Tag: LUXTURNA

Nearly Three Years Later, LUXTURNA®™ Treatments Continue to See Success

Since its launch in March 2018, breakthrough gene therapy LUXTURNA®™ continues to be successful in helping improve vision in people with inherited retinal disease due to mutations in both copies of the RPE65 gene and viable retinal cells as determined by a healthcare professional. The therapy treats LCA2, known as LCA/RPE65, one of more than 25 forms of Leber congenital amaurosis. 

The drug – developed by Spark Therapeutics and a team of retinal research superstars that included Dr. Katherine A. High  and Dr. Jean Bennett – came to fruition after 12 years of research and millions of dollars in investment. 

Spark Therapeutics could not comment on the number of people who have received the gene therapy, but spokesman Kevin Giordano recently said the company has shipped well over 200 vials of the therapy since the U.S. Food & Drug Administration approval in December 2017. One vial of the drug treats one eye.

Trained retinal surgeons at one of the 10 eligible treatment centers in the United States deliver the gene therapy to the back of the eye by subretinal injection using a needle the size of an eyelash; about a week or so later, the patient undergoes the procedure in the other eye.

Read: 10 US Centers Offering Treatment

“Spark Therapeutics is thrilled patients continue to benefit from LUXTURNA (voretigene neparvovec-ryzl),” Giordano, Spark’s External and Product Communications Lead, said. “A gene therapy is a major milestone, not only for those of us at Spark, but also for the patient community and broader gene therapy field.”

The cost of the drug – $425,000 for each eye – initially caused anxiety among patient families, but Giordano had good news about insurance coverage.

“Payer coverage has exceeded expectations, and to our knowledge no treatment-eligible patient has been denied treatment due to their insurance coverage,” he said.

LUXTURNA also is being used beyond this country through license and supply agreements with Novartis, which has the rights to commercialize the drug in Europe and all other markets outside the United States. Spark manufactures and supplies the gene therapy to Novartis, according to Giordano.

Also, results from ongoing studies continue to support the drug’s safety profile and efficacy.

“In 2019, Spark presented four-year durability data from the LUXTURNA Phase 3 clinical trial,” Giordano said. 

Read: LUXTURNA safety information

For privacy reasons, Spark Therapeutics cannot share patient results.

But we can – at least a couple of them because they came from patients and families sharing their stories with us.

For Hannah, ‘Hope Realized’

Hannah Reif, daughter of Amy and Chris Reif of Maple Glen, PA, underwent LUXTURNA gene therapy in July 2018. Dr. Albert M. Maguire, who is married to researcher Dr. Bennett, performed Hannah’s surgery at Children’s Hospital of Philadelphia (CHOP).  

Hannah with a big smile, wearing a light blue green coat and holding a drink
Hannah Reif

“We closely watched the clinical trials and the FDA approval process for seven years, starting when Hannah was diagnosed with LCA/RPE65 at just a few months of age,” Amy said. “Seven years of hope. 

“Two years out from Hannah’s surgery, I can say we feel grateful and fortunate that she was treated with LUXTURNA. No regrets. LUXTURNA was hope realized. It delivered what it promised.”

She said what that has meant for Hannah has been nothing short of life changing.

“It has given her more independence, which has been wonderful for her self-confidence. It has given her the ability to see what she couldn’t before.”

Since the surgery, Hannah’s vision in dim lighting and her visual acuity improved. She is now 9 and just finished third grade. 

Sometimes, her mom said, it’s the little things that are the most amazing.

“A year after the surgery, she was about to eat hot oatmeal and said, ‘Hey, I see steam. Hey, I can see that,’ ” Amy said.

“There are still things that pop up that she’s seen for the first time, like when she said, ‘Mom, did you know there’s a pattern on this toy?’ It’s fun to see her discovering.”

Amy said she and her family will be forever grateful to Dr. Bennett.

“There has been a lot of talk about heroes recently and Dr. Bennett is our hero. We are grateful for this groundbreaking treatment that she developed, that has been life-changing, not only for our daughter, but also for the sons and daughters and loved ones of so many others as well.”

‘His Vision Changed Everything’

Creed Pettit, one of the first recipients LUXTURNA, received the gene therapy at age 9 in March 2018. Dr. Audina M. Berracol  performed the surgery at Bascom Palmer Eye Institute in Miami, Fla.

His mom, Sarah St. Pierre Schroeder, told us that her now-11-year-old is doing amazing and only occasionally has issues with dim lights, “but nothing like before.”

Their days in Mount Dora, Fla., have changed in a major way.

“He still starts his day with his trusty smoothie and waffle, but after that, Creed wants to create new pranks (today was putting ice in the tub). He said it was nice and warm so I could soak my feet.”

Creed in blue glasses, holding his Uno Cards
Creed Pettit

Creed now loves to play board games – Trouble, Sorry, Battleship and Uno. 

“His vision has changed everything. He can manipulate small objects, he is using pointer fingers, and loves trying to roll his eyes in the mirror.”

Creed still likes to draw, and he loves riding and popping wheelies on his bike named Carlitos. He also likes to talk.

“Talking more is an understatement! Sunup to sundown, he is talking. He has also learned how fun it is to use his imagination, something he never did before. He creates awesome stories during this time.  He is so much more independent; I have to remind myself of that often.”

At first, she and her husband, Chad, could see that Creed’s vision improved some, but once he became confident about his gene replacement, they noticed him finding toys and games.

“He was suddenly enjoying things he didn’t before. He now expresses when he can’t see. Yesterday it rained all day, I kept waiting for him to tell me it was too dark inside, but he was fine. He just started doing staring contests. I love looking at his eyes during the contest.”

Sarah said she is incredibly grateful.

“Creed’s surgery is something we still thank God, St. Raphael, St. Lucy and Sister Miriam Teresa, for every night.” 

Like many kids across the country, Creed finished school at home because of the coronavirus pandemic. He graduated from fifth grade and thought because he finished school at home, he wouldn’t have to wear the graduation cap.

“But I was not going to let that slide,” his mom said. “I made one and took pictures.”

Anxiety, and a Friend to Call On

Throughout his journey, though, Creed felt anxious, something Sarah had learned that might happen when, before Creed’s surgery, she talked with Tami Morehouse, a LUXTURNA clinical trial participant at age 44.

Tami, a Sofia Sees Hope Ambassador, tries to calm fears and advises potential gene therapy patients and their parents that even though undergoing the surgery has the potential to do such good by improving vision, they should think about their expectations, especially with children.

“We are comfortable in our own zone; give us a little bit of change and it can throw us off,” Tami said.

Sarah understands. 

“He started to have a lot of anxiety. He had a hard time sleeping. I feel everything changed so fast that he was overwhelmed, but we have worked hard on getting past that.”

Sarah and her family are in a great place now. But after they were home from the hospital in Miami and settled into their routine, she said she became very emotional.

“All the tears I had held in for nine years started to come out. I felt I no longer had a purpose; I was so used to staying busy. I did not know who I was supposed to be.” 

She got some help and realized she still was needed because people need her help learning about and understanding this groundbreaking gene therapy.

“I still find myself shocked over how this has changed Creed’s life and so many other lives.”

All About Clinical Trials

Clinical trials are never done in a vacuum, or in a medieval basement where Dr. Frederick Frankenstein (pronounced Fronkensteen), his pretty lab assistant, Inga, and faithful houseboy, Igor, create a monster. 

While the creature from the 1974 movie “Young Frankenstein” turns out to be somewhat civilized, (see Gene Wilder as the young doctor and Peter Boyle as the monster doing the soft-shoe in white tie and black tails to “Puttin’ on the Ritz”), a caption above that lab team in a slide shown at the Hope in Focus (formally Sofia Sees Hope) second LCA Family Conference cautions: “Regulatory Oversight is Critical!”

Humor credit goes to Ben Shaberman, Senior Director of Scientific Outreach and Community Engagement for Foundation Fighting Blindness. He moderated a four-member panel discussion in a session called “All About Clinical Trials” at the July conference in Philadelphia. Shaberman reports on retinal research for the Foundation’s print and electronic publications. He also presents scientific advancements at local and national events and enjoys working with constituents to help them understand their retinal disease and current research that may benefit them.

Making sure trials are safe

Dr. Wiley Chambers II, MD headshot
Dr. Wiley Chambers II, MD

Panelist Dr. Wiley A. Chambers, the U.S. Food and Drug Administration’s Supervisory Medical Officer in the Office of New Drugs, said terrible outcomes can happen in trials not approved and regulated by the FDA. 

