RHO-Related Retinopathy

Mendelian MONDO:0700380 Pathograph 9 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy

RHO-related retinopathy is an umbrella of inherited retinal diseases caused by pathogenic variants in RHO, which encodes rhodopsin, the rod photoreceptor visual pigment. The dominant subtype is retinitis pigmentosa 4 (RP4), a progressive rod-cone dystrophy in which misfolded or mistrafficked rhodopsin drives proteotoxic stress and rod photoreceptor apoptosis, followed by secondary cone degeneration and irreversible vision loss. A minority of RHO variants are gain-of-function substitutions (G90D, T94I) that constitutively activate rhodopsin in darkness, producing congenital stationary night blindness autosomal dominant 1 (CSNBAD1), a non-progressive condition without retinal degeneration. With over 150 identified pathogenic variants, RHO mutations are collectively the most common cause of autosomal dominant RP and account for approximately 4% of all genetically solved inherited retinal disease.

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2
Inheritance
4
Pathophys.
8
Phenotypes
9
Pathograph
1
Genes
2
Medical Actions
2
Subtypes
1
Trials
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Most RHO-related disease is autosomal dominant; gain-of-function and dominant negative mechanisms underlie both the RP4 and CSNBAD1 branches.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
This review directly supports autosomal dominant inheritance as the principal mode across both the degenerative and stationary RHO branches.
Autosomal recessive inheritance HP:0000007
Rare null or severe hypomorphic RHO alleles can produce autosomal recessive RP through loss of rhodopsin function.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"Recessive RP is usually associated with loss of rhodopsin function, whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
This review identifies loss-of-function as the mechanism underlying the rare recessive RP branch within the RHO family.
◆

Subtypes

2
Retinitis Pigmentosa 4 MONDO:0013395
The dominant branch: autosomal dominant progressive rod-cone dystrophy presenting with childhood or early-adult nyctalopia, followed by progressive peripheral field loss and late central visual impairment. A generalized phenotype (75% of patients) progresses faster than a sector phenotype (25%), with median age to low vision at 52 years based on central visual field.
Show evidence (2 references)
PMID:32301896 SUPPORT Human Clinical
"Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
Multicenter natural-history cohort of 100 RHO-associated RP patients documents RP4 as the major subtype with two recognized severity classes.
PMID:29042326 SUPPORT Human Clinical
"Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
This comprehensive review establishes RP4 as the dominant disease branch within the RHO family.
Congenital Stationary Night Blindness Autosomal Dominant 1 MONDO:0012498
Rare gain-of-function RHO branch (G90D, T94I) causing congenital, non-progressive night blindness without retinal degeneration. Constitutive rhodopsin activation generates dark continuous noise that saturates rod phototransduction in the absence of light.
Show evidence (2 references)
PMID:38743626 SUPPORT Model Organism
"G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization."
Knock-in mouse study mechanistically demonstrates that constitutive G90D-rhodopsin activity in darkness is the proximal cause of the stationary night-blindness phenotype.
PMID:29042326 SUPPORT Human Clinical
"Mutations in rhodopsin are also associated with dominant congenital stationary night blindness (adCSNB) and, less frequently, recessive RP (arRP)."
This review explicitly places CSNBAD1 within the RHO mutation spectrum as a distinct gain-of-function subtype.
⚙

