we’ve seen this week on Vector, some rare childhood cancers such as medulloblastoma and neuroblastoma are starting to give up their molecular secrets, raising the possibility (and in medulloblastoma’s case, the reality) of precision treatments. Many cancers, though, are so rare that there aren’t even cell lines in which to study them. Yet they could hold important insights. The first tumor suppressor gene, Rb, was discovered in retinoblastoma, a cancer affecting a mere 500 U.S. children each year.

Doctors often have no clear consensus for diagnosing and treating rare cancers, and outcomes tend to be poor in both children and adults. Andrew Hong, MD, a postdoctoral fellow in the Broad Institute’s Cancer Program and a pediatric oncologist at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, is part of a research team that wants to fix that.

Armed with recent advances in culture technology, the scientists aim to engineer cell lines for as many rare cancers as they can get samples for — and then interrogate them for therapeutic targets. A proof-of-concept published in Nature Communications last month finds a lot of potential in their approach. Read more on Broad Minded, the Broad Institute’s science blog.

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New cancer target, let-7, unifies theories on neuroblastoma’s origins


Striking the nerve tissue, neuroblastoma is the most common cancer in infants and toddlers. Great strides have been made in its treatment, but advanced cases still are often fatal, and children who survive often face life-long physical and intellectual challenges related to their treatment.

A study published online by Nature last week, led by researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, finds that a microRNA called let-7 is central in curbing neuroblastoma. The study unifies several theories about neuroblastoma and could bring focus to efforts to find a targeted, nontoxic alternative to chemotherapy.

The findings also have implications for other solid tumors in which let-7 is lost, such as Wilms tumor, lung, breast, ovarian and cervical cancers, says first author John Powers, PhD, of the Division of Pediatric Hematology/Oncology at Boston Children’s Hospital.

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Beyond appearances: Molecular genetics revises brain tumor classification and care

What a brain tumor looks like isn’t the best predictor of prognosis. (Jensflorian/Wikimedia Commons)
What a brain tumor looks like isn’t the best predictor of prognosis. (Jensflorian/Wikimedia Commons)

Scott PomeroyScott Pomeroy, MD, PhD, is Neurologist-in-Chief at Boston Children’s Hospital. He practices in the Brain Tumor Center and is a member of the F.M. Kirby Neurobiology Center.

For almost a century, brain tumors have been diagnosed based on their appearance under a microscope and classified by their resemblance to the brain cells from which they are derived. For example, astrocytoma ends with “-oma” to designate that it is a tumor derived from astrocytes. In some cases, especially in children, brain tumors resemble cells in the developing brain and are named for the cells from which they are presumed to arise, such as pineoblastoma for developing cells within the pineal gland or medulloblastoma for developing cells within the cerebellum or brainstem.

In June, the World Health Organization (WHO), which sets the worldwide standard, released an updated brain tumor classification scheme that, for the first time, includes molecular and genetic features.

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When antibiotics fail: A potential new angle on severe bacterial infection and sepsis

bacterial infection sepsisBacterial infections that don’t respond to antibiotics are of rising concern. And so is sepsis — the immune system’s last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.

Reporting this week in Nature, scientists in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.

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Double stem cell transplant and other tools are helping children survive neuroblastoma

neuroblastoma double stem cell transplant
Emily Coughlin during her neuroblastoma treatment

When Emily Coughlin complained of a sore knee in May 2009, doctors initially suspected Lyme disease. After antibiotics failed to relieve the pain, Emily was diagnosed with neuroblastoma, a cancer that begins in nerve cells outside the brain, just shy of her fourth birthday. Though neuroblastomia is rare — about 700 new cases occur annually in the United States — it is the most common cancer in infants and toddlers.

In the early 1990s, when Lisa Diller, MD, was starting her career at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Emily would have faced five-year survival odds of less than 15 percent. “It was a devastating diagnosis,” recalls Diller, now chief medical officer of Dana-Farber/Boston Children’s.

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Mom-entrepreneur forms gene therapy company to tackle Sanfilippo syndrome

Karen and Ornella Aiach Sanfilippo gene therapy

Sanfilippo syndrome A is a neurodegenerative condition caused by a genetic error in metabolism: because of a missing enzyme, long-chained sugar molecules cannot be broken down. Toxic substrates accumulate in cells, causing a rapid cognitive decline and, later, motor decline. Most affected children die in their teens or earlier.

There is no treatment, and when Karen Aiach’s daughter Ornella was diagnosed with Sanfilippo syndrome A, no companies were even working on the disease.

As a mother, Aiach could not accept that.

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3D-printed models assist complex brain surgery for encephalocele

Encephalocele 3D printing

At five months’ gestation, Bentley Yoder was given little chance to live. A routine 20-week “gender reveal” ultrasound showed that a large portion of his brain was growing outside of his skull, a malformation known as an encephalocele. But he was moving and kicking and had a strong heartbeat, so his parents, Sierra and Dustin, carried on with the pregnancy.

Born through a normal vaginal delivery (the doctors felt that a C-section would interfere with Sierra’s grieving process), Bentley surprised everyone by thriving and meeting most of his baby milestones.

But the large protuberance on his head was holding him back. It steadily got larger, filling with cerebrospinal fluid. Bentley couldn’t hold his head up for more than a few seconds.

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