Dr. Chambers previously cited a disastrous case in which a 77-year-old woman traveled to an alleged clinic to have “stem cells” injected in her eyes in the hope of a cure or at least help for her macular degeneration. The procedure entailed separating “stem cells” from the woman’s belly fat and injecting them into her eyes to supposedly regenerate tissue. Not covered by insurance and not federally regulated, the procedure cost almost $9,000 and caused her vision to badly deteriorate after her retinas peeled away from her eyes.

The FDA assigns an Investigational New Drug (IND) number to every legitimate clinical trial.

“Just be careful when you go to a clinical trial or a physician that it is a legitimate trial,” Dr. Chambers said. “If they can’t give you an IND number, then walk away.” 

The website Clinicaltrials.gov includes trials that do have an IND number and unregulated trials that do not have an IND number. Avoid them. One must specifically ask if they have been issued an IND number, signaling the federal OK to proceed with clinical studies that happen in three phases.

Dr. Chambers also noted that trials are not for the benefit of participating patients. At the heart of a clinical trial is that researchers do not know what’s going to happen. A key word here is equipoise – a balance or counterbalance – of something. 

“We do the clinical trial and find out, does this have some efficacy and is it safe?”

Clinical trials tell as much information as possible, balanced with a doable study and doable patient commitment.

“It’s a balancing act,” he said. “The trials are to help inform people afterward.”

A long, expensive process

Research studies in humans are for potential therapies; they take 10 years or more to complete and can cost tens or hundreds of millions of dollars.

It took 12 years and $500 million to research and develop LUXTURNA™, an engineered virus delivered by subretinal injections of the human RPE65 gene, a gene that, when mutated, causes a form of LCA called LCA2 (RPE65-LCA). 

Tami in a pink shirt and Michael besides her in a bright orange shirt sitting at the 2019 LCA Family Conference
Tami and Michael Morehouse

Panel members Tami Morehouse and her husband, Michael, experienced firsthand what it feels like to take part in a Phase 1/2 LCA/RPE65 gene therapy trial. Intervention at earlier ages can offer better results with degenerative diseases like LCA and other inherited retinal diseases (IRDs) because photoreceptors diminish with age. 

The Cleveland-area couple talked about Tami’s pioneering experience as the oldest person, at 44, to take part in the LUXTURNA trial and regain some vision.

“It’s a huge, life-changing event for us,” Michael said.

Walking in Philadelphia three days after her first injection, Tami asked her husband if a building up ahead had stripes on it. Turns out, it was a parking garage with spaces between levels appearing as solid stripes. Before the injection, she could not see any part of the parking deck; her ability to discern solids and stripes meant the treatment already began improving her vision.

Tami had some vision in college and walked across the graduation stage by herself.  Michael described her progressive vision loss as, “Go on, go on, big drop; go on, go on, big drop; no diagnosis.

“She was on a path to darkness and she knew it,” he said.

Taking the risk for the reward

He heard Jean Bennett, MD, PhD, on a Sunday radio show talking about her retinal research on the emerging therapy that came to fruition as LUXTURNA. He called her office early the next day, and said to the audience, “Guess who answered the phone?” (Here’s a link to a story on Dr. Bennett’s presentation at this conference.)  

Seven months later they received an email from Dr. Bennett, with the subject line: “Are you ready?”

Dr. Bennett conducted the studies with her partner in research and in marriage, Dr. Albert M. Maguire.  

In answer to a question about what she was thinking before beginning the trial, Tami said, “I don’t want to go totally blind.”

“In all honesty, I never thought that I’d ever have a shot at seeing … I kind of underestimated my possibilities. I became a much more functional person in day-to-day living. I would see who’s approaching. See my kids, my (softball-playing) daughter dancing off third base, taunting her catcher. 

“I got way more than I anticipated.”

Tami is part of the Sofia Sees Hope Family Connections program, calming fears and sharing her experiences with many patients along the way, including very young ones. 

“Even though huge strides have been made in clinical trials, they’re very frightened, they’re very nervous. 

“Jean and Albert explained so much; they relieved my fears in such a way that I’ve been able to transmit that to families, to moms. It’s a lot of pressure for some moms. 

“Just being able to say that it won’t hurt when Dr. Maguire inserts a needle in your eye because you’re out like a light; that is a beautiful thing because you don’t even know what’s happening to you.”

Tami advised potential surgical patients and their parents that even though undergoing surgery has the potential to do such good by improving vision, they should think about their expectations. “We are comfortable in our own zone; give us a little bit of change and it can throw us off.”

“If mom and dad or older siblings are calmer, the children are going to be more comfortable, too.”

Setting realistic expectations

Panelist Dr. Michel Michaelides, a founding member and head of clinical ophthalmology at MeiraGTx based in New York City and London, said clinical trials impact the daily lives of study participants because they’re required to undergo multiple tests, many of which, he said, are boring and tedious.

“We spend a lot of time letting people know what they’re really in for.”

Black and White headshot of Dr. Michel Michaelides
Dr. Michel Michaelides, a Founding Member and Head of Clinical Ophthalmology at MeiraGTx

Dr. Michaelides is the Principal Investigator of four interventional clinical trials and has 10 ongoing ethically approved studies. He is Professor of Ophthalmology at London’s UCL Institute of Ophthalmology in the Department of Genetics and Molecular Therapy, and Consultant Ophthalmologist at Moorfields Eye Hospital in the Departments of Inherited Eye Disease, Medical Retina and Pedriatric Ophthalmology.

Moderator Shaberman asked him what he says about therapy options to people who have lost a lot of vision. In advanced cases of vision loss, Dr. Michaelides said, optogenetics might be a relevant course of action. Optogenetics is the science of making cells in the retina that do not normally detect light, become light sensitive, and thereby aim to replace the lost light-sensitive cells (rods and cones/photoreceptors).

“The idea is to make cells that are not light sensitive, (be) light sensitive.”

Another course is retinal implant technology, also known as the “Bionic Eye” or “Artificial Vision,” in which doctors insert a light-sensitive microchip into the retina to provide a way to detect light. These implants can be placed on the surface of the retina (epi-retinal implants) or underneath the retina (sub-retinal implants). He also suggested the use of internal or external cameras with these implants, saying, “I think there’s going to be greater development in that area.”

Another avenue is stem cell therapies (cell therapies), in which donor cells could be used to grow fresh retinal cells for transplantation into the eye to replace lost cells. 

He also is involved in the development of therapies using stem cells to replace lost light-detecting retinal cells. He has been Principal Investigator of the first ocular stem cell therapy trial, which involved transplanting retinal pigment epithelial cells (non-light-detecting cells) in patients with advanced Stargardt Disease. 

His clinical trial for a potential LCA4 (AIPL1-LCA) therapy currently is recruiting participants.

Dr. Michaelides’ ocular research comprises 300 peer-reviewed publications and 25 book chapters. One of those research papers came into focus at the LCA conference in July, where an audience member – a mother of a child with LCA2 (RPE65-LCA) – told her story.

“Even after an ERG (electroretinography),*” she said, “nobody told us it was LCA.” 

She said reading one of his research publications on RPE65 put her family on the right track.

“That’s what we took to our doctor,” she said. “So, you’ve been really important to our journey.”

Retinal Disease Gene Therapy Breakthroughs Trace Their Roots to 19th Century Research

Theodor Karl Gustav von Leber would be proud. So would Adolphe Franceschetti and Carl-Henry Alström. 

Their research from the 19th and 20th centuries laid the foundation for groundbreaking gene therapy to treat Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs). Translational research focused on LCA helped bring forth unprecedented numbers of genetic clinical trials now underway for IRD treatments and cures.

Dr. Tomas S. Aleman, associate professor of ophthalmology and director of the Hereditary Retinal Degeneration Clinics at the Perelman Center for Advanced Medicine and the Center for Advanced Retinal and Ocular Therapeutics at the University of Pennsylvania, discussed the beginnings of research into retinal degeneration as part of his presentation at the Hope in Focus (formally Sofia Sees Hope) second LCA Family Conference in Philadelphia last summer.

Dr. Aleman joined three panelists in a conference session called “One Disease, Many Approaches,” moderated by Brian Mansfield, PhD, executive vice president of research and interim chief scientific officer for the Foundation Fighting Blindness. 

