Leber Congenital Amaurosis 10

1. Disease Information

Overview

Leber congenital amaurosis 10 (LCA10) is a severe, autosomal recessive inherited retinal dystrophy caused by biallelic pathogenic variants in the CEP290 gene (centrosomal protein 290). It represents the most common genetic subtype of Leber congenital amaurosis, accounting for approximately 15–30% of all LCA cases in Caucasian populations and over 20% across multiple cohorts (leroy2021lebercongenitalamaurosis pages 1-2, huang2021leber’scongenitalamaurosis pages 6-7, gong2024infantilenystagmussyndrome—associated pages 4-5). LCA10 typically presents in early infancy with severe visual impairment or blindness, classifying it as one of the most severe forms of inherited retinal degeneration and a leading cause of childhood blindness (leroy2021lebercongenitalamaurosis pages 1-2, leroy2021lebercongenitalamaurosis pages 2-4).

Key Identifiers

The following table summarizes the core identifiers and defining characteristics of LCA10:

Table: This table summarizes the core identifiers and defining characteristics of Leber congenital amaurosis 10, including its causal gene, hallmark variant, inheritance, prevalence, and onset. It is useful as a compact disease knowledge base entry scaffold grounded in the retrieved evidence.

Synonyms and Alternative Names

Common synonyms include: LCA10, CEP290-associated LCA, CEP290-related retinal degeneration, CEP290-associated inherited retinal degeneration, and Leber congenital amaurosis type 10 (leroy2021lebercongenitalamaurosis pages 1-2, pierce2024geneeditingfor pages 1-3). The disease information is derived from aggregated disease-level resources including cohort studies, clinical trials, review literature, and curated databases such as OMIM, OpenTargets, and ClinicalTrials.gov.

2. Etiology

Disease Causal Factors

LCA10 is a monogenic Mendelian disorder caused exclusively by biallelic loss-of-function mutations in the CEP290 gene located on chromosome 12q21.32 (huang2021leber’scongenitalamaurosis pages 6-7). There are no known environmental, infectious, or lifestyle contributions to disease causation.

Genetic Risk Factors

The most common pathogenic variant is the deep intronic mutation c.2991+1655A>G (also referred to as the IVS26 variant or p.Cys998X), which is found in 60–89% of CEP290-related LCA patients depending on the cohort and ancestry (leroy2021lebercongenitalamaurosis pages 1-2, gong2024infantilenystagmussyndrome—associated pages 4-5, coppieters2010geneticscreeningof pages 13-14). This variant creates a cryptic splice donor site within intron 26, generating an aberrant exon containing a premature stop codon. This results in approximately 50% of CEP290 transcripts containing the cryptic exon and producing truncated, nonfunctional protein, while the remaining ~50% are correctly spliced (leroy2021lebercongenitalamaurosis pages 1-2, mcdonald2024retinalciliopathiesand pages 7-8). The reduced CEP290 protein level (~10% correctly spliced mRNA with residual full-length protein) is sufficient for ciliary function in most organs but is inadequate for the highly specialized photoreceptor cilium, explaining the retinal-specific phenotype (mcdonald2024retinalciliopathiesand pages 7-8).

Other pathogenic CEP290 variants include c.4723A>T (4–11% frequency), as well as numerous additional missense, nonsense, frameshift, and splice-site mutations at lower frequencies (leroy2021lebercongenitalamaurosis pages 1-2). CEP290 mutations are classified as pathogenic per ACMG/AMP guidelines and are germline in origin. The functional consequence is loss of function.

Modifier Genes

AHI1 (Abelson Helper Integration Site 1) has been identified as a potential modifier gene for CEP290-related phenotypes. In a Belgian cohort, two novel heterozygous AHI1 missense variants (p.Asn811Lys and p.His758Pro) were found in CEP290-LCA patients with neurological involvement (coppieters2010geneticscreeningof pages 4-7, coppieters2010geneticscreeningof pages 16-17). AHI1 plays a functional role in ciliogenesis and vesicle trafficking by mediating Rab8a localization, and AHI1 variants may modulate neurological severity in CEP290-related disease (coppieters2010geneticscreeningof pages 16-17).

