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Gene Therapy for Blindness Works!

Corey Haas would likely have been blind by now, if not for gene therapy in 2008.
Corey Haas would likely have been blind by now, if not for gene therapy in 2008.

The news this week presented at a major vision conference and published in The New England Journal of Medicine about gene therapy to treat childhood blindness paints an unnecessarily grim picture. Because I wrote a book about it and know affected families, I’d like to add some much-needed perspective.

Two papers in the NEJM, Jacobson et al and Bainbridge et al, report follow-up results on gene therapy performed since 2008 for RPE65-associated Leber congenital amaurosis (RPE65-LCA for short). Various measurements and images show a continual degeneration of the photoreceptors (rods and cones) despite the fact that many patients became able to see for the first time and some still do. One of the research groups reported initial findings of continued disease in 2013, which DNA Science covered (Another bump in the road to gene therapy). This week, that bump appears to be a boulder.

The bottom line from someone (me) who’s seen kids with newfound vision: Numbers and scans don’t tell the whole story. These aren’t the only ways to assess visual function. A formerly blind child who can now ride a bike, step off a curb unaided, or see a sibling’s face should count too, even if the ability wanes.

Briard sheepdogs have a natural form of RPE65-LCA, but the new studies show it is more severe in humans. (Foundation for Retinal Research)
Briard sheepdogs have a natural form of RPE65-LCA, but the new studies show it is more severe in humans. (Foundation for Retinal Research)

Tracking continuing disease despite clinical improvement is important in making a treatment the best it can be, experts agree. But let’s not dismiss what’s been accomplished.

I spoke with Jean Bennett, MD, PhD, who leads the gene therapy trial for RPE65-LCA at Children’s Hospital of Philadelphia (CHOP), where results do not indicate continued degeneration (see my news report in Medscape). The CHOP group didn’t publish in this week’s NEJM. I also talked to Eric Pierce, MD, PhD, who worked with Dr. Bennett on the early clinical trial and is now at the Massachusetts Eye and Ear Infirmary. They point out where caveats and explanations of study design might help in interpreting the new NEJM findings.

• The number of patients followed in the two new reports is very small (3 of 15 in one study, 12 in the other) and only a tiny portion of the retinas were examined. Hundreds of patients have had the procedure. “I could pick 3 patients in our trial and look at the data and say it doesn’t work, and I can also pick another 3 and say it works fantastically,” Dr. Bennett said.

• The Jacobson paper compares treated eyes to historical samples, not to the patients’ untreated eyes, which would control for individual differences in the rate of degradation as the disease progresses and for normal aging, a more personalized approach.

• Retinal sensitivity at 6 years is still considerably higher than it was before treatment. The intervention works.

• Many patients see when they didn’t before gene therapy, even if tests such as electroretinography and optical coherence tomography (OCT) reveal impaired photoreceptor function and degeneration.

• Bainbridge et al used a promoter (a DNA sequence that controls the rate of gene expression) that wasn’t as powerful as the CHOP one, necessitating higher doses that may have caused the inflammation seen in some patients and contributed to delayed response and diminished efficacy. “Most of the problems were likely recovery from the surgical procedure and using a virus that doesn’t deliver any punch,” said Dr. Bennett.

An editorial in the NEJM by Alan F. Wright, MD, PhD of the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh sets a negative tone: “Without a highly efficient vector delivery system and sufficient surviving retinal pigment epithelium and photoreceptors, treatment success will be transient.”

But it’s ok for a treatment to be transient!

My mother underwent surgery, chemo, and radiation for breast cancer that wasn’t a cure, but it bought her 17 years. Drugs to treat diabetes, hypertension, acne, you name it, aren’t a one-shot deal. If I didn’t take a thyroid pill every day, I’d be dead.

Penicillin took many years to be developed -- so will gene therapy.
Penicillin took many years to be developed — so will gene therapy.

Dr. Pierce compares the trajectory of gene therapy to that of penicillin. “When it was introduced in the 1940s, not everybody responded, and we learned over time that we use different doses and routes of administration to treat different diseases. Should we have given up on penicillin? Call it bad because it didn’t work on everyone the first time we tried it? We needed to learn to use it effectively and develop additional antibiotics to treat what penicillin doesn’t. It will be the same story for gene therapy.”

Adds Dr. Bennett, “It would be naive to think that any drug is going to work perfectly all of the time. And it is also naive to think that we can immediately turn someone who is severely visually impaired to someone with 20/20 vision. We are still learning about the variables that determine success.”

Dr. Pierce thinks that the new findings are going to make gene therapy better in the long run. “People have been trying to develop treatments for LCA and related inherited blindness for 100 years. Nothing has ever worked before and here are the first set of therapies that actually work. It’s still a huge advance, but we need to perfect it.”

Given the difficulties of vector design and the pace at which gene transfer experts are learning to improve delivery, starting over would set back the clinical trial clock. And that would harm patients, said Dr. Bennett. “It would take another 15 years to get to this point and during that time a few more generations of affected individuals would go blind. There is something that works now!” A company, Spark Therapeutics has formed to commercialize the gene therapy developed at CHOP, and their website has several success stories. Dr. Bennett and her husband, ophthalmologist Dr. Al Maguire, who performs the procedures, have waived all rights to profit.

So what’s wrong with a treatment that must be repeated every few years in order to give a child sight? Nothing at all, says Kristin Smedley, a mom of two profoundly blind sons who would give anything for the chance at gene therapy. “Until other therapies are available, gene therapy is the best hope right now for my boys. Even if this approach only restores a fraction of vision, that fraction could mean no longer needing a cane to navigate or being able to read print instead of Braille.”

Michael Smedley
Michael Smedley

The Smedley family’s form of LCA is caused by mutation in a gene called CRB1. In March I attended the annual gala for their Cure Retinal Blindness Foundation. During the cocktail hour, someone was singing at the piano, “Born to Run.” I turned to my husband.

“Who would have the confidence to try to match Bruce Springsteen, and on that song? And sound just like him?”

Michael Smedley did. Blindness hasn’t stopped him from being a musician, an actor, and an athlete. I can hardly imagine what he will be capable of as an adult, when  he will likely, finally, be able to see. For gene therapy to vanquish CRB1-associated LCA is on Dr. Bennett’s short list. She heard him perform the Boss’s anthem too, followed a little while later by a sing-along to Don’t Stop Believing on an electric keyboard onstage in front of the packed ballroom. It was magical.

We can take a lesson from Michael Smedley and Journey. I’m all about science and not belief, but the families with blind children shouldn’t let the NEJM reports this week bring them down. Gene therapy for LCA works!

(A similar post appeared on May 4 at


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