In a research paper published in 1871, Dr. Theodor Karl Gustav von Leber recognized early-infancy severe retinal disease with pupils that are “amaurotic,” related to amaurosis, meaning dimming, darkening, dark or obscure. Amaurotic pupils do not relate to light normally, expanding and contracting more slowly than normal or not responding to light at all. A large group of early-onset inherited retinopathies causing blindness carry his name as Leber’s Congenital Amaurosis. 

“His descriptions still endure,” Dr. Aleman told his audience of more than 80 people from across the country and Mexico.

The evolution of research

Dr. Tomas S. Aleman, associate professor of ophthalmology and director of the Hereditary Retinal Degeneration Clinics at the Perelman Center for Advanced Medicine and the Center for Advanced Retinal and Ocular Therapeutics at the University of Pennsylvania

Dr. Adolphe Franceschetti authored more than 500 articles throughout his life (1896-1968), realizing the retinal origin of the blindness and working on ocular genetics, Dr. Aleman said. A specific behavior comprised of poking, pressing and rubbing the eyes with a knuckle or finger to mechanically evoke perception of light is called Franceschetti’s oculo-digital sign and is characteristic of LCA. Researchers suspect this behavior in affected children may contribute to deep-set eyes and keratoconus, a condition in which the normally round cornea thins and bulges into a cone-like shape, causing distorted vision.

Dr. Carl-Henry Alström confirmed that LCA is genetic in nature, and he is credited with recognizing in the 1950s syndromic forms of LCA and other early-onset retinopathies such as Bardet-Biedl Syndrome, a rare genetic disorder with highly variable symptoms that may include retinal degeneration, obesity, reduced kidney function and many other features.

LCA occurs in 1 in 30,000 to 1 in 80,000 people and makes up 5 percent of all retinal dystrophies. Twenty percent of children with visual impairment and attending special schools have LCA.  

LCA, thought of as one disease until 40 years ago, now consists of more than 27 forms.

“It’s a large pack of diseases,” Dr. Aleman said.

Decades of work toward success

He characterized LCA as a molecularly heterogenous or diverse group of diseases with most primary disease location within the cells that perceive light or photoreceptors. Dr. Aleman detailed the complexities of clinical exams, vision testing and the spectrum of severity of vision loss observed in LCA. One such scenario, known as structural-functional dissociation, occurs when the loss of vision is disproportional to the loss of photoreceptors and is frequently seen in LCA, particularly very early in life. Such scenario represents the ideal for gene corrective treatment strategies. 

RPE65-LCA studies led by a group of researchers at the University of Pennsylvania dating back to the late 1990s solidly demonstrated LCA could be treated. Dr. Aleman  cited the importance of the translational research and clinical trials that led to federal approval of LUXTURNA™, a gene therapy treatment for LCA2 or RPE65-LCA, saying other, more frequent and neglected diseases have gotten attention through the RPE65 story.

He singled out two researchers, Jean Bennett, MD, PhD, who joined him on the conference panel, and her partner in research and marriage, Dr. Albert M. Maguire. He pointed out that their foresight and drive pushed research beyond the initial gratification granted by the spectacular results of early multi-institutional RPE65 gene therapy trials, to fulfill the practical need of an approved treatment for use in the clinic. The treatment, which produces dramatic gains in visual sensitivity, is the first and is, to date, the only gene therapy product approved for clinical use for an inherited retinal disease in the United States and Europe.

More patients have been treated with LUXTURNA since its approval in December 2017 by the U.S. Food and Drug Administration than those who received the medication during the clinical trials.

“I like to think that if it wasn’t for Jean and Albert, we wouldn’t be where we are today,” he told the gathering of patients, patient advocates, family members, researchers, doctors and biotechnology leaders.

No cure yet; work continues

Having one retinal gene therapy approved for use in the clinic, 900 patients enrolled in trials across 30 sites, and progress on therapies for the most severe forms of LCA, Dr. Aleman said, “That should stimulate ourselves to continue.”

He noted that much work remains to be done: LCA has not been cured, and researchers do not have a solution for every type of LCA. Gene therapy may not be enough for every patient or form of LCA, and the potential outcomes after treatments should not be expected to be the same across the heterogeneous group of diseases under the LCA umbrella.

In closing his presentation, Dr. Aleman posed three questions regarding LCA treatment and research: 

  • Can we treat hereditary retinal degenerations/LCA? “Yes, the answer is yes.
  • Can we defeat LCA? “And the answer is also yes.” 
  • Do we have the tools and people to do it? “The answer is also yes.”

Dogs as test cases

In her presentation, Dr. Jean Bennett described how the RPE65 gene, when mutated, causes LCA2 or RPE65-LCA. In early research, Briard herding dogs that carried the mutated gene gained improved vision after receiving subretinal injections of an engineered virus of the human RPE65 gene. The treatment works by encoding an enzyme that converts light into electrical signals interpreted by the brain.

Dr. Bennett was one of the first investigators to use viral vectors, in which a virus is used as a vector or carrier that is genetically engineered to deliver the gene to specific cells in the retina. She is professor of ophthalmology at the Center for Advanced Retinal and Ocular Therapeutics and the F.M. Kirby Center for Molecular Ophthalmology at the Perelman School of Medicine. Please see a related story detailing her conference presentation. 

Pam Stetkiewicz, PhD, vice president of program management at Editas Medicine, described a different approach using gene editing technology developed by Editas. The treatment uses molecular biology to create genomic medicine that precisely edits – by locating and removing – the targeted mutation in LCA10 or CEP290-LCA. She said the technology builds on the foundation inspired by Dr. Bennett’s gene replacement therapy.

More treatments in the works
Pam Stetkiewicz, PhD, vice president of program management at Editas Medicine

Editas Medicine, based in Cambridge, Mass., in partnership with Allergan, based in Dublin, Ireland, use CRISPR/Cas9 gene-editing technology to accomplish DNA editing. The treatment, called EDIT-101, cuts out the mutation and is delivered to photoreceptors by subretinal injection. The editing permanently corrects the original, non-functioning protein essential for vision.

Dr. Stetkiewicz said Editas hopes to use the medicine to treat LCA10. Additionally, the company is developing experimental medicines to treat Usher Syndrome 2A and Retinitis Pigmentosa, among other IRDs. Editas is also working to develop engineered cell medicines to treat cancers and blood diseases, including Sickle Cell Disease. 

The FDA approved the company’s 10,000-page data package, securing the required Investigational New Drug (IND) application to begin clinical studies with EDIT-101 in humans.

Editas and Allergan currently are recruiting patients with CEP290-LCA for a natural history study that will create the basis to test safety and efficacy in the Phase 1/2 clinical trial of EDIT-101.

Dr. Stetkiewicz said preclinical data shows that EDIT-101 is well-tolerated, efficacious and safe. Measurement of editing intended DNA versus unintended DNA is called specificity. Human retinal explants, pieces of tissue cultured for growth, treated with EDIT-101 resulted in a high level of intended editing with zero unintended editing, meaning the treatment has an excellent genomic specificity profile.

“So, we’re thrilled with this result,” she said. 

Phase 1/2 clinical trials will begin in the second half of this year with 18 patients age 3 years and older at clinical sites in Massachusetts, Florida, Oregon and Michigan.

DNA, RNA, & LCA
Michael Schwartz, M.S., MBA, is vice president of ophthalmology at ProQR Therapeutics and is the global project leader for Sepofarsen (QR-110), an RNA therapy under development.

Panelist Michael Schwartz, M.S., MBA, is vice president of ophthalmology at ProQR Therapeutics and is the global project leader for Sepofarsen (QR-110), an RNA therapy under development. 

ProQR, based in The Netherlands with offices in Cambridge, Mass., is developing an antisense oligonucleotide (AON) product, Sepofarsen (QR-110), designed as a disease-modifying therapy for LCA due to the c.2991 +1655A>G mutation (p.Cys998X) in the CEP290 gene. The company is developing AON products, which are RNA therapies primarily for ophthalmic inherited disease. AON are short, single-stranded RNA molecules that interact with messenger RNA to prevent translation of a targeted gene.

Sepofarsen works like genetic tape to block the mutation p.Cys998X in the CEP290 gene.

To help understand what this means, Schwartz presented background on DNA, RNA and LCA:

The body comprises many different cells, and we have DNA in each of these cells. DNA contains many instructions for making all the different proteins, which are important building blocks needed by a cell.