Pathophysiology

4
Rhodopsin Misfolding and ER Stress
The majority of pathogenic RHO variants, most prominently P23H, produce misfolded rhodopsin that is retained in the endoplasmic reticulum rather than delivered to photoreceptor outer segments. Accumulation of misfolded rhodopsin triggers the unfolded protein response and proteotoxic stress. A second group of variants (e.g., P347L) produce correctly folded but mistrafficked rhodopsin that fails to reach the outer segment due to disrupted C-terminal sorting signals. Both mechanisms impair rod photoreceptor homeostasis and converge on rod apoptosis.
retinal rod cell CL:0000604
RHO hgnc:10012 ↓ DECREASED
protein folding GO:0006457 ↓ DECREASED response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED photoreceptor cell maintenance GO:0045494 ↓ DECREASED
Downstream
Rod Photoreceptor Apoptosis Persistent ER stress and proteotoxicity from misfolded or mistrafficked rhodopsin overwhelm the adaptive unfolded protein response and trigger programmed rod cell death.
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
This review supports the breadth of RHO missense variation underlying the RP4 pathophysiology trunk.
Rod Photoreceptor Apoptosis
Proteotoxic or homeostatic failure in rod photoreceptors, driven by misfolded or mistrafficked rhodopsin, leads to rod-selective apoptotic cell death. This node is the shared convergence point for all RP4-causing RHO variants regardless of upstream mechanism class.
retinal rod cell CL:0000604
neuron apoptotic process GO:0051402 ↑ INCREASED photoreceptor cell maintenance GO:0045494 ↓ DECREASED
Downstream
Night blindness Primary rod photoreceptor loss from apoptosis produces nyctalopia, the earliest and most consistent presenting symptom of RP4, reflecting direct rod-mediated scotopic dysfunction.
Secondary Cone Degeneration and Progressive Vision Loss Primary rod loss deprives cones of rod-derived trophic support and disrupts the retinal environment, driving secondary cone degeneration and loss of central vision.
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
This natural-history cohort supports progressive rod-driven degeneration as the central RP4 pathological process.
Secondary Cone Degeneration and Progressive Vision Loss
Following primary rod loss, photoreceptor degeneration extends to involve cones, producing progressive central visual field constriction and eventual loss of visual acuity. Retinal remodeling with pigment migration produces characteristic bone-spicule pigmentation on fundus examination.
retinal rod cell CL:0000604 retinal cone cell CL:0000573
photoreceptor cell maintenance GO:0045494 ↓ DECREASED
Downstream
Progressive peripheral visual field loss Advancing rod-cone degeneration constricts peripheral visual fields progressively, with median age for low vision (central visual field <20°) of 52 years in the generalized phenotype.
Reduced visual acuity Late cone involvement and macular degeneration produce central visual acuity loss. Median age to mild visual acuity impairment is 72 years.
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005)."
Structural OCT data link photoreceptor-RPE complex thinning to visual acuity loss, supporting progressive cone involvement in the late stage.
Constitutive Rhodopsin Activation in Darkness
Gain-of-function RHO variants (G90D, T94I) shift the receptor toward an active conformation in the absence of photon absorption. This generates dark continuous phototransduction noise that saturates the rod signaling cascade, mimicking constant low-level illumination and abolishing the rod's capacity for dark-adapted detection of dim light. Unlike RP4, this branch does not cause photoreceptor degeneration.
retinal rod cell CL:0000604
RHO gain-of-function variant hgnc:10012 ↕ DYSREGULATED
G protein-coupled opsin signaling pathway GO:0016056 ↕ DYSREGULATED phototransduction GO:0007602 ↕ DYSREGULATED
Downstream
Congenital night blindness Persistent constitutive rhodopsin activation desensitizes rods in darkness, causing non-progressive congenital night blindness without retinal structural degeneration.
Show evidence (2 references)
PMID:38743626 SUPPORT Model Organism
"dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho."
Quantitative mouse data establish that the extraordinary magnitude of constitutive G90D noise explains profound rod desensitization in CSNB.
PMID:29042326 SUPPORT Human Clinical
"Mutations in rhodopsin are also associated with dominant congenital stationary night blindness (adCSNB) and, less frequently, recessive RP (arRP). Recessive RP is usually associated with loss of rhodopsin function, whereas the dominant conditions are a consequence of gain of function and/or..."
This review places gain-of-function constitutive activation as the mechanistic basis distinguishing CSNBAD1 from the RP4 branch.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RHO-Related Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Eye 7
Night blindness VERY_FREQUENT Nyctalopia HP:0000662
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
Retinitis pigmentosa is defined by rod photoreceptor dysfunction presenting as nyctalopia; this comprehensive review establishes RHO mutations as the most common adRP cause, directly supporting night blindness as the cardinal early phenotype of primary rod dysfunction.
Progressive peripheral visual field loss VERY_FREQUENT Constriction of peripheral visual field HP:0001133
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
The multicenter cohort confirms progressive peripheral field loss as the dominant early functional deficit in RP4, with rate varying by phenotype class.
Rod-cone dystrophy VERY_FREQUENT Rod-cone dystrophy HP:0000510
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
This review directly ties RHO mutations to the rod-first degenerative clinical pattern of retinitis pigmentosa.
Reduced visual acuity FREQUENT Reduced visual acuity HP:0007663
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities."
Natural-history data directly quantify the late onset of central acuity loss (median 72 years to mild impairment), supporting a predominantly rod-first degenerative trajectory with late cone and macular involvement.
Reduced rod electroretinogram VERY_FREQUENT Abnormal electroretinogram HP:0000512
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005)."
Structural-functional correlation tracking BCVA and visual field loss in this natural-history cohort supports ERG decline as a readout of progressive rod-cone photoreceptor loss in RP4.
Negative electroretinogram waveform VERY_FREQUENT Abnormal electroretinogram HP:0000512
Show evidence (1 reference)
PMID:38743626 SUPPORT Model Organism
"Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration."
This mechanistic study of G90D-rhodopsin CSNB establishes that the ERG abnormality reflects rod desensitization without structural degeneration, consistent with the negative ERG pattern (preserved photoreceptor a-wave, impaired bipolar b-wave) of CSNBAD1.
Congenital night blindness VERY_FREQUENT Nyctalopia HP:0000662
Show evidence (1 reference)
PMID:38743626 SUPPORT Model Organism
"Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration."
This CSNB mechanistic study defines the stationary and non-degenerative nature of the gain-of-function RHO phenotype.
Other 1
Spicular retinal pigmentation FREQUENT Spicular pigmentation of the retina HP:0007737
Show evidence (1 reference)
PMID:29042326 SUPPORT Human Clinical
"Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
Pigmentary retinopathy (including bone-spicule pigmentation) is a defining fundus feature of the RP4 clinical entity caused by RHO mutations.
🧬

