Gene therapy, vision rehabilitation for IRDs

Photography by Steve Craft.

Excerpted from page 56 of the May/June 2022 edition of AOA Focus.

Sherry Day, O.D., clinical assistant professor at the University of Michigan Kellogg Eye Center and section leader for Vision Care Services and the new Vision Rehabilitation Section, discusses collaboration in cases of Inherited Retinal Diseases (IRDs) and illustrates the importance of vision rehabilitation as a parallel treatment modality—not an end-stage treatment. Dr. Day is a member of the AOA’s Vision Rehabilitation Committee.

When do you consider genetic testing for a patient?

Doctors of optometry are in a unique position to begin diagnoses and management of patients with IRDs and their lifelong vision impairment. Suspicions for IRDs are made with clinical symptoms and ocular findings in addition to testing, such as color vision, visual field, OCT and ERG (if available). There are only four IRDs for which there is a clinical trial or gene therapy: achromatopsia (ACHM), choroideremia (CHM), Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). With CHM, for instance, patients initially report night blindness and poor dark adaptation. A ring scotoma may be present with visual field testing and ERG shows rod-cone degeneration. Central macular vision is usually preserved until the fifth or sixth decade of life. This is an X-linked genetic condition affecting males, with females being carriers. The prevalence is about 1 in 50,000 or 100,000. There are currently two clinical trials for CHM.

How can gene testing be accessed?

Doctors can order commercially available genetic testing through ID Your IRD (Spark Therapeutics) or Blueprint Genetics (partnering with Foundation Fighting Blindness and MyRetinaTracker). Both evaluate between 293-300 genes with blood, buccal or saliva samples with results provided in as little as three weeks.

In addition to identifying the culprit genes, these companies also provide genetic counseling, which is essential for siblings, relatives and family planning. Once the gene is identified, go to clinicaltrials.gov. If the mutation is homozygous for RPE65, you can refer the patient to one of 10 centers in the U.S. that administer the FDA-approved gene therapy, Luxturna (Spark). Gene therapy is not for everyone. Currently, only voretigene-neparvovec-rzyl (Luxturna) has been approved for LCA RPE65 mutation. Others may qualify for clinical trials, which you can find on the above website.

How is gene therapy delivered?

There are two concepts in gene therapy: replacing/editing the gene and suppressing it. If you’re targeting an autosomal dominant gene, you want to suppress the activity of the mutated gene; with a recessive gene, such as X-linked LCA, you want to edit it. There are different ways of delivering therapy, but subretinal injection gets closest to the genes that are affected. Intravitreal injections must pass through the vitreous to get to the retina to be effective, whereas the subretinal space is more accessible. Subretinal and intravitreal delivery both typically use an AAV vector, which allows the vector to replicate inside the patient but does not change the patient’s DNA.

How is long-term care addressed?

With the clinical symptoms and reduced best-corrected vision, low-vision rehabilitation should be started concurrently because IRDs commonly manifest in childhood. Vision-enhancing devices and school accommodations should be implemented early as part of the child’s individual education plan and as early as possible to remain competitive in school. For example, in the letters that I write to schools, I include specific accommodations such as font size of printed text, extended time for work/exams, prescribed devices and uses for them.

Who manages that care?

Our multidisciplinary IRD care team consists of retinal dystrophy specialists (MDs), genetic counselors, ERG specialists, low-vision optometrists, an occupational therapist, orientation mobility specialist, social worker and now a psychotherapist. Doctors of optometry are crucial to identifying IRD patients, coordinating their care and getting vision rehabilitation (VR) onboard as early as possible for these patients to live independent lives. VR is not an end-stage referral; early rehabilitation is vital.