When the cell needs a building block, it first copies instructions to a shorter blueprint called RNA; the RNA is then used to guide how to make a new protein, like CEP290. Together, these different proteins make sure the cell works as it should, resulting in normal vision.

But things don’t always go right. Inherited diseases are caused by mistakes in the DNA, and then these mistakes are copied into the RNA, as in the p.Cys998X mutation in CEP290.

This means that the proteins also will have the mistakes in them. They can’t work properly, and the cell cannot function as it should. This is what causes LCA.

He also detailed the workings of RNA therapies, saying they consist of short RNA molecules, with the aim to repair the mutation in a patient’s RNA – without changing the DNA – and to restore the function of the protein and the cell to hopefully improve vision.

A normal CEP290 protein maintains cilium structure in the photoreceptors of the retina and enables normal protein transport to the photoreceptor outer segment.

The CEP290 p.Cys998X mutation creates an environment that results in an aberrant exon that disrupts the splicing code of genes by truncating the CEP290 protein, ultimately leading to the degeneration of the photoreceptor cells.

Sepofarsen, delivered by intravitreal injection, blocks the recognition of the aberrance, and that results in favoring production of normal protein. 

“We can actually reverse the phenotype of that mutation,” Schwartz said.

ProQR is finalizing interim results of its ongoing Phase 1/2 trial involving 11 people from ages 8 to 44. Schwartz said most of the patients had clinically meaningful improvement. The company’s Phase 2/3 trial began, with the first patient dosed in April. The 24-month trial expects to enroll 30 patients.

He cited an exceptional patient responder in the Phase 1/2 trial in which an adult with only light perception vision before the trial could now read letters on the eye chart.

“They said they could see things out of the treated eye that they had not seen for decades.”

Dr. Jean Bennett: ‘Seeing the Light with Retinal Gene Therapy’

Known as a pioneer in gene therapy, Jean Bennett, MD, PhD, surveyed her audience of patients and families living with Leber congenital amaurosis and declared: “YOU are all the pioneers!”

Dr. Bennett, addressing more than 80 people from 15 states and Mexico at the Hope in Focus (formally Sofia Sees Hope) second LCA Family Conference, characterized the meeting as a great place to reach out to patients to participate in clinical trials. Researchers normally recruit study patients through advertising.

Along with families living with LCA and other inherited retinal diseases (IRDs), people attending the summer conference in Philadelphia included patient advocates, doctors, researchers and biotechnology industry leaders.

Dr. Bennett is Professor of Ophthalmology at the Center for Advanced Retinal and Ocular Therapeutics and the F.M. Kirby Center for Molecular Ophthalmology at the Perelman School of Medicine, University of Pennsylvania. She gave her presentation as part of a conference session called “One Disease, Many Approaches.”

Viral Vectors Key 

Dr. Bennett was one of the first investigators to use viral vectors, in which a virus is used as a vector or carrier that is genetically engineered to deliver the gene to specific cells in the retina.

Lancelot, a golden colored dog standing on the steps with the U.S. Capital behind him
Lancelot on steps of the U.S. Capitol.

She emphasized that LUXTURNA™, the breakthrough genetic treatment she and her colleagues developed at Children’s Hospital of Philadelphia (CHOP) and Spark Therapeutics, began with the successful treatment of a special being: Lancelot, the first in a line of Briard herding dogs, who helped drive research to bring to market gene therapy that improved vision by focusing on a particular mutated gene.

Dr. Bennett and her colleagues studied Lancelot and the other dogs after learning that a veterinary ophthalmologist had identified the gene which, when mutated, led to blindness in Swedish Briard dogs. 

The research dogs received an engineered virus delivering the human RPE65 gene, a gene that, when mutated, causes LCA RPE65, also known as LCA2, one of the more than 25 forms of LCA. Doctors delivered the drug by subretinal injection through a needle the size of an eyelash. The treatment works by encoding an enzyme that converts light into electrical signals interpreted by the brain.

Dr. Bennett’s presentation, “Seeing the Light with Retinal Gene Therapy: From Fantasy to Reality,” features a photograph of Lancelot wearing glasses and perusing his article in Nature Genetics magazine. 

Lancelot accompanied her on her frequent Congressional visits to lobby for more research funding. Dr. Bennett said Lancelot’s distant cousin, Venus, and later her pups, Mercury and Saturn, also successfully received the treatment. 

According to an article in the Philadelphia Inquirer, “Before the treatment, Venus preferred to crouch in a corner for fear of bumping into objects. But after the treatment, it was clear that Venus and the other dogs were able to see. They could easily navigate obstacle courses set up by researchers. Venus was a new dog, eager to walk around and explore grass, birds, and squirrels for the first time.”

Dr. Bennett, noting Venus’ recent passing, said, “She died of old age. Still seeing.” The headline on Venus’ July 16 obituary in the Philadelphia Inquirer read: “Main Line dog, used to help cure blindness in humans, dies at 12.”

First Dogs, Then People

The trials on dogs led to successful treatment in people beginning in 2007 after Dr. Bennett and her husband, Dr. Albert Maguire, teamed up with Dr. Katherine High to run human clinical trials. Christian Guardino, an America’s Got Talent Golden Buzzer award winner from Long Island, received treatment at age 13 during the trials, as well as others, including Cleveland-area resident Tami Morehouse, who at age 44 at the time, was the oldest participant in the trial. 

LUXTURNA, approved by the U.S. Food and Drug Administration in December 2017, is the first and only approved gene therapy for inherited disease in the United States and Europe. The breakthrough medicine unlocked the potential of the Human Genome Project to provide options for people when there were none.

The treatment fostered pioneering changes in medical practices, motivating ophthalmologists and insurers to do genetic testing, and it created a path for genetic treatments to blindness.

Dr. Bennett said she is thankful for the clinical trial participants, team members, regulatory bodies, advisors and the dogs who helped along the way.

Genetic research still faces a host of challenges, including the rapid degeneration of cells needed for gene therapy to work and too long a span of time to get results for diseases that progress very slowly.

More patients have been treated with LUXTURNA post-FDA approval than the 29 who received treatment during the trials. In the first few months after approval, more than a dozen people underwent treatment at CHOP, one of the 10 approved treatment centers in the United States. Also, the first patient in Paris received the gene therapy in January.

Successes with the New Treatment

'Retinal Gene Therapy is Alive and Well' slide

Before LUXTURNA, no path existed for pediatric drug development in ophthalmology. In a slide titled “Retinal Gene Therapy is Alive & Well,” Dr. Bennett said more than 700 people are enrolled in clinical trials at more than 30 sites. 

“We obtained approval and paved the way for all future pediatric gene therapy trials,” she said. 

As this genetic superhero said at the beginning of her presentation – that the audience members are the pioneers – Dr. Bennett looked out at the gathering as she ended her talk and declared: “It is the families who are really the heroes.”

Human Genome Project: Critical to Modern Gene Therapy Success

The long and sometimes uncompromising road to completing the Human Genome Project (HGP) paved the way for today’s surge in genetic therapy, Dr. Katherine A. High said in her presentation at the second Hope in Focus (formally Sofia See’s Hope) LCA Family Conference.

“It was a tremendous achievement,” Dr. High said, “And it forms an important bedrock for everything we are trying to do in gene therapy.”

The HGP began in 1990 with an international, collaborative quest to map and understand all the genes of human beings and their roles in health and disease. The project, completed in 2003, revealed that there are probably about 20,500 human genes, referred to collectively as our genome, according to the National Human Genome Research Institute (NHGRI).

Dr. Katherine High and Laura Manfre next to a Welcome poster
Dr. Katherine High and Sofia Sees Hope co-co-founder Laura Manfre at the LCA Family Conference in July.

Dr. High, keynote speaker and accomplished hematologist with a longstanding interest in gene therapy for genetic disease, kicked off the July 27 conference in Philadelphia.

More than 80 patients, family members, advocates, doctors, researchers and biotech industry leaders from 15 states and Mexico gathered for exchanges of knowledge and ideas about Leber congenital amaurosis, inherited retinal diseases (IRD) and other rare diseases. The conference grew out of the Sofia Sees Hope Family Connections program that brings together families living with LCA and other IRDs in a supportive community to help alleviate feelings of isolation that often come with a rare-disease diagnosis. 

