Washington, DC. — (CNN) When her son was just 3-months-old, Elizabeth Guardino began to notice that he never responded when she smiled. Dangling a toy in front of his face, Christian did not follow it with his eyes.

“He also started to stare at the sun wide-eyed,” said Guardino of Patchogue, New York. “That also shook us quite a bit.”

These “triggers” sent her to get Christian’s vision tested when he was 6 months old.

The diagnosis was Leber’s congenital amaurosis (LCA), a rare inherited eye disease that causes severe visual impairment beginning in infancy. Scientists have identified at least 13 different types of LCA with separate genetic causes.

“How it was explained to me is I would have to carry a gene and so would my husband, so it’s that rare of an occurrence,” said Guardino. Still, there was some hopeful news that day.

Christian had the type of LCA that would remain stable or slightly improve with age.

“No one knew what his diagnosis really meant,” she recalled. “Including ourselves.”

She clung to the hope that her son’s impairment wouldn’t worsen with age. As he grew, he developed his natural gift for music, which served as a consolation when he struggled to keep up with friends. However, when Christian reached age 12 or so, Elizabeth started seeing a decline in his vision.

On Facebook she happened upon an LCA support group. “I thought this cannot be, because it’s so, so rare,” said Guardino. A family conference in Philadelphia was scheduled for July 2012.

“We jumped on that bandwagon,” she said. Talking to the specialist there, she learned that Christian, 12 at the time, would go completely blind.

“It took every ounce of strength for me to not go running out of that room screaming. It was devastating,” she said.

Later, when tests confirmed a mutation of the RPE65 gene, she consented to treating Christian with an experimental drug made by Philadelphia-based Sparks Therapeutics, Inc.

Luxturna (voretigene neparvovec), an untried gene therapy, would be her gamble to save what little vision her son still had.

Drug safety and effectiveness

“We very much included Christian in that decision because, I mean, that’s a heck of a decision for someone to make for another human being when you don’t know what the outcome could be,” she said. “Christian was gung ho, right from the get-go.”

“Our goal going in was just to stop the progression of the disease, but we wound up getting so much more,” she said.

The life-changing therapy Christian experienced may now be poised to make history.

On Thursday, a Food and Drug Administration advisory committee will meet to review Luxturna. Outside experts will present research and recommendations on the safety and effectiveness of the treatment for patients with retinal dystrophy caused by a confirmed RPE65 mutation. Patients will also make a case by sharing their personal experiences.

Monique da Silva, a spokeswoman for Sparks Therapeutics explained that the company believes the total “population in the US, Europe and select additional markets in the Americas and Asia/Pacific is up to approximately 6,000 individuals” who have RPE65 mutations. The US National Library of Medicine estimates that LCA occurs in 2 to 3 per 100,000 newborns, though not all of these are RPE65 mutations.
The public meeting will conclude with a vote on whether or not to recommend the treatment for approval. This will be followed by a decision from the FDA. While the agency frequently follows the recommendations of its advisory committees, it is not required to when making approval decisions.
A greenlight for Luxturna would be historic. If approved, it would become the first gene therapy for the treatment of an inherited disease in the United States.

How it works

Luxturna works by supplying a third gene — a normal RPE65 gene — to retinal cells. It is a liquid that is injected directly into the eye with a microscopic needle during a surgical procedure, explained Dr. Vinit B. Mahajan, an associate professor of ophthalmology, Vitreoretinal Surgery and Disease Byers Eye Institute at Stanford University.

“In those drops of liquid that we’re injecting is a gene therapy virus … a virus that contains a healthy version of the gene,” said Mahajan, who was involved in the phase 3 clinical trial of the drug while teaching at the University of Iowa, one of the testing centers for the treatment.

Essentially then, the drug adds a third version of the gene, a normal version, to the cell, while the two mutated genes causing the disease remain inside the cell as well, explained Mahajan. They are not removed or replaced.

“We make the healthy gene in a lab” in the form of DNA, said Mahajan. DNA is essentially a chemical made up of four separate molecules (commonly referred to as G, A, T and C), and in labs around the world scientists have been synthesizing DNA for many years now, he explained.

“The trick here was how do we get it inside the cell and how do we deliver it to the eye?” he said. To solve this problem, the researchers at Children’s Hospital of Philadelphia and the University of Pennsylvania engineered a virus capable of delivering the healthy gene into the cells.

