Disease Roundup: Leber Congenital Amaurosis

In this brief roundup, we look at what's going on in the CRISPR Medicine field for Leber congenital amaurosis, an inherited group of rare retinal diseases that are the leading cause of childhood blindness.

By: Karen O'Hanlon Cohrt - Apr. 14, 2021

Leber congenital amaurosis (LCA) is a group of rare and incurable inherited retinal diseases that manifest at birth or in the first few months of life and progress over time, leading to blindness by the 3rd or 4th decade of life.

LCA is an autosomal recessive disease, arising from loss-of-function mutations in any one of at least 27 known genes that play a role in retinal function. Mutations in many of these genes result in dysfunctional rods and cones, which are the light-gathering cells of the retina, and mutations in the RPE65 and CEP290 genes are among the most prevalent. Disease severity depends on the exact mutations present.

RPE65 is a critical isomerase in the classical visual cycle in vertebrates that regenerates the active visual chromophore 11-cis-retinal. The function of CEP290 is not entirely understood but it appears to play a role in the centrosomes and cilia, which are important for cell division and perception of sensory input, respectively.

New treatments are urgently needed

LCA is estimated to occur in 1-2 out of 100,000 live births worldwide, and until the recent approval of the gene replacement therapy Luxturna (first in the US in 2017, and in the EU in 2018), treatment was limited entirely to symptom control and supportive care. Although rare, LCA is the most common cause of childhood blindness.

Luxturna, developed by Spark Therapeutics (since acquired by Roche), is based on sub-retinal injection of a functional RPE65 cDNA delivered via an adeno-associated virus (AAV) and represents the first dedicated therapy for LCA. It improves vision in some individuals but is not curative and concerns exist about its long-term efficacy, with reports of continual retinal degeneration after 1-3 years. Furthermore, its use is restricted to a subset of children and adults that have mutations in both RPE65 alleles and who have a certain threshold of retinal function at the time of treatment.

The first in vivo CRISPR therapy

The world’s first ever in vivo CRISPR therapy is currently being evaluated in the BRILLIANCE clinical trial for LCA10, for which no treatments exist as of yet.

The therapy, known as EDIT-101, is developed by Editas Medicine, US, in partnership with Dublin-based Allergan. EDIT-101 is based on CRISPR-Cas correction of mutations in the CEP290 gene. Mutations in this gene are responsible for LCA10, which accounts for 20-30 % of all LCA cases.

EDIT-101 is designed to restore normal CEP290 protein expression, photoreceptor function and vision. The gene-editing therapy is delivered as a ribonucleoprotein (RNP) complex consisting of Cas9, gRNA and an intact copy of the CEP290 gene. The RNP approach is attractive as CEP290 is too large to be delivered via viral vectors. While CEP290 mutations disable photoreceptors in the retina, the retinal cells are still present and viable in LCA10, which leads to real hopes that EDIT-101 can restore cellular function and improve vision in such individuals.

CRISPR-based gene-editing strategy behind EDIT-101. EDIT-101 is delivered into the retina via a...
CRISPR-based gene-editing strategy behind EDIT-101. EDIT-101 is delivered into the retina via a ribonucleoprotein complex (RNP) to correct mutations in the CEP290 gene in vivo. Image source: https://www.editasmedicine.com/


The trial will enrol a total of18 paediatric (3-17 years) and adult individuals with LCA10 who have a certain baseline level of visual function. The study is open-label and will be run in multiple centers over five cohorts that will each receive one of three doses that will be administerd via subretinal injection.

Dosing in the low-dose cohort was completed last year, and Editas reported in February 2021 that it had initiated dosing in the mid-dose cohort.

The first clinical results for EDIT-101 are expected this year.

Base editing is also being explored as a therapeutic strategy for LCA

Krzysztof Palczewski’s group at the University of California Irvine (UCI) is exploring CRISPR base editing as a new treatment modality for LCA. In work published in Nature Biomedical Engineering late last year, this group showed for the first time that base editing can correct an LCA-causing mutation in vitro and in vivo, with restoration of visual function in a mouse model for retinal disease. We interviewed lead author of that study Susie Suh, an MD PhD student from the Palczewski lab shortly after the work was published, who told us more about this proof-of-concept study.

In the UK, charity organisation Fight for Sight is funding cutting-edge gene-editing research at University College London, which will undertake the first study to investigate direct CRISPR-based repair of disease-causing mutations in photoreceptor cells in human models of inherited retinal diseases including Leber’s congenital amaurosis, as well Stargardt disease, retinitis pigmentosa and others.

As the CRISPR field advances, it is likely that base-editing therapeutic strategies for LCA will move towards clinical development, and we will continue to bring updates as they come.

In the meantime, you can get a complete overview of the current gene-editing clinical trials in our CRISPR Medicine News Clinical Trials Database.


HashtagArticleHashtagIn-vivoHashtagRibonecleoprotein (RNP)HashtagAdeno-associated virus (AAV)HashtagHereditary BlindnessHashtagLeber Congenital AmaurosisHashtagRare DiseaseHashtagCRISPR-CasHashtagEditas Medicine, Inc.HashtagTrialsHashtagClinical

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