Genetic Associations

1
RHO pathogenic variants (Causative)
Gene: RHO hgnc:10012
Autosomal dominant
Show evidence (2 references)
PMID:29042326 SUPPORT Human Clinical
"Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
This review is the primary reference establishing RHO as the most common single adRP gene with a large pathogenic variant spectrum.
CGGV:assertion_29542633-051c-4b06-af52-d2c5a2a8ee90-2025-02-20T170000.000Z SUPPORT Other
"RHO | HGNC:10012 | inherited retinal dystrophy | MONDO:0019118 | SD | Definitive"
ClinGen classifies the RHO–inherited retinal dystrophy gene-disease relationship as Definitive with semidominant inheritance, reflecting the predominance of AD disease alongside rare AR null-allele cases.
💊

Medical Actions

2
QR-1123
Action: Pharmacotherapy NCIT:C15986
QR-1123 is an investigational allele-selective RNase H-mediated gapmer ASO that targets and degrades the P23H mutant RHO mRNA while sparing wild-type RHO transcripts. It was administered as a single intravitreal injection. ProQR suspended the development program in April 2022 following a strategic restructuring after the ILLUMINATE trial failure for sepofarsen.
Show evidence (1 reference)
clinicaltrials:NCT04123626 SUPPORT Human Clinical
"This study evaluates the safety, tolerability and efficacy of QR-1123 injection in the eye (intravitreal; IVT) injections (one eye/unilateral) in subjects receiving a single dose or repeat doses."
AURORA Phase 1/2 first-in-human study confirms QR-1123 was clinically evaluated as an intravitreal ASO for adRP due to the P23H RHO mutation.
Low vision rehabilitation and supportive care
Action: supportive care MAXO:0000950
Low vision aids, orientation and mobility training, and genetic counseling form the current standard of care for RP4. No approved pharmacotherapy exists.
Show evidence (1 reference)
PMID:32301896 SUPPORT Human Clinical
"Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life."
Natural-history data highlighting the optimal intervention window underscore the role of supportive care in managing this progressive disease pending disease-modifying therapies.
🔬

