About Leber congenital amaurosis
Leber congenital amaurosis (LCA) is a hereditary retinal dystrophy that occurs in about 2-3 per 100,000 births.1 Abnormalities in the ability of the retinal pigment epithelium (RPE) and neurosensory retina to metabolize vitamin A into 11-cis retinal, prevents photopigment generation and the normal visual signals from being sent to the visual cortex. It accounts for roughly 5% of all retinal dystrophies.2,3
LCA usually manifests early in life, but the fundus often initially appears normal. Later, the retinal presentation can include bone-spicule pattern pigmentation, “fleck” patterns or a pigmented “marbling” pattern; these presentations are due to the changes in the RPE. Macular atrophy is also common along with optic nerve abnormalities. LCA can be associated with nystagmus, keratoconus, photophobia, early cataracts and in extreme cases best corrected visual acuity of 20/400 to no light perception.4 It is also often associated with poor or sluggish pupil reactions.2,3
Management typically includes appropriate refractive correction and low vision aids. More recently, with increased accessibility and reliability of genetic testing, promising treatment trials are underway.2,3 The specific gene mutations involved in this condition have been identified and gene editing techniques are being used to target and correct them.2,3
About gene editing
Gene editing is the scientific technology that allows addition, subtraction or alteration of genetic information within DNA. There are several new techniques to complete gene editing, the relevant one here is CRISPR, which stands for clustered regularly interspaced short palindromic repeats.5
The Brilliance clinical trial is the first attempt at using this specific gene editing technique inside the eye in treatment of disease; in this case to treat LCA 10.6 The specific mutation of c.2991+1655A>G in intron 26 of the CEP290 gene has been pinpointed as involved with this hereditary retinal condition.7 The CRISPR gene editing tool aims to correct or “edit” this disease-causing portion of DNA.1 The gene-editing vehicle, AGN-151587 (AKA EDIT-101) is administered through subretinal injection. An adeno-viral vector is used to carry the editing tool to its target where it can swap mutated genome material.7
The Brilliance clinical trial
The Brilliance trial is being conducted by Editas and Allergan pharmaceutical companies and its purpose is to evaluate efficacy and safety of gene editing in treatment of LCA 10. It began in 2019 with anticipated completion in 2024.7
The study will investigate changes in visual acuity, contrast sensitivity, light-dark adaptation, gaze tracking and color vision. Pupil reaction, through pupillometry and full-field stimulus threshold testing (FST), will also be monitored as treatment progresses. Color vision will be monitored using the D-15 test. Kinetic and microperimetry will be used at baseline and throughout to monitor macular function and response to light stimuli.7
The study will also track the impact of treatment on general mobility, quality of life and safety. Mobility will be tested by asking subjects to navigate an obstacle course with the level of difficulty altered via changes in lighting and contrast of the obstacles. Quality of life will be monitored through questionnaires that are modified for subject age group and level of vision impairment. Drug toxicity will be monitored as well for potential adverse effects.7
To qualify for the study, the subjects must be older than 3 years old with a known mutation of the gene mentioned above. The vision level of subjects ranges from light perception to roughly 20/50.7
Impact for patients
I had the pleasure of speaking with a Brilliance clinical trial participant, Mr. Michael Kalberer, to gain a new perspective on the trial and how meaningful these advancements truly are for patients. Michael’s clinical trial site is at Massachusetts Eye and Ear.
Michael was initially diagnosed with Retinitis Pigmentosa (RP). He had been invited to present alongside a retina specialist on his condition and this led to an unexpected outcome. The specialist lectured on RP versus LCA and Michael realized that after 11 years with his diagnosis, it wasn’t quite right. While the symptoms and ophthalmic findings of the two conditions are very similar, Michael knew his own ocular history and symptom progression aligned more with LCA than RP. This prompted him to pursue genetic testing for a definitive answer.
Once Michael found out that his diagnosis was, in fact, LCA he used My Retina Tracker and his contacts in the ophthalmology community to find out about the promising new clinical trial called Brilliance. He was very excited to be selected as a participant and remained motivated to begin treatments as quickly as possible despite pandemic delays.
Michael said he had no apprehension about starting the trial because he knew it could only help; he was happy and grateful to have the chance to possibly improve his condition. Michael felt his disease was progressing rapidly and at that time testing had demonstrated that only approximately 3% of retinal function remained in his testing eye and 8% in his better seeing eye.