The virus is then injected under the retina to get the gene near the cells Mahajan said. Recovery from any eye surgery usually takes several weeks to a few months, yet, some of the patients from the clinical trial recovered visual function almost immediately.

This was true for Christian who, like other patients, wore a patch for a couple of days after the surgery, his mother said.

“They removed the patch in a dimly lit room,” recalled Elizabeth. “And he turned and he noticed us sitting there and he said, ‘Mom, is that you and Papa?’ He would never have seen us sitting there prior to that.”

Christian is not unusual in this positive result. Overall, most of the more than 30 patients who have received treatment with Luxturna during clinical trials have “done great,” said Mahajan. “Patients who had essentially been blind were seeing. It was surprisingly quick. It’s remarkable.”

In the Phase 3 clinical trial, 27 out of 29 participants — 93% — who received the gene therapy demonstrated a gain in functional vision as assessed by a mobility test performed in a maze, according to da Silva. Meanwhile the eight patients who received the drug in an earlier clinical trial have also shown improved vision.

Importantly, the drug caused no terrible side effects in participants and so far they have maintained their visual improvements.

Potential downsides

“So the biggest concern is this is a virus, and even though we want it to go to a specific cell — cells in the eye — the concern is that the virus can go get into other cells in the body where you don’t want it,” said Mahajan. “So instead of just replacing a gene, it might damage some of your normal genes.”

Another possibility is the wayward virus might cause an allergic reaction — an immune reaction where it is not tolerated by the body. Worst case scenario, such an immune reaction could lead to death.

However, the virus is not delivered into blood cells which travel the entire body, it is delivered into the eye, which is self-contained and isolated. What you inject in the eye mostly stays in the eye,” said Mahajan, adding that the surgical delivery helps this as well. “The eye isn’t 100% leak-proof but it’s not very leaky,” said Mahajan.

Another risk, according to Dr. Stephen H. Tsang, an associate professor of ophthalmology and associate professor of pathology and cell biology at Columbia University’s Institute for Genomic Medicine, is the vision improvements may not last.

Tsang, who was not involved in the clinical trial, has reviewed other experimental gene-based therapies for retinal disease being developed by other companies and research institutes. Some are similar to Luxturna in that they use a virus to deliver the gene.

While the participants in clinical trials for similar gene therapies “did really well” at first, said Tsang, “three years later, they went to baseline” — their eyesight reverted to its original poor condition.

Christian Guardino, who is now five years out from treatment with Luxturna, has maintained his newfound vision. However, his mother said that whenever he’s sick or tired, his vision weakens. “It’s almost like his Achilles’ Heel,” she said.

“It’s difficult to compare the trials because the preparation of the viruses is different in each case,” said Tsang. Still, he questions whether Luxturna is a one-time drug for patients. Maybe, he speculated, “it’s not going to be once, but twice or thrice … it could be that every three years, patients might need a boost.”

Future therapies

Despite his misgivings, Tsang believes the new gene therapy is “very exciting” because a “favorable result from the FDA” would mean doctors will soon have a treatment to offer patients with this rare retinal disease. “Before, we had nothing,” he said.

If approved, the new gene therapy would be another victory for combating rare diseases, also known as orphan diseases.

“If you told me a few years ago that this therapy is only good for (so few) people, I would not have thought anyone would want to work on it,” said Tsang.

Mahajan said the new drug is a pioneering effort that opens the door for other companies working toward new genetic therapies for other diseases, both rare and common.

“We’ve been doing gene therapy in the mouse for many years — we’ve cured lots of mice,” said Mahajan. “Bringing it to patients is a watershed moment.”

Certainly it has been so for Christian Guardino, now 17 years old, whose visual impairment once meant the falling snow and the moon crossing the night sky were unseen mysteries.

Today he’s seen snowflakes, the moon … and more.

Christian’s dream to become a singer took flight during season 12 of “America’s Got Talent,” when he auditioned in an episode that aired in June. Though he was eventually eliminated in the semifinals, he told his mother the ability to walk unaided onto the stage and see faces in the audience gave him confidence.

He wears special glasses and uses assistive technologies to help him see the blackboard and enlarge the print of written materials for his classes at Patchogue-Medford High School. “He’s doing really well in mainstream (classes),” said his mother.
She added that Christian recently told her he is still learning to use his newfound vision.

“If I could tell you how many times I had to sit and wait because he would just stop and stare at something,” said Elizabeth Guardino.

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