Clinical Trials

1
NCT04123626 PHASE_I SUSPENDED
AURORA: first-in-human Phase 1/2 study of intravitreal QR-1123 (single and repeat doses) in adults with adRP due to the P23H RHO mutation. Open-label single-dose cohorts and double-masked repeat-dose cohorts. Program suspended by ProQR in April 2022.
Target Phenotypes: Rod-cone dystrophy HP:0000510 Night blindness HP:0000662
Show evidence (1 reference)
clinicaltrials:NCT04123626 SUPPORT
"This study evaluates the safety, tolerability and efficacy of QR-1123 injection in the eye (intravitreal; IVT) injections (one eye/unilateral) in subjects receiving a single dose or repeat doses."
AURORA (NCT04123626) was the sole clinical trial of QR-1123 and the most advanced ASO program for RHO-related RP to date.
{ }

Source YAML

click to show 
name: RHO-Related Retinopathy
creation_date: "2026-06-22T00:00:00Z"
category: Mendelian
description: >
  RHO-related retinopathy is an umbrella of inherited retinal diseases caused by
  pathogenic variants in RHO, which encodes rhodopsin, the rod photoreceptor
  visual pigment. The dominant subtype is retinitis pigmentosa 4 (RP4), a
  progressive rod-cone dystrophy in which misfolded or mistrafficked rhodopsin
  drives proteotoxic stress and rod photoreceptor apoptosis, followed by
  secondary cone degeneration and irreversible vision loss. A minority of RHO
  variants are gain-of-function substitutions (G90D, T94I) that constitutively
  activate rhodopsin in darkness, producing congenital stationary night
  blindness autosomal dominant 1 (CSNBAD1), a non-progressive condition without
  retinal degeneration. With over 150 identified pathogenic variants, RHO
  mutations are collectively the most common cause of autosomal dominant RP and
  account for approximately 4% of all genetically solved inherited retinal
  disease.
disease_term:
  preferred_term: RHO-related retinopathy
  term:
    id: MONDO:0700380
    label: RHO-related retinopathy
synonyms:
- RHO-associated retinal dystrophy
- rhodopsin-associated retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
has_subtypes:
- name: RP4
  display_name: Retinitis Pigmentosa 4
  subtype_term:
    preferred_term: retinitis pigmentosa 4
    term:
      id: MONDO:0013395
      label: retinitis pigmentosa 4
  description: >
    The dominant branch: autosomal dominant progressive rod-cone dystrophy
    presenting with childhood or early-adult nyctalopia, followed by progressive
    peripheral field loss and late central visual impairment. A generalized
    phenotype (75% of patients) progresses faster than a sector phenotype (25%),
    with median age to low vision at 52 years based on central visual field.
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
    explanation: >
      Multicenter natural-history cohort of 100 RHO-associated RP patients
      documents RP4 as the major subtype with two recognized severity classes.
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
    explanation: >
      This comprehensive review establishes RP4 as the dominant disease branch
      within the RHO family.
- name: CSNBAD1
  display_name: Congenital Stationary Night Blindness Autosomal Dominant 1
  subtype_term:
    preferred_term: congenital stationary night blindness autosomal dominant 1
    term:
      id: MONDO:0012498
      label: congenital stationary night blindness autosomal dominant 1
  description: >
    Rare gain-of-function RHO branch (G90D, T94I) causing congenital,
    non-progressive night blindness without retinal degeneration. Constitutive
    rhodopsin activation generates dark continuous noise that saturates rod
    phototransduction in the absence of light.
  evidence:
  - reference: PMID:38743626
    reference_title: "Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization."
    explanation: >
      Knock-in mouse study mechanistically demonstrates that constitutive
      G90D-rhodopsin activity in darkness is the proximal cause of the
      stationary night-blindness phenotype.
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in rhodopsin are also associated with dominant congenital stationary night blindness (adCSNB) and, less frequently, recessive RP (arRP)."
    explanation: >
      This review explicitly places CSNBAD1 within the RHO mutation spectrum