Founder Effects

The c.2991+1655A>G variant represents a European founder mutation, with particularly high prevalence in Northern European populations. In a Belgian cohort, CEP290 accounted for 30% of all LCA mutations, with c.2991+1655A>G found in 89% of CEP290-related LCA patients (coppieters2010geneticscreeningof pages 13-14). In a German cohort, CEP290 accounted for 21% of all LCA-associated gene variants and 29% among LCA patients specifically (zobor2023geneticandclinical pages 1-2). CEP290 mutations are notably less prevalent in Chinese and Japanese populations (huang2021leber’scongenitalamaurosis pages 6-7).

Gene-Environment Interactions

No gene-environment interactions have been established for LCA10. As a purely genetic ciliopathy, the disease course is determined by the nature and severity of the CEP290 mutations.

3. Phenotypes

LCA10 presents as a severe cone-rod dystrophy with the following characteristic phenotypic features:

Table: This table summarizes the core phenotypic features reported for CEP290-associated Leber congenital amaurosis 10, aligned to suggested HPO terms and annotated with typical frequency, onset, severity, and progression. It is useful for knowledge-base curation and phenotype harmonization.

Quality of Life Impact

LCA10 has a profound impact on quality of life and development. Most patients experience severe visual impairment from infancy, which significantly affects developmental milestones, educational attainment, independence, and overall well-being (leroy2021lebercongenitalamaurosis pages 1-2, leroy2021lebercongenitalamaurosis pages 5-6). The societal burden includes substantial direct medical costs and indirect costs from loss of productivity and need for supportive services (leroy2021lebercongenitalamaurosis pages 1-2).

4. Genetic/Molecular Information

Causal Gene: CEP290

CEP290 (centrosomal protein 290; OMIM 610142; HGNC:29021; Ensembl ENSG00000198707) is located on chromosome 12q21.32 and encodes a 290 kDa centrosomal protein that localizes to the transition zone of the photoreceptor connecting cilium (huang2021leber’scongenitalamaurosis pages 6-7, OpenTargets Search: Leber congenital amaurosis-CEP290).

Pathogenic Variants

• c.2991+1655A>G (IVS26 variant): Deep intronic founder variant creating a cryptic exon with premature stop codon (p.Cys998X); found in 60–89% of CEP290-LCA patients; classified as pathogenic (leroy2021lebercongenitalamaurosis pages 1-2, coppieters2010geneticscreeningof pages 13-14, mcdonald2024retinalciliopathiesand pages 7-8)
• c.4723A>T: Second most common variant (4–11% frequency) (leroy2021lebercongenitalamaurosis pages 1-2)
• Over 150 additional pathogenic variants have been identified in CEP290 across the ciliopathy spectrum, including missense, nonsense, frameshift, and splice-site mutations
• All variants are germline in origin
• Functional consequence: Loss of function

Allelic Heterogeneity and Pleiotropy

CEP290 mutations cause a spectrum of ciliopathies beyond LCA10, including Joubert syndrome, Senior-Løken syndrome, Meckel-Gruber syndrome, and Bardet-Biedl syndrome (gong2024infantilenystagmussyndrome—associated pages 4-5, huang2021leber’scongenitalamaurosis pages 6-7). The isolated retinal phenotype in LCA10 is attributed to the hypomorphic nature of the common c.2991+1655A>G variant, which permits residual CEP290 function in most organs (gong2024infantilenystagmussyndrome—associated pages 4-5, mcdonald2024retinalciliopathiesand pages 7-8).

Chromosomal Abnormalities

No large-scale chromosomal abnormalities are associated with LCA10. The disease is caused by point mutations or small insertions/deletions within the CEP290 gene.

5. Environmental Information

As a monogenic Mendelian ciliopathy, LCA10 has no established environmental, lifestyle, or infectious contributory factors. There are no known environmental protective or risk factors. Environmental exposures, toxins, radiation, diet, and infectious agents do not play a role in disease etiology.

6. Mechanism / Pathophysiology

Molecular Pathways and Cellular Processes

CEP290 is a structural protein of the ciliary transition zone—the gatekeeping compartment between the inner and outer segments of photoreceptors. Using advanced microscopy, CEP290 has been localized throughout the connecting cilium between doublet microtubules and the ciliary membrane with nine-fold symmetry (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3).

The pathophysiological cascade in LCA10 proceeds as follows:

1. Initial trigger: Biallelic CEP290 mutations reduce or eliminate functional CEP290 protein at the photoreceptor connecting cilium (mcdonald2024retinalciliopathiesand pages 7-8, corralserrano2023eupatilinimprovescilia pages 3-6).

