September 2020


Gene Therapy
Gene therapy making progress in ophthalmology

by Liz Hillman Editorial Co-Director

In some gene therapies, an adeno-associated virus (AAV) vector is used to transfer normal, correct genetic material into patients’ cells. In ophthalmology, Luxturna is the only FDA-approved gene therapy, and it uses an AAV vector to deliver a functional RPE65 gene to retinal cells.
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Gene therapy is the holy grail for an inherited disease, said Thomas Ciulla, MD. And the eye is a great target for gene therapies for many reasons.
“The reason ophthalmology is particularly attractive is because the eye loans itself well to study,” Dr. Ciulla explained. “It’s an enclosed organ. It’s immune privileged against a viral vector, especially in the subretinal space. There is sophisticated diagnostic technology where we can monitor the structure and function of the retina quite well. Viral vector generally does not meaningfully travel to different areas of the body (at least not significantly), so there is limited risk of an immune reaction elsewhere.”
Elliott Sohn, MD, who also mentioned several of the reasons listed by Dr. Ciulla, said that one of the reasons the eye has been able to gain a foothold in gene therapy research is that it is relatively easy to access. What’s more, there are many rare, blinding retinal diseases that don’t have any treatment available.
“The other advantages are that we can diagnose genetic disorders at a relatively high rate of accuracy. We can test some of these disorders in a dish first. We can develop treatments in a lab, then test them on animals, stem cell based retinal cells, as well as human explants (cadaveric retinas) and see the effects of these therapies. Because we’re trying to affect one or maybe two layers of cells and these cells are laid out in a laminar pattern, we can try to address the problem directly in that cell type by bringing that therapy to the specific region needed. That we have a high ability to target a certain area of disease with a treatment that might last indefinitely, that they don’t have to be on much immune suppression, and that we’re able to demonstrate these things in the laboratory before we go to humans are some of the advantages of gene therapy in ophthalmology.”
As such, gene therapy for ocular diseases is a significant area of research. In fact, the first gene therapy to receive FDA approval for an inherited disease is for an ocular condition.

What’s available?

Luxturna (Spark Therapeutics) became the first gene therapy approved to treat a hereditary genetic disease in the U.S. in 2017. This gene therapy delivers a functional RPE65 gene to retinal cells via an adeno-associated virus vector. Luxturna treats patients with biallelic RPE65 mutation-associated retinal dystrophy, which affects between 1,000 and 2,000 patients in the U.S. People with this autosomal recessive condition experience progressive vision loss from a young age that can become completely blinding.
Dr. Ciulla, who was the medical strategy lead of ophthalmology for Spark Therapeutics, said the introduction of Luxturna brought novel paradigms to clinical ophthalmology. One was a new endpoint called multiluminance mobility testing, which he explained reflects a patient’s ability to navigate in different lighting conditions. Another new paradigm was subretinal surgical administration; when Luxturna became available, Dr. Ciulla said ocular gene therapy treatment centers had to be established with staff who were trained to administer the therapy. A third new paradigm involved reimbursement for potential one-time therapies. Spark Therapeutics, Dr. Ciulla said, worked to help develop different payment models for the drug, as the current healthcare system is not equipped to properly value new therapies that yield long-lasting benefits in one administration.
Because most of the research toward gene therapies is for rare, inherited disorders, such as RPE65 mutation, Dr. Sohn noted that the therapy is often expensive.
“The price of the medicine is a challenge for companies to continue doing research or to get approval because of the cost they have to project in terms of charging private insurance carriers and the government,” said Dr. Sohn, a clinical investigator for the Phase 2/3 Luxturna trials. However, he went on to describe the long-term economic benefits to the individual, family, and ultimately the healthcare system when these therapies are administered.

What’s in the pipeline?