Dr. High and her team at Children’s Hospital of Philadelphia (CHOP), including Dr. Jean Bennett and Dr. Albert Maguire, developed – from clinical trials to regulatory approval – the first gene therapy for any inherited genetic disease in the United States; it also is the first genetic therapy targeting a retinal disease worldwide. The treatment focused on LCA caused by mutations in the gene RPE65, one of the more than 25 different genes, that, when mutated, can lead to LCA.

‘The Long & Winding Road’

Spark Therapeutics, a company that spun off the team’s research at CHOP, developed the therapy called LUXTURNA™ after 12 years of research and more than $500 million in investment. The U.S. Food and Drug Administration (FDA) approved the human-engineered, injectable drug in December 2017. Beginning in 2018, patients with low vision caused by LCA-RPE65 underwent surgery to help improve their eyesight. 

LUXTURNA and the dozens of clinical trials now underway for retinal disease would not be possible if not for the HGP. Dr. High, Spark’s president and head of research and development, elaborated on the genome project in her presentation, “The Long and Winding Road: How the Human Genome Project and Gene Therapy Research Led to the First Gene Therapies for Genetic Disease.”

The ultimate product of the HGP – detailed information about the structure, organization and function of the complete set of human genes – can be thought of as the basic set of inheritable instructions for the development and function of a human being, according to NHGRI information.

Dr. High said the burden of genetic disease falls heavily on children’s hospitals, with 25 million Americans having a rare genetic disease. 

A 4-year-old made genetic history after receiving the first genetic transfer in the United States in 1990, leading eventually to licensing of a product for the same disease in Europe in 2016. But that span of time did not represent an unbroken chain of successes, Dr. High said. “Instead, it was punctuated by a number of adverse events and failed results.”

Rocky road to success

A teenager died in a 1999 genetic trial in Philadelphia, and in 2003, children in a Parisian clinical trial developed leukemia. 

A Wall Street Journal article about Spark Therapeutics

“Gene therapy was just not ready for prime time and there was a decline in trials and participation.”

Headlines such as “Gene Therapy Still Lacks Breakthrough” and “Gene Therapy: cursed or inching toward credibility” mirrored waning interest from pharmaceutical companies and investors.

Instead, the American and European Societies of Gene and Cell Therapy, the National Institutes of Health (NIH), of which the National Human Genome Research Institute is part, and academic medical centers, like CHOP and its Center for Cellular & Molecular Therapeutics, sustained genetic therapy research through rough times, allowing investigators to develop therapeutics based on best science, not commercial considerations, Dr. High said.

Investing in the RPE65 blindness clinical trials during this time ultimately led to the development and FDA approval of LUXTURNA.

“The ability to work through those adverse events brought us to where we are now,” she said.

An ‘extraordinary’ level of activity

In the United States, the clinical development phase of a drug begins when a sponsor files an Investigational New Drug application (IND) with the FDA. IND submissions with gene therapy products went from zero in 1963, to three in 1990, to more than 100 in 2017. Following LUXTURNA’s market entrance in 2018, sponsors submitted more than 200 INDs.

“The level of activity in the last few years is truly extraordinary. It’s a very compelling statement of how people are investing time and energy into gene therapy,” which High said is probably the most complicated treatment researchers have tried to develop.

“It’s a complex therapeutic. The outside is a protein. The inside is a piece of DNA and those things have to be assembled in the exact proportions or it’s not going to work right.”

Dr. High also described the increased progression of identifying genes involved with vision – from zero in 1980 to more than 300 by January 2019. 

“It’s daunting to think about the number of development programs that might need to be initiated and taken all the way through. But a journey of a thousand miles begins with a single step.”

LCA Families Finding Strength with Each Other

Heather Le’s anxiety accompanying her daughter’s diagnosis of Leber congenital amaurosis melted into relief when she connected with a mom whose daughter was also born with LCA. And this mom – Christina Reichardt – came with the bonus of being Doctor Mom. Christina Reichardt, the mother of LCA patient Ashlyn, is a doctor of optometry in Tucson, Ariz.

The two connected when Heather, of San Diego, Calif., learned from Christina that her daughter underwent a procedure at Children’s Hospital of Los Angeles (CHLA) to correct an LCA gene mutation. Heather’s daughter, Monroe, and Christina’s daughter, Ashlyn, have LCA with a mutation in their RPE65 gene.

Dr. Aaron Nigel administered the ground-breaking genetic therapy called LUXTURNA™ to Ashlyn last May and June when she was 10 years old. Two months later, 6-year-old Monroe had the same surgery, in which a human-engineered virus containing a healthy version of the gene is injected under each retina, a week apart.

Dr. Nigel asked Christina if she would connect with other families living with LCA-RPE65, a request she considered an honor.

“It’s has been the biggest blessing to connect,” Christina said. “I truly consider these moms as friends and know we will always have the special LUXTURNA connection.”

She said she talks to at least one RPE65 mom a week: “It’s a highlight, sharing experiences and stories and life. Checking in the days of surgery and the days thereafter.

“It’s good for both of us,” she said. “We need to heal, too, as parents.”

Group of doctors with Christina and her family

Driving home from Ashlyn’s surgery, Christina talked with Heather, who was thrilled to get answers from the “mommy and doctor side.”

“She walked me through everything. I don’t know what I would do without that woman,” Heather said. “I mean she has been absolutely amazing. Since I had Christina to reach out to, I was more at ease because she was there for me to ask any mother questions I had.”

Christina enjoyed sharing her experiences.

“We still keep up with one another. We share videos and photos. I shared pre-op and post-op experiences, how Ashlyn felt, medicine talk of how she felt and the best way I found to get her drops and ointment in her eyes.”

Heather and Christina are among the many people who have connected and helped each other in their journeys with LCA or other inherited retinal diseases (IRDs). Sharing stories, LCA families shed feelings of isolation that often accompany diagnoses of rare diseases, and they become part of an understanding and resourceful community.

Hope in Focus (formally Sofia Sees Hope) encourages and helps make these kinds of connections through its Family Connections program, its  Facebook page and events, including its upcoming second LCA Family Conference in Philadelphia from July 26-28.

Genetic diagnosis is key

To get a clinical diagnosis, Christina and Heather knew they would have to have their daughters genetically tested.

Even though Heather felt scared, she knew she needed that diagnosis to get more answers. Shortly after Monroe turned 4, she received her RPE65 genetic diagnosis. (See Monroe’s Jan. 1, 2019, story on our website.)

Christina knew three hours after giving birth that something was not quite right with her daughter. Ashlyn was misdiagnosed with night blindness and, being a mom with a medical specialty in vision, she knew she had to start figuring out exactly what was affecting her daughter’s vision.

“I insisted on genetic testing.* She was tested genetically prior to this for other things. Since she was an infant, I said, ‘let’s just genetically test for everything.’ In my heart I felt there’s something more. If we don’t have a diagnosis that’s correct, we won’t have the information to help her.”

Christina, who practices optometry with her dad, said she had heard of LCA, but didn’t know much about it.

“This journey with Ashlyn has made me a better doctor.”

Ashlyn with pink glasses holding her doll with pink glasses

She felt happy to have a diagnosis, shocked because it’s not a common disease and upbeat, saying: “Hey, this is something we can do something about. This is it; this is what we’re going to do. We never looked back.”

The RPE65 diagnosis marked the first of many firsts.

“A feeling of peace and fear, but with that fear a calmness, once I was able to connect to others in the same situation,” Christina said. “Diagnosis was huge. Ashlyn was diagnosed much older than many.

“I believe many kids are still not diagnosed. Getting the word out is going to be very important. That (genetic) test is what we all should consider … It was incredible timing because it was like, boom, we got the diagnosis in May of 2017, LUXTURNA was approved in December and she had her surgery in May 2018. The whole thing went from not moving at all to warp speed.”

Moms helping moms

Along the road to surgery, Christina received answers to her many questions from Beth Guardino of Patchogue, New York, mother of Christian, who underwent the same surgery during LUXTURNA’s 2013 clinical trials. (See Christian’s March 25, 2018, story on our website.)*

“I reached out to her,” Christina said after finding Beth’s story on Facebook. “She was to me who I was to Heather. I had a bazillion questions, so we were on the phone all the time. It’s so awesome … I just feel that all parents need that connection. It’s a scary thing to go through. There’s a lot of unknowns, and getting it from another mom is invaluable, the mom questions.