2. Ciliary structural defects: Loss of CEP290 results in aberrant connecting cilium membrane structure, confinement of the ciliary necklace and Y-links to the proximal connecting cilium, and stunted axonemes with abnormal ciliary vesicles (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3).

3. Transition zone protein redistribution: Transition zone proteins AHI1 and NPHP1 are abnormally restricted to the proximal connecting cilium, while other proteins (NPHP8, CEP89) remain unaffected, indicating CEP290 has selective roles in TZ protein spatial distribution (moye2025subciliarylocalizationof pages 1-3).

4. Impaired protein trafficking: CEP290 dysfunction disrupts the ciliary gateway, leading to accumulation of rhodopsin and opsins in the outer nuclear layer instead of proper transport to the outer segment (corralserrano2023eupatilinimprovescilia pages 3-6).

5. Outer segment formation failure: Outer segment disc formation is inhibited, accompanied by accumulation of extracellular vesicles (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3).

6. Photoreceptor degeneration: The combined effects of structural ciliary abnormalities, impaired protein trafficking, and failed outer segment formation result in progressive photoreceptor loss and retinal degeneration (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3, corralserrano2023eupatilinimprovescilia pages 3-6).

Suggested GO Terms

• GO:0060271 (cilium assembly)
• GO:0032391 (photoreceptor connecting cilium)
• GO:0001750 (photoreceptor outer segment)
• GO:0042462 (eye photoreceptor cell development)
• GO:0046548 (retinal rod cell development)

Cell Types Involved

• Photoreceptor cells (CL:0000210) — primary cells affected
• Rod photoreceptors (CL:0000604) — develop but rapidly degenerate postnatally
• Cone photoreceptors (CL:0000573) — central cones lost early
• Retinal pigment epithelium cells (CL:0002586) — secondary involvement

7. Anatomical Structures Affected

Organ Level

• Primary organ: Eye (UBERON:0000970)
• Specific structure: Retina (UBERON:0000966), particularly the photoreceptor layer
• Body system: Visual/nervous system

Tissue and Cell Level

• Photoreceptor layer (UBERON:0001787)
• Outer nuclear layer (UBERON:0001789)
• Photoreceptor outer segments (UBERON:0001817)
• Connecting cilium/transition zone of photoreceptors

Subcellular Level

• Primary cilium (GO:0005929)
• Transition zone (GO:0035869)
• Basal body/centriole (GO:0005814)
• Ciliary membrane (GO:0060170)
• Photoreceptor disc membrane (GO:0097449)

Localization

• Bilateral, symmetric involvement
• Both eyes affected; foveal architecture may be relatively preserved despite disproportionate vision loss (leroy2021lebercongenitalamaurosis pages 2-4)

8. Temporal Development

Onset

• Typical age of onset: Congenital to early infancy (leroy2021lebercongenitalamaurosis pages 1-2, leroy2021lebercongenitalamaurosis pages 2-4)
• Onset pattern: Insidious/congenital; visual impairment is usually recognized within the first months of life

Progression

• Disease course: Progressive retinal degeneration
• Rod photoreceptors develop but rapidly degenerate postnatally; most patients lose rods by their second decade (leroy2021lebercongenitalamaurosis pages 2-4)
• The retina may initially appear normal, with white flecks or marbleized fundus appearing in the first to second decade, followed by pigmentary retinopathy (leroy2021lebercongenitalamaurosis pages 2-4, coppieters2010geneticscreeningof pages 13-14)
• Severe vision loss (counting fingers or worse) occurs in 62–89% of patients (leroy2021lebercongenitalamaurosis pages 2-4, huang2021leber’scongenitalamaurosis pages 6-7)
• Disease duration: Chronic, lifelong
• Critical periods: Early childhood represents a window of opportunity for therapeutic intervention before irreversible photoreceptor loss

9. Inheritance and Population

Inheritance Pattern

• Autosomal recessive (leroy2021lebercongenitalamaurosis pages 1-2, huang2021leber’scongenitalamaurosis pages 6-7)
• Complete penetrance for biallelic pathogenic variants
• Variable expressivity, particularly influenced by specific genotype and modifier genes (gong2024infantilenystagmussyndrome—associated pages 4-5, coppieters2010geneticscreeningof pages 4-7)