There are several companies working on gene therapies for recessive disorders. Dr. Ciulla listed achromatopsia (AGTC, MeiraGTx), Stargardt disease (Oxford Biomedica/Sanofi), and Usher syndrome (Oxford Biomedica/Sanofi) as under clinical investigation. He also said gene augmentation is being studied for X-linked recessive disorders, such as choroideremia (Biogen, Spark Therapeutics) and retinitis pigmentosa (AGTC, Biogen, MeiraGTx), and mitochondrially inherited disorders such as Leber hereditary optic neuropathy (GenSight). Iveric Bio is working on a “knockdown and replace” strategy to treat autosomal dominant retinitis pigmentosa.
Gene therapy to treat more commonly occurring wet AMD is in development as well. Dr. Ciulla said REGENXBIO is developing a ranibizumab-like anti-VEGF protein for subretinal delivery, and Adverum is creating an aflibercept-like anti-VEGF for intravitreal delivery. For dry AMD, Hemera Biosciences is developing HMR59 to produce the protein CD59 that blocks the final step of the complement cascade, Dr. Ciulla explained.
“These have potential to be very important therapies because they could provide long-lasting benefits to reduce treatment burden, but the clinical trials are still underway. We have to assess for inflammation and durability, whether they completely alleviate the need for further treatment in most patients or decrease the need for injections, which would be valid as well. We will also need to determine which patients benefit most,” Dr. Ciulla said.


At this point, Dr. Sohn said the important thing for general and anterior segment ophthalmologists to know about gene therapy treatment is that there is currently only one FDA-approved treatment, though several are in trials.
“Accurate testing is very important for patients with inherited retinal diseases because they may have a disease that can be treated with an FDA-approved treatment or qualify for a trial for a non-RPE65-mediated inherited retinal disease,” Dr. Sohn said. “With that comes the very important responsibility of understanding what the doctor is seeing on exam to identify a patient with an inherited retinal condition. Educating oneself about what these diseases look like on exam and by history and when to send these patients for testing or to an inherited eye disease specialist is of utmost importance.”
Dr. Sohn said his colleague Edwin Stone, MD, PhD, developed an educational website with images and videos of inherited retinal disease conditions,, to help provide ophthalmologists with a reference for inherited retinal diseases.
“Education is extremely important for the physician because if you just send the patient for genetic testing, the doctor needs to explain that to the patient. To know what to test a patient for, how to interpret the test, and communicate this effectively to the patient and family are crucial,” Dr. Sohn said.
Timing is also important for effective gene therapy, Dr. Sohn said. Patients need to still have functional cells for a gene therapy to be effective. If cells are no longer functional, that’s where a stem cell therapy could come into play. See page 37 for coverage of stem cell therapies and ocular conditions.

At a glance

• Gene therapy has the potential to be a “one-and-done” treatment for rare, inherited retinal disorders and potentially for disorders with a significant treatment burden, such as wet AMD.
• The eye lends itself well to gene therapy treatment, in theory, for many reasons, including it being a closed system that has elements
of immune privilege with a large number of identified genetic mutations that could be targeted.
• Currently, there is only one FDA-approved gene therapy for an inherited retinal condition (Luxturna, Spark Therapeutics), but several others are in the pipeline.

About the doctors

Thomas Ciulla, MD

Volunteer clinical professor
of ophthalmology
Indiana University School
of Medicine
Indianapolis, Indiana

Elliott Sohn, MD
Associate professor
of ophthalmology and
visual sciences
University of Iowa
Iowa City, Iowa

Relevant disclosures
: Clearside Biomedical
Sohn: Oxford Biomedica


Categories of gene therapy

•Gene augmentation: Adding a gene to a cell 
•Gene editing: Revising the existing genetic code 
•Gene inactivation: Silencing a gene, often a dominant negative one 
•Selective toxicity: Introducing “suicide” genes and immune sensitization, as in chimeric antigen receptor (CAR)-T cells to recognize cancer cells 
•RNA therapeutics: Targeting RNA instead of DNA within the gene 

Source: Thomas Ciulla, MD

Gene therapy making progress in ophthalmology Gene therapy making progress in ophthalmology
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