“From Beth talking to us before Ashlyn received LUXTURNA, to my conversations with several moms as their kids embarked on the same journey – it has been comforting to talk to another mom who has ‘been there, done that,’ to hear her son’s perspective, how she as a mom dealt, how much time and medicine was needed and just to talk about fear and feelings. She was a true blessing and made me more confident walking into such a big unknown.”

Four days after surgery, Christina’s family took a paddle boat ride. Ashlyn looked up at the sky and said, “Mom, what’s that?”

“It’s the sky, honey. That’s a cloud.”

“That’s a cloud?”

“Before she had no visual acuity to see fish or color in the tank,” Christina said. “She ran over to the tank. ‘I see the fish; I see a yellow fish and a pink fish.’ Things like that, that you don’t think about are huge for her.

“She didn’t realize that the toilet (water) swirls when you flush it. ‘Whoa. I thought it just made noise. It’s a swirl,’ her daughter realized.

“Now she walks so easily and runs. Now everything’s novel and exciting.”

Diagnosis to Treatment: Pioneering LCA Patient Eases the Journey

As a global advocacy organization dedicated to helping those affected by blindness caused by rare inherited retinal disease, Hope in Focus (formally Sofia Sees Hope) connects families with Leber congenital amaurosis (LCA) and other IRDs through its Family Connections program and through events such as its second LCA Family Conference set for July 26-28 in Philadelphia.

The conference offers opportunities to engage in thoughtful and interactive exchanges of knowledge, ideas and viewpoints in sessions focusing on research, future treatments, advocacy and people sharing their stories.

Tami Morehouse, third from left, during a panel at the 2018 LCA Family Conference in Groton, CT.

Pioneering LCA patient Tami Morehouse attended the patient advocacy session of the first LCA Family Conference last October in Groton, CT, and participated as a panelist in a session titled: “The Road to Treatment: Understanding How Therapies Are Developed.”

She made research history in the LCA world and in the nation in 2009, when at age 44 during trials for genetic therapy medication, doctors injected under her retinas a human-engineered virus that restored an essential protein for vision. Spark Therapeutics developed the drug that was marketed as LUXTURNA™ following U.S. Food & Drug Administration approval in December 2017.

Tami lives in the Cleveland area and is among the LCA patients who have shared their stories to help others navigate the obstacles that accompany the diagnosis of a rare disease and the journey in finding a treatment.

We’ll share the words she shared with two families – the mom of a boy who received the new genetic therapy treatment, and a mom, and her little boy, who asked a lot of questions about the surgery.

Making Family Connections

Tami holds a special place in the heart Sarah St. Pierre Schroeder, whose then-9-year-old son, Creed, became the youngest person to receive the new genetic therapy for LCA with a mutation in his RPE65 gene. (See our series of stories about Creed, his spring 2018 surgery and his journey.)

Because Tami is the oldest person who successfully received the experimental treatment in both eyes in a clinical drug trial a decade ago, she possesses invaluable insight into the unknowns faced by Sarah and her third grader, who live in Mount Dora, Fla.  

Sarah said she is forever grateful for Tami talking with her.

“I will never forget the emotions I felt when Tami reached out to me. Every sentence in her email brought me more comfort about what I was doing for Creed,” Sarah said.

“She was so open about her journey, I felt like we had known each other forever. I felt like she was with us in Miami (where Creed underwent surgery at Bascom Palmer Eye Institute).

“Suddenly I was able to ask someone all the questions I had and get answers. Not just ‘maybe this will happen.’ ”  

Here’s some of what Tami shared with us about talking with Sarah:

I’ve had some great conversations with those who have either been involved in the process of treatment of LCA or are hopeful they might be involved in a clinical trial in the future. I’m sure you aren’t surprised when I say that emotions usually run pretty high during these conversations.

Sarah was the first parent I talked with. I kept thinking about her and Creed in the days prior to Creed’s procedure. I remembered how I felt when I was in their shoes and couldn’t help but reach out to them on the night before Creed’s procedure. As it turned out, Sarah seemed very open and happy to talk with someone who had been there and understood a little about all that they were feeling and wondering about.

Sarah and I had lots of communication that night and the day of his procedure, which seemed like it would never get here, and in the days following.

Hearing about the improvements in Creed’s vision and how it has changed his life has been so much fun. Thinking about it is still a bit overwhelming sometimes, but wonderful. I’m so glad for him.

It’s nice to check in with Sarah from time to time to talk about the progress and adjustments they are making. I hope they enjoy our interactions as much as I do.

Here is some of what Tami had to share after talking with a mom considering gene therapy for her son. (Tami spoke to the woman and her son as a confidant and did not want to disclose their names.)

The mom asked that I talk with her little one specifically about what the procedure was like. She wanted him to talk with someone who had actually gone through it. We had a great conversation.

I talked to him about things like, the fact that my surgery wasn’t painful for me but did feel a little funny afterward; that I did have to have lots of eye drops; that my surgery didn’t even take very long; that the doctors and nurses were really nice; that my family could be with me after the surgery when I needed them; and that I was pretty comfortable through the whole thing.

I told him that the best part is that I can see a little better than I could before I had the surgery.

At the beginning of the conversation, the little guy seemed pretty quiet and uncomfortable. As the conversation went on, he appeared more relaxed and seemed to be listening pretty intently. His first question was, “WOW, you mean you had surgery already? WOW!”

He also asked if I thought he would be able to get used to all the eye drops and if it would be a long time before he could play video games after his surgery. I told him that I wasn’t sure of how long he would have to wait to play games, but that if he was patient, his reward might be some really good pizza and chocolate chip cookies, which is what I got to eat after my surgery was over. I got a big giggle out of him then. He said that he is pretty happy that he might get the surgery.

If one thing I said to this child makes his surgery easier for him, I’ll be so happy. I just hope it happens for him as they anticipate.

Mom and I talked about the reasons why she feels good about the safety of the (clinical) trial. That’s always a huge issue with just about everyone that I’ve talked to prior to receiving treatment or participating in any trial. Safety always comes first. Understanding why a procedure is determined to be safe is very important.

We also talked about the importance of being aware of what kinds of results treatment might provide for her son, as well as what she and her son are expecting or hoping for from a particular treatment. There were a couple of participants in the trial with me that seemed to have really high expectations that just weren’t possible. Luckily, it seems like this little guy and his mom are in a good place when it comes to their expectations.

Anytime I talk with people seeking any treatment for any rare inherited retinal disease, I strongly encourage them to do their best to understand as much as possible about the procedure, care and services that they are considering or receiving. This can be made easier by reading everything available about the treatment they are pursuing. Unfortunately, sometimes reading and understanding some of this printed information are two different things.

The more that is known about the treatment ahead of time, the easier it is to understand what is going on when making decisions prior to and during treatment.

Asking questions and expressing any concerns that come up is also very important when making decisions about accepting or going through treatment. Taking any available opportunity to develop relationships and open lines of communication with any medical and/or clinical staff is very important. Doing this can make it much easier for patients, as well as physicians, to openly ask questions and express concerns. This can make all the difference in the world when it comes to getting the answers and information needed.

Another thing to consider for individuals who do receive treatment and experience restored vision, is how improved vision may affect their lives.

For some, this is a wonderful thing. For others, this can be a bit of a challenge.

Thank you, Tami.

The Role of the Patient Voice in Rare Disease Advocacy

It’s you. It’s all about you.

The journey from identifying a rare disease, to conducting studies, to approving a treatment, is long – but it always starts with the patient, and the information patients share among the medical, biotechnological and advocacy communities, as well as within the patient community.

At a fall gathering of families living with Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs), Lisa Bernier found help and support for her visually impaired daughter for the first time in seven years. Bernier and her 25-year-old daughter, Aimee, traveled to the first-ever Hope in Focus (formally Sofia Sees Hope) LCA Family Conference at the insistence of Aimee’s optometrist.

“Advocacy ends after school ends,” Bernier says.

Lisa and Aimee Bernier

Aimee has Bardet-Biedl Syndrome (BBS), a complex disorder affecting many parts of the body, including the retina. She and others with BBS have retinal degeneration similar to retinitis pigmentosa (RP). Aimee had good experiences at the Perkins School for the Blind and graduated in 2011. Then it became difficult for her mother to find support.

“We’re basically on our own, to advocate for ourselves,” Bernier says. Her 30-year-old son also has BBS with many, but not all, of the same characteristics, and his vision loss is five years’ advanced.