Epidemiology

• Overall LCA prevalence: Approximately 1:30,000 to 1:80,000 newborns; ~1:50,000 in Europe and North America (leroy2021lebercongenitalamaurosis pages 1-2, zobor2023geneticandclinical pages 1-2)
• LCA10 proportion: CEP290 accounts for 15–30% of LCA cases, making it the most common genetic subtype in Caucasians (huang2021leber’scongenitalamaurosis pages 6-7, zobor2023geneticandclinical pages 1-2)
• Estimated LCA cases in Germany: ~2,000 (zobor2023geneticandclinical pages 1-2)
• LCA affects 20% of blind children and accounts for 5% of all inherited retinal diseases (zobor2023geneticandclinical pages 1-2)

Population Demographics

• Ethnic distribution: Highest frequency in Northern European/Caucasian populations; the c.2991+1655A>G variant is a European founder mutation (leroy2021lebercongenitalamaurosis pages 1-2, huang2021leber’scongenitalamaurosis pages 6-7)
• Less prevalent in Chinese and Japanese populations (huang2021leber’scongenitalamaurosis pages 6-7)
• CEP290 was the most common LCA-associated gene in Belgian (30%), German (21–29%), and other European cohorts (coppieters2010geneticscreeningof pages 13-14, zobor2023geneticandclinical pages 1-2)
• Equal sex ratio; no sex predilection documented
• Consanguinity increases risk in populations where it is practiced (coppieters2010geneticscreeningof pages 13-14)

10. Diagnostics

Clinical Tests

• Electroretinography (ERG): Severely reduced or extinguished scotopic and photopic responses; often the first objective diagnostic test (leroy2021lebercongenitalamaurosis pages 2-4, zobor2023geneticandclinical pages 1-2)
• Optical Coherence Tomography (OCT): Shows photoreceptor layer thinning with relatively preserved foveal architecture (leroy2021lebercongenitalamaurosis pages 2-4)
• Fundus Autofluorescence (FAF): Abnormal autofluorescence patterns (leroy2021lebercongenitalamaurosis pages 2-4)
• Full-Field Stimulus Testing (FST): Used to measure retinal sensitivity, particularly in clinical trials (pierce2024geneeditingfor pages 1-3)
• Fundoscopy: Initially normal; white flecks, salt-and-pepper or marbleized appearance, and pigmentary changes develop over time (leroy2021lebercongenitalamaurosis pages 2-4, coppieters2010geneticscreeningof pages 13-14)

Genetic Testing

• Recommended approach: Targeted next-generation sequencing gene panels for inherited retinal diseases (344+ genes), followed by Sanger sequencing for confirmation; achieves diagnosis in ~84.7% of pediatric IRD cases (leroy2021lebercongenitalamaurosis pages 2-4)
• Single gene testing: Direct sequencing of CEP290, particularly for the common c.2991+1655A>G variant
• Whole exome/genome sequencing: Useful for cases not resolved by panel testing
• Note: The deep intronic c.2991+1655A>G variant may not be detected by standard exome sequencing; dedicated assays or intronic coverage are required

Differential Diagnosis

• Other LCA subtypes (RPE65-LCA2, GUCY2D-LCA1, CRB1-LCA8, AIPL1-LCA4)
• Early-onset retinitis pigmentosa
• Congenital stationary night blindness
• Achromatopsia
• Other ciliopathies with retinal involvement (Joubert syndrome, Senior-Løken syndrome)

11. Outcome/Prognosis

Disease Course and Morbidity

• Most patients experience severe visual impairment or legal blindness by the first decade of life (leroy2021lebercongenitalamaurosis pages 2-4, huang2021leber’scongenitalamaurosis pages 6-7)
• LCA10 is the most severe form of LCA, associated with profoundly impaired vision at an earlier age compared to other subtypes such as LCA2 (leroy2021lebercongenitalamaurosis pages 5-6)
• Life expectancy is typically normal when the disease presents in its isolated retinal form (LCA10 without syndromic features)
• Disease-specific mortality is not elevated for non-syndromic LCA10

Complications

• Progressive photoreceptor degeneration leading to complete blindness
• Developmental delays due to severe early vision loss
• Potential for syndromic features (renal dysfunction, neurological involvement) in patients with certain CEP290 genotypes (coppieters2010geneticscreeningof pages 13-14)

Prognostic Factors

• Specific genotype (homozygous c.2991+1655A>G vs. compound heterozygous variants)
• Baseline visual acuity was identified as the only predictor of treatment response in sepofarsen trials (russell2022intravitrealantisenseoligonucleotide pages 6-7)
• Residual photoreceptor count at time of intervention
• Age at treatment initiation

12. Treatment

Current Approved Treatments

There are currently no approved treatments specifically for LCA10 (leroy2021lebercongenitalamaurosis pages 5-6). The only FDA/EMA-approved gene therapy for any LCA subtype is voretigene neparvovec (Luxturna) for RPE65-associated LCA (LCA2).