Aside from offering the promise of a treatment for LCA, the clinical trial has been rewarding for Michael in other ways. His team of doctors at Massachusetts Eye and Ear took time to really help him understand his condition and how the physiology correlates with the symptoms. Being part of the trial has also helped him to articulate his own visual experiences to better explain how the condition manifests for him personally. This has led to more constructive conversations both with his doctors and with other people with hereditary retinal disorders that he mentors.
Because of Michael’s commitment to understanding LCA and passion about the Brilliance trial, he quickly became an advocate for it. He enjoys this role and the teaching of others that comes along with it. I asked Michael what type of advice he gives to those people who may be candidates but are apprehensive (so that we as optometrists can hopefully do the same).
According to Michael:
“Blindness is not the one thing that defines you, it's just part of who you are. Learn as much about your condition as you can and how it impacts you personally and psychologically. The trial is an opportunity that won’t guarantee results and it’s a choice you should make with your doctors and your support system. For me, it was a chance to contribute to something greater than I ever anticipated.”
To find out more about the Brilliance trial
If you have a patient or know someone interested in being a part of this, or similar research studies, you can direct them to the US National Library of Medicine’s Clinical Trials database.
The Foundation Fighting Blindness also maintains a registry called My Retina Tracker which collects data from patients with upward from 20 inherited retinal conditions. LCA is just one such condition, along with others like retinitis pigmentosa, Best disease, Stargardt disease, and Usher Syndrome to name a few. The genetic testing component of the tracker is free for patients. The tracking system provides information to researchers on the prevalence and impact of diseases along with a place to reach out to potential participants for future research studies.8
In the last decade, there have been great leaps in genetic research, including in the realm of eye care. As optometrists, it’s up to us to stay abreast of the emerging tests and gene therapies that could have positive effects on the lives of our patients. As these emerging treatments continue to mature and become economically feasible, they will undoubtedly have incredible impacts on how we provide care.
- Andrea, Steffen. (2019, August 2). First CRISPR trial to edit Genes inside the body will help Treat Blindness. Intelligent Living. Retrieved September 11, 2021, from https://www.intelligentliving.co/first-crispr-trial-gene-edit-blindness/.
2. CRISPR trial for Inherited Blindness underway. American Academy of Ophthalmology. (2019, August 1). Retrieved September 11, 2021, from https://www.aao.org/headline/crispr-trial-inherited-blindness-underway.
3. Leber congenital amaurosis. EyeWiki. (2020, November 2). Retrieved September 11, 2021, from https://eyewiki.org/Leber_Congenital_Amaurosis.
4. U.S. Department of Health and Human Services. Leber congenital amaurosis. Genetic and Rare Diseases Information Center. Retrieved September 11, 2021, from https://rarediseases.info.nih.gov/diseases/634/leber-congenital-amaurosis.
5. U.S. National Library of Medicine. (2020, September 18). What are genome editing AND Crispr-cas9?: MedlinePlus Genetics. MedlinePlus. Retrieved September 11, 2021, from https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/
6. Ledford, H. (2020, March 5). CRISPR treatment inserted directly into the body for first time. Nature News. Retrieved September 11, 2021, from https://www.nature.com/articles/d41586-020-00655-8/.
7. Single ascending dose study in participants with lca10 - full text view. Full Text View - ClinicalTrials.gov. Retrieved September 11, 2021, from https://clinicaltrials.gov/ct2/show/NCT03872479.
8. My retina tracker registry. Foundation Fighting Blindness. Retrieved September 11, 2021, from https://www.fightingblindness.org/my-retina-tracker-registry.
Bio for Michael Kalberer
Michael earned his BA in psychology and Speech Communications from Hofstra University and his master’s degree in Social Work from Adelphi University. He has Cerebral Palsy and LCA. With his background as a New York State Licensed Social Worker and relevant personal experience, Michael lectures college students, medical students, and other professionals, on a variety of topics including disability etiquette and cultural competence. He has been invited to speak at numerous universities and on national TV and is active in the Foundation Fighting Blindness. For more information about Michael or to get in touch, he can be reached at michaeljkalbererpresent.com.