(Editor’s note: Laws vary from state to state, but typically, public education is required to provide services to students in need until age 21, even after high school graduation. Children with learning disabilities who receive services under the Individuals with Disabilities Education Act (IDEA) or the Rehabilitation Act of 1973 (RA) in public elementary and secondary school may continue to have legal rights under federal laws in college programs and in employment. When students graduate from high school or reach age 21, their rights under the IDEA come to an end. As resources can vary greatly from state to state, finding support and resources for a child may fall on the family post-graduation.)

During the early years, Bernier searched for any information on BBS and RP through reading the New England Journal of Medicine, which described those with BBS as having low cognitive skills and dying from kidney failure. Even when Aimee was born, the doctors didn’t understand BBS. Bernier and her husband were grateful to be introduced to the doctors and genetic staff at Shriners Hospitals for Children in Springfield, Mass., where they helped with the health care needs of Aimee and her brother until they were 18.

Bernier said she was thrilled to be at the conference in a roomful of retinal experts, patient advocates, and families attending the Oct. 6 gathering.

Active Patient Community Is Key

During multiple sessions, attendees heard updates on research, learned about the roles played by organizations developing treatments, and gained insight into how an active patient community can support and accelerate treatment.

Spark Therapeutics,  Applied Genetic Technologies Corporation (AGTC), National Organization for Rare Disorders (NORD),  Foundation Fighting Blindness (FFB), and Sofia Sees Hope are among the many partners working to collaborate with and learn from the patient community to propel research momentum.

More than 50 people from New England, across the country and Mexico attended the conference, including the session titled “The Role of the Patient Voice in Developing Treatments for Rare Disease.” Sofia Sees Hope Executive Director Annette Tonti moderated a three-member panel comprised of:

• Jamie Ring, Head of Patient Advocacy at Spark Therapeutics, which developed the gene therapy called LUXTURNA™ that helps restore vision to people with RPE65 genetic mutations;

Jill Dolgin headshot
Jill Dolgin

• Jill Dolgin, PharmD, Head of Patient Advocacy at AGTC, a clinical stage biotechnology company focusing on rare IRDs and developing therapies that replace “broken” genes with normal, functional genes;

• Kristen Angell, Associate Director of Advocacy at NORD, a voice for the 30 million Americans with rare diseases and the official U.S. sponsor of Rare Disease Day, which takes place annually on the last day of February.

Personal experiences of family and/or friends dealing with rare diseases motivated all three women to become advocates for patients. As Angell paradoxically put it: “Rare disease has always been common in my family.”

Ring, Dolgin and Angell are a critical part of a relatively new profession – patient advocacy – to help people find support and learn how to become engaged in the process of drug development and research to find treatments for rare diseases.

Kristen Angell headshot
Kristen Angell

Ring from Spark Therapeutics said she has a passion for helping amplify the voices of the patients and their families and making sure those voices are understood and considered.

“People feel their story doesn’t matter,” she said. “The thing in rare disease is that YOU ARE the expert,” and patient information is critical to doctors and biotechnology companies alike. “At Spark, we want to make sure that patient voice has a seat at the table.”

Connections and Clarity

“There’s no one-size-fits-all,” Ring said. “Simply connecting with other people is probably the most important thing you can do … and having the clarity of your diagnosis allows you to do that most effectively.”

For IRDs, it is essential to know your gene and it’s a good idea to register with My Retina Tracker, a confidential, online, patient registry managed by the Foundation Fighting Blindness. Patient data tracked through registries and collected by researchers helps scientists and biotechnology companies develop clinical drug trials.

AGTC’s Dolgin told the audience that 7,000 rare diseases exist, but fewer than 15 percent have advocacy groups that can assist patients with resources, advocate for clinical research, and find access to vital therapies.

Dolgin, a trained pharmacist, emphasized: “As patient advocates in the pharmaceutical industry, we’re representing the patient at the corporate table.” A priority for the company is to find and educate people with IRDs and encourage them to get genetically tested.

Patients need to be identified, encouraged to enroll in natural history studies, and followed systematically through natural history studies long before beginning the clinical drug trials necessary to seek approval for commercial use from the U.S. Food and Drug Administration. Natural history studies are critical components to clinical research, providing an understanding of the rate of disease progression without treatment to the rate of disease progression after treatment.

Angell said NORD developed 20 patient registries for 20 different diseases in the last few years. She oversees the Rare Action Network, with 5,000 members nationally and ambassadors in 32 states, including Connecticut. The network empowers patients and families to directly reach out to lawmakers to encourage and support the rare disease community.

Angell also encouraged using social media and suggested setting up programs with local chambers of commerce to make people aware of patients in their own community.

“Awareness goes hand in hand with advocacy.”

Shared Experiences & Knowledge

The role of the patient voice continues even more so after development of a treatment. Ask the people with families living with LCA. Sofia Sees Hope has been working to connect these families who have similar concerns and many of them have supported one another and become friends.

Tami Morehouse attended the patient advocacy session and served as panelist in a conference session earlier in the day called “The Road to Treatment: Understanding How Therapies Are Developed.” She is a pioneering LCA patient, in that at age 44 in 2009, Morehouse became the oldest person at the time to take part in the successful Phase 1 RPE65 gene therapy trial, a precursor to the FDA’s December 2017 approval of LUXTURNA.

She’s had many conversations with people involved in the process of LCA treatment or are hopeful they might be involved in a future clinical trial. The first person she talked with was Sarah St. Pierre Schroeder, the mother of now 10-year-old Creed Pettit. They communicated last April on the eve of the boy’s surgery in which doctors at Miami’s Bascom Palmer Eye Institute would inject under his retina a human-engineered virus that gives instructions on how to produce an essential protein for vision.

“I kept thinking about her and Creed in the days prior to Creed’s procedure,” Morehouse said. “I remembered how I felt when I was in their shoes and couldn’t help but reach out to them on the night before Creed’s procedure. As it turned out, Sarah seemed very open and happy to talk with someone who had been there and understood a little about all that they were feeling and wondering about.”

Creed’s mom felt enormous relief in talking with Morehouse.

“I will never forget the emotions I felt when Tami reached out to me,” St. Pierre Schroeder said. “Every sentence in her email brought me more comfort about what I was doing for Creed. She was so open about her journey, I felt like we had known each other forever.”

LUXTURNA took decades of research, many millions of dollars and countless advocacy connections to come to fruition. It is a long journey that begins with the patient and comes full circle.

After Treatment with LUXTURNA, It’s a New Year, New Vision

Two little girls – one on the East Coast and one on the West Coast – ring in this New Year with something they’ve never had before – their vision.

Eight-year-old Hannah Reif of Maple Glen, PA, and 6-year-old Monroe Le of San Diego, CA, underwent breakthrough genetic therapy surgeries to fix a mutation in their RPE65 gene, which had caused a rare inherited retinal disease (IRD) called Leber congenital amaurosis (LCA).

Dr. Albert M. Maguire performed Hannah’s surgery at Children’s Hospital of Philadelphia (CHOP) in July. Dr. Aaron Nigel performed Monroe’s surgery at Children’s Hospital of Los Angeles (CHLA) in August.

Dr. Maguire is part of the married research team that brought the genetic therapy treatment developed by Spark Therapeutics called LUXTURNA™ to fruition. Dr. Jean Bennett and Dr. Maguire researched and conducted studies working with mice and dogs, and then humans in clinical trials. They developed the first genetic therapy treatment for LCA2 (RPE65), and the first treatment in the United States for any inherited disease. The U.S. Food and Drug Administration approved it in December 2017.

Hannah had a milder form of LCA, with night blindness and poor peripheral vision. Her mother, Amy, still marvels at the idea of genetic research focusing on her daughter’s gene mutation.

Using a syringe, Dr. Maguire injected under Hannah’s left retina a human-engineered virus containing a healthy version of the gene, which supplants the mutated gene. Within 24 hours of the July 10 surgery, Hannah had increased sensitivity to light; six days later, she could see the water line in her glass, rather than sticking her finger in the glass to feel for the water. On Day 7, she saw a star for the first time; six days later she underwent surgery on her right eye.

‘She can see’

Hannah can now see everything in her environment more easily and her visual acuity has improved from 20/200 to 20/100.

Shortly after surgery, Hannah flipped on her desk lamp and was so startled by the brightness that she began to cry. Now, Hannah says, “I don’t even remember what it was like before my surgery.”

Amy and her husband, Chris, revel in their little girl playing with her horse figurines in a dark room on a cloudy day, and they say her night vision has improved a thousand-fold.