Experimental Treatments in Clinical Trials

The following table summarizes the clinical trial landscape for LCA10:

Table: This table summarizes the main registered clinical studies for CEP290-associated Leber congenital amaurosis 10, including interventional therapy trials and the natural history study that informed trial design. It is useful for comparing modalities, development stage, recruitment status, and sponsors across the current LCA10 treatment landscape.

EDIT-101 (CRISPR-Cas9 Gene Editing)

EDIT-101 is a CRISPR-Cas9 gene editing therapy delivered via AAV5 subretinal injection, designed to excise or disable the aberrant cryptic exon created by the IVS26 variant in CEP290, thereby restoring normal splicing (pierce2024geneeditingfor pages 1-3). The BRILLIANCE trial (NCT03872479), a Phase 1–2 open-label study published in the New England Journal of Medicine (2024), enrolled 14 participants (12 adults aged 17–63 and 2 children aged 9 and 14). Key findings included: - No serious treatment-related adverse events or dose-limiting toxicity (pierce2024geneeditingfor pages 1-3) - 6 participants showed meaningful improvement in cone-mediated vision assessed by FST (pierce2024geneeditingfor pages 1-3) - 9 participants (64%) showed meaningful improvement in BCVA, red light sensitivity, or mobility test scores (pierce2024geneeditingfor pages 1-3) - 6 participants showed meaningful improvement in vision-related quality-of-life scores (pierce2024geneeditingfor pages 1-3) - Suggested MAXO term: MAXO:0001001 (gene therapy)

Sepofarsen (QR-110; Antisense Oligonucleotide)

Sepofarsen is an RNA antisense oligonucleotide administered by intravitreal injection that targets the c.2991+1655A>G variant to restore normal CEP290 mRNA splicing (russell2022intravitrealantisenseoligonucleotide pages 1-2). In the Phase 1b/2 trial (NCT03140969) published in Nature Medicine (2022), 11 patients received multiple doses: - 90.9% developed ocular adverse events in the treated eye, mostly mild and dose-dependent (russell2022intravitrealantisenseoligonucleotide pages 1-2) - 8 of 11 patients developed cataracts, 6 requiring lens replacement (russell2022intravitrealantisenseoligonucleotide pages 1-2) - Statistically significant improvements in visual acuity and retinal sensitivity were reported (russell2022intravitrealantisenseoligonucleotide pages 1-2, russell2022intravitrealantisenseoligonucleotide pages 6-7) - 45% of patients gained at least 15 ETDRS letters (saripalli2026genetherapyand pages 2-4, russell2022intravitrealantisenseoligonucleotide pages 6-7) - The Phase 2/3 ILLUMINATE trial (NCT03913143) ultimately failed to meet its primary endpoint of mean change in BCVA at 12 months (ling2023therapeuticgeneediting pages 8-9) - A new HYPERION Phase 3 trial (NCT06891443) is currently recruiting with Laboratoires Théa as sponsor

Pharmacological Approaches

Preclinical studies have identified two mutation-agnostic small molecule approaches: - Eupatilin (flavonoid): Improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, CEP290 knockout RPE1 cells, and retinal organoids, and reduced rhodopsin retention in the outer nuclear layer (corralserrano2023eupatilinimprovescilia pages 3-6) - Taprenepag (EP2 receptor agonist): EP2-mediated cAMP elevation enhanced ciliogenesis across all CEP290-mutant cell types and in Cep290-deficient mice, promoting photoreceptor outer segment development and partially restoring retinal responses

Supportive Care

• Low-vision aids and assistive devices
• Orientation and mobility training
• Educational accommodations for visually impaired children
• Genetic counseling for family members
• Suggested MAXO term: MAXO:0000015 (supportive care)

13. Prevention

Primary Prevention

• No primary prevention measures exist for LCA10 beyond genetic counseling and reproductive planning
• Carrier screening: Recommended for individuals with family history of LCA or known CEP290 carrier status
• Preimplantation genetic testing (PGT) and prenatal testing are available for families with known CEP290 variants
• Suggested MAXO term: MAXO:0000127 (genetic counseling)