Hannah smiling big with lit birthday candles in front of her
8-year-old Hannah Reif of Maple Glen, PA.

“It’s just wonderful to watch her do things and see things. She’s not saying, ‘Hey, look what I’m doing.’ She just does it. She can see.”

Her mom said most recently, she’s just discovered the blue veins under her skin and the “H” and “C” on the bathtub faucets.

Her parents and others have noticed she’s more confident in school, in church and socially with her friends. Although she still needs some supports in place at school, Hannah’s doing great in her second-grade class.

On past Christmas mornings, she’d open a gift and have to be told what it was. Not this year!

Amy also recalled Hannah walking into their church sanctuary, brightly decorated for Christmas with ribbons, greens and flowers.

“As she walked through the doors, she looked around in amazement and said in a soft, sweet voice, ‘Wow!’ ”

‘Like night and day’

Kindergartener Monroe Le underwent surgery Aug. 14 on her left eye and a week later on her right eye.

“She’s like night and day,” said her mom, Heather.

Before surgery, Monroe’s vision was 20/300 for both eyes and now it’s 20/150.

So much has changed since 2012; Heather knew something was wrong with baby Monroe at 2 weeks when she looked toward the light rather than her.

Monroe with her hands near her eyes
6-year-old Monroe Le of San Diego, CA.

“I remember crying and saying to my husband, ‘She’s blind. She’s blind,’ and he said, ‘She’s not’ … from 2 weeks until she was diagnosed, we were knocking on doctors’ doors.”

Heather was scared to have her daughter genetically tested, but she knew it would give her answers. Doctors diagnosed Monroe with LCA shortly after she turned 4; two months later she received her RPE65 genetic diagnosis.

“Oh, I’m so happy that I did it,” Heather said. “If I hadn’t gotten that test, Monroe wouldn’t have been a candidate for LUXTURNA.”

Her daughter received help to get up to speed with motor skills, and early on met a little girl named Penny, her forever friend, who has had difficulties with speech.

“They’re amazing, they love each other so much,” Heather said. “They complemented each other so well because Monroe would help her with the talking and Penny would help her with the seeing.”

Two days after her first surgery, Monroe insisted on being the one to retrieve a cap from an ointment tube dropped on the carpet. “She covered her non-surgerized eye and found it immediately.”

In school, Monroe no longer needs special lighting and doesn’t have to sit in the front of the room. “She even has been able to play four square.”

Monroe also sees her most favorite place in the world, Disneyland, and her most favorite attraction – Pirates of the Caribbean with Capt. Jack Sparrow – in a whole new light.

“There have been numerous times in a trip there where she asks me, ‘Mama is that new, or has it always been there and I’m just seeing it for the first time?’ ”

Heather and her husband, Bruce, see a much more confident little girl who no longer needs to hold hands in dim places.

“I can’t believe it’s the same girl who was so timid and afraid to let go of my hand,” she said. 

‘As A Doctor, You Will Never Forget’

Transforming laboratory research into real-life therapy for patients is a rare occurrence.

But when it does happen, it’s big. Huge, in fact.

Ask Dr. Audina M. Berrocal, the pediatric retinal surgeon who performed ground-breaking retinal surgery in March on 9-year-old Creed Pettit. Creed lived with severe vision loss caused by a rare inherited retinal disease (IRD) called Leber congenital amaurosis (LCA)* manifested by a mutation in his RPE65 gene. At the time of his treatment, he was the nation’s youngest patient to receive it.

Dr. Berrocal’s surgery at Miami’s Bascom Palmer Eye Institute on the third-grader marked one of those extraordinary times when research goes from clinical to surgical – from bench to bedside.

“It’s one of those honestly amazing moments in medicine,” she said. “Things that you think you are never going to see and here I am, doing it. As a doctor you will never forget.”

Dr. Berrocal, Dr. Byron Lam (who diagnosed Creed at age 2½ with LCA), and a surgical team, removed the vitreous, a gel-like substance attached to the retina’s surface – though Creed’s vitreous was thinner than normal – before administering the medication – LUXTURNA™ – a genetically engineered virus that supplanted Creed’s mutated RPE65 gene with healthy versions of the gene.

“The challenge is to lift the retina with the medication,” she said. “Detaching the retina, especially of a child, is pretty hard to do. We are looking through microscopes and special equipment that makes seeing the retinal layers easier, but it’s still challenging.”

Working with two syringes filled with the medication that is viable for only four hours, Dr. Berrocal said she could not find the right subretinal space to inject the treatment with the first syringe. She then successfully injected LUXTURNA with the second syringe.

“With the first case, everything is new,” she said of the surgery, which took about an hour. “The second eye, everything went smoother, quicker and faster.”

‘Science that revolutionizes medicine’

“It’s extraordinary,” she said. “It makes you feel you are on the brink of a new area of science that is going to revolutionize medicine and eradicate disease. This truly is the brink of an era of gene manipulation and gene therapy.

“To be living this as a physician is really, really unique and special.”

Before the surgery, Dr. Berrocal trained with people from Spark Therapeutics, LUXTURNA’s developer, to learn about the drug’s pharmacology and to train in the knowledge of the surgical process. This genetic treatment came to fruition after decades of research and millions of dollars, followed by approval by the Food and Drug Administration in December.

“The viral vector provides the correct gene that you need,” she said of the medication’s delivery system. “The concept can be used for any gene and I think this is truly the beginning of a revolution of genetic manipulation.”

Soon after the surgery, Creed enjoyed improved vision.

“We never expected it to change so quickly. I don’t think anyone was expecting it.”

“No one believed it,” she said when Creed’s mother, Sarah, reported two days after the surgery that her son’s vision dramatically improved.

No one except Dr. Berrocal.

“The thing is, people do not always believe mothers, but as a mom myself, I will tell you that no one knows a child better than mom. If Creed’s mom is saying that Creed never walked around with such little light before, then it’s true.”

A family tradition

Given her background, Dr. Berrocal being at this point in her career seems a little unsurprising. Her father, Dr. Jose Berrocal, trained with Dr. Charles Schepens, a Belgian ophthalmologist known as the father of modern retina surgery.

Her father became Bascom Palmer’s first trained retina specialist and the first such specialist in Puerto Rico. Dr. Berrocal’s older sister, Dr. Maria H. Berrocal, became a retina specialist and practiced with their father. Both women turned to medical school after graduating with degrees in political science and realizing politics wasn’t for them.

Dr. Berrocal, now 51, has two daughters and one son with her physician husband. She grew up helping her dad in the office, as ophthalmology was part of the family. She is now medical director of Retinopathy of Prematurity Services at Bascom Palmer and professor of Clinical Ophthalmology at the University of Miami.

Asked whether her sister was jealous of her doing breakthrough surgery, Dr. Berrocal laughed and said, “She’s very proud of me.”

Dr. Berrocal’s father always told her she’d end up doing something with kids, and she sealed the deal working under a mentor dealing with pediatrics and retinas in her 2002 fellowship at Bascom Palmer in Vitreoretinal Diseases and Surgery.

“I truly like kids more than I like adults. They’re honest, sincere, concrete. You can never lie to them; if you do, you lose their trust forever.”

Empowering children

Dr. Berrocal respects Creed, listened to him and talked to him as an adult. She said he wasn’t interacting during their first meeting in January. Over time, she won him over by caring about what he wanted and needed, especially the little things. Creed didn’t like having the ID band on his wrist, so she took off the band and he felt better.

“He’s much more comfortable with me now,” she said. “It makes it really special.”  

“They have to feel that they’re part of the process. It’s their body and it’s their eyes. I think empowering kids to be part of the process, taking in their feelings and their emotions, directing the conversation to them – that’s essential to make it work.”

Dr. Berrocal, as with most retinal specialists, is much more used to seeing children lose their vision and become blind.

“One of the most important things for me in this process has been watching a kid regain vision. This was a kid who couldn’t do things. He’s seeing the world in a different way. That is so powerful and so overwhelming. We cannot forget the importance of getting him ready for something so overwhelming.

“Learning to see again is hard emotionally. We have to somehow have these kids talk about it, how different their lives will be. How to guide them through it…We have never reversed the road to blindness before.”

Dr. Berrocal sees Creed for check-ups and more, confiding: “I can’t separate.”

Looks like that won’t be a problem for the surgeon – when she retires she knows Creed will be at the party.