Secondary Prevention

• Early molecular diagnosis through NGS-based gene panels enables identification of affected individuals and potential enrollment in clinical trials before irreversible photoreceptor loss
• Newborn screening is not currently standard for LCA10

Genetic Counseling

• For autosomal recessive inheritance, each offspring of two carrier parents has a 25% risk of being affected
• Carrier frequency for c.2991+1655A>G in Northern European populations is not precisely established but is expected to be relatively common given the high proportion of LCA10 among LCA cases

14. Other Species / Natural Disease

Comparative Biology

CEP290 is highly conserved across vertebrate species. Mutations in orthologous genes cause retinal degeneration in multiple species: - Mouse (Mus musculus, NCBI Taxon: 10090): The rd16 mouse carries an in-frame deletion in Cep290 resulting in early-onset retinal degeneration with disrupted RPGR interaction (malglaive2023pharmacologicalcampstimulation pages 26-30). Cep290 knockout mice exhibit severe photoreceptor ciliary defects including aberrant connecting cilium membrane, stunted axonemes, and failure of outer segment formation (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3). - Zebrafish (Danio rerio, NCBI Taxon: 7955): Zebrafish cep290 mutants exhibit progressive cone photoreceptor degeneration with upregulation of inflammatory and stress-related pathways, but fail to stimulate regeneration despite Müller glia proliferation capacity - Human iPSC-derived retinal organoids: Patient-derived organoids carrying homozygous c.2991+1655A>G show reduced ciliation, shortened cilia, absent CEP290 at the connecting cilium, and impaired outer segment development (mcdonald2024retinalciliopathiesand pages 7-8, corralserrano2023eupatilinimprovescilia pages 3-6)

Limitations of Animal Models

A humanized mouse model carrying the c.2991+1655A>G intronic mutation failed to exhibit a retinal phenotype due to limited recognition of the cryptic splice site by the mouse spliceosome, necessitating development of fully human-derived model systems (mcdonald2024retinalciliopathiesand pages 7-8).

15. Model Organisms

Mouse Models

• rd16 mouse: In-frame deletion in Cep290/Nphp6; exhibits early-onset retinal degeneration with disrupted RPGR interaction; recapitulates cone disease with natural disease progression (malglaive2023pharmacologicalcampstimulation pages 26-30)
• Cep290 knockout mouse: Complete loss of CEP290 results in ciliogenesis initiation but aberrant connecting cilium membrane, stunted axonemes, abnormal ciliary vesicles, failure of outer segment disc formation, and photoreceptor degeneration (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3)
• Nphp6 hypomorph mouse: All-cone model generated to mimic human retinal ciliopathy (malglaive2023pharmacologicalcampstimulation pages 26-30)
• Humanized c.2991+1655A>G knock-in mouse: Failed to recapitulate retinal phenotype due to species-specific spliceosome differences (mcdonald2024retinalciliopathiesand pages 7-8)

Zebrafish Models

• cep290−/− zebrafish exhibit progressive cone photoreceptor loss, microglia activation, inflammation, and upregulation of genes in apoptosis, stress response, and PDGF signaling pathways; rod precursor proliferation occurs but Müller glia-mediated regeneration is not triggered

Human Cell Models

• Patient-derived iPSC retinal organoids are the gold standard for modeling CEP290-LCA10 pathology, recapitulating reduced ciliation, shortened cilia, absent CEP290 at the connecting cilium, impaired outer segment development, and protein trafficking defects (mcdonald2024retinalciliopathiesand pages 7-8, corralserrano2023eupatilinimprovescilia pages 3-6)

Summary

Leber congenital amaurosis 10 is the most common genetic subtype of LCA, caused by biallelic loss-of-function mutations in CEP290, with the deep intronic founder variant c.2991+1655A>G being predominant in European populations (leroy2021lebercongenitalamaurosis pages 1-2, coppieters2010geneticscreeningof pages 13-14). The disease manifests as severe congenital/early-onset cone-rod dystrophy due to failure of photoreceptor ciliary transition zone function, leading to progressive photoreceptor degeneration (moye2025subciliarylocalizationof pages 11-12, moye2025subciliarylocalizationof pages 1-3, corralserrano2023eupatilinimprovescilia pages 3-6). While no approved treatments exist, both CRISPR-Cas9 gene editing (EDIT-101) and antisense oligonucleotide therapy (sepofarsen) have demonstrated promising safety profiles and efficacy signals in clinical trials (pierce2024geneeditingfor pages 1-3, russell2022intravitrealantisenseoligonucleotide pages 1-2, russell2022intravitrealantisenseoligonucleotide pages 6-7). The BRILLIANCE trial published in the New England Journal of Medicine (2024) demonstrated that in vivo CRISPR-Cas9 gene editing can safely improve photoreceptor function in LCA10 patients (pierce2024geneeditingfor pages 1-3), and a new Phase 3 trial of sepofarsen (HYPERION, NCT06891443) is currently recruiting. Novel mutation-agnostic pharmacological approaches targeting cAMP-mediated ciliogenesis pathways are also emerging in preclinical development, offering hope for broader therapeutic coverage across the CEP290 mutation spectrum (corralserrano2023eupatilinimprovescilia pages 3-6).

References

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8. (pierce2024geneeditingfor pages 1-3): Eric A. Pierce, Tomas S. Aleman, Kanishka T. Jayasundera, Bright S. Ashimatey, Keunpyo Kim, Alia Rashid, Michael C. Jaskolka, Rene L. Myers, Byron L. Lam, Steven T. Bailey, Jason I. Comander, Andreas K. Lauer, Albert M. Maguire, and Mark E. Pennesi. Gene editing for cep290 -associated retinal degeneration. New England Journal of Medicine, 390:1972-1984, Jun 2024. URL: https://doi.org/10.1056/nejmoa2309915, doi:10.1056/nejmoa2309915. This article has 234 citations and is from a highest quality peer-reviewed journal.

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17. (russell2022intravitrealantisenseoligonucleotide pages 6-7): Stephen R. Russell, Arlene V. Drack, Artur V. Cideciyan, Samuel G. Jacobson, Bart P. Leroy, Caroline Van Cauwenbergh, Allen C. Ho, Alina V. Dumitrescu, Ian C. Han, Mitchell Martin, Wanda L. Pfeifer, Elliott H. Sohn, Jean Walshire, Alexandra V. Garafalo, Arun K. Krishnan, Christian A. Powers, Alexander Sumaroka, Alejandro J. Roman, Eva Vanhonsebrouck, Eltanara Jones, Fanny Nerinckx, Julie De Zaeytijd, Rob W. J. Collin, Carel Hoyng, Peter Adamson, Michael E. Cheetham, Michael R. Schwartz, Wilhelmina den Hollander, Friedrich Asmus, Gerard Platenburg, David Rodman, and Aniz Girach. Intravitreal antisense oligonucleotide sepofarsen in leber congenital amaurosis type 10: a phase 1b/2 trial. Nature Medicine, 28:1014-1021, Apr 2022. URL: https://doi.org/10.1038/s41591-022-01755-w, doi:10.1038/s41591-022-01755-w. This article has 155 citations and is from a highest quality peer-reviewed journal.

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19. (saripalli2026genetherapyand pages 2-4): Karthik Saripalli. Gene therapy and leber congenital amaurosis: a review of treatments and clinical trials. American Journal of Student Research, pages 143-151, Jan 2026. URL: https://doi.org/10.70251/hyjr2348.41143151, doi:10.70251/hyjr2348.41143151. This article has 0 citations.

20. (leroy2021lebercongenitalamaurosis pages 6-7): Bart P. Leroy, David G. Birch, Jacque L. Duncan, Byron L. Lam, Robert K. Koenekoop, Fernanda B. O. Porto, Stephen R. Russell, and Aniz Girach. Leber congenital amaurosis due to cep290 mutations—severe vision impairment with a high unmet medical need. Retina, 41(5):898-907, Feb 2021. URL: https://doi.org/10.1097/iae.0000000000003133, doi:10.1097/iae.0000000000003133. This article has 70 citations.

21. (malglaive2023pharmacologicalcampstimulation pages 26-30): France de Malglaive, Iris Barny, Shahd Machroub, Lucas Fares-Taie, Ema Cano, Nicolas Goudin, Tania Attie-Bittach, Josseline Kaplan, Isabelle Perrault, Luis Briseno-Roa, Jean-Michel Rozet, and Jean-Philippe Annereau. Pharmacological camp stimulation via prostaglandin receptors rescues ciliary defects in cep290-deficient human and mouse models. bioRxiv, Oct 2023. URL: https://doi.org/10.1101/2023.10.06.561156, doi:10.1101/2023.10.06.561156. This article has 3 citations.

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