      as a distinct gain-of-function subtype.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Most RHO-related disease is autosomal dominant; gain-of-function and dominant
    negative mechanisms underlie both the RP4 and CSNBAD1 branches.
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
    explanation: >
      This review directly supports autosomal dominant inheritance as the
      principal mode across both the degenerative and stationary RHO branches.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Rare null or severe hypomorphic RHO alleles can produce autosomal recessive
    RP through loss of rhodopsin function.
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recessive RP is usually associated with loss of rhodopsin function, whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
    explanation: >
      This review identifies loss-of-function as the mechanism underlying the
      rare recessive RP branch within the RHO family.
prevalence:
- population: >-
    IRD clinical genetics cohort (Foundation Fighting Blindness Consortium,
    41 international centers, 33,834 patients)
  percentage: 4%
  notes: >-
    RHO was the fifth most common solved gene in a large multinational IRD cohort,
    accounting for 4% of all genetically solved cases. This ranks behind ABCA4,
    USH2A, RPGR, and PRPH2.
  evidence:
  - reference: PMID:39908130
    reference_title: "Characterizing the Genetic Basis for Inherited Retinal Disease: Lessons Learned From the Foundation Fighting Blindness Clinical Consortium's Gene Poll"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common genetic etiologies were ABCA4 (17%), USH2A (9%), RPGR (6%), PRPH2 (5%), and RHO (4%)."
    explanation: >
      The FFB Consortium gene poll provides the most current large-scale
      estimate of RHO burden across all inherited retinal disease.
- population: Autosomal dominant RP (adRP) cohorts, Western populations
  notes: >-
    RHO mutations are the single most frequent cause of adRP, accounting for
    approximately 20–26% of adRP cases in North American and European cohorts.
    The P23H variant (c.68C>A) alone accounts for approximately 2,000–3,000
    clinically affected patients in the United States.
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
    explanation: >
      This comprehensive review establishes RHO as the leading single-gene
      cause of adRP across Western populations.
  - reference: PMID:39278389
    reference_title: "Prevalence Estimates and Genetic Diversity for Autosomal Dominant Retinitis Pigmentosa Due to RHO, c.68C>A (p.P23H) Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated clinical prevalence of adRP due to RHO P23H based on literature review was approximately 2000-3000 patients."
    explanation: >
      Meta-analysis and population genetics modeling provide an independent
      US-specific estimate for the P23H variant alone.
pathophysiology:
- name: Rhodopsin Misfolding and ER Stress
  description: >
    The majority of pathogenic RHO variants, most prominently P23H, produce
    misfolded rhodopsin that is retained in the endoplasmic reticulum rather
    than delivered to photoreceptor outer segments. Accumulation of misfolded
    rhodopsin triggers the unfolded protein response and proteotoxic stress.
    A second group of variants (e.g., P347L) produce correctly folded but
    mistrafficked rhodopsin that fails to reach the outer segment due to
    disrupted C-terminal sorting signals. Both mechanisms impair rod
    photoreceptor homeostasis and converge on rod apoptosis.
  gene:
    preferred_term: RHO
    modifier: DECREASED
    term:
      id: hgnc:10012
      label: RHO
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: protein folding
    modifier: DECREASED
    term:
      id: GO:0006457
      label: protein folding
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: photoreceptor cell maintenance
    modifier: DECREASED
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
  downstream:
  - target: Rod Photoreceptor Apoptosis
    description: >
      Persistent ER stress and proteotoxicity from misfolded or mistrafficked
      rhodopsin overwhelm the adaptive unfolded protein response and trigger
      programmed rod cell death.
    evidence:
    - reference: PMID:29042326
      reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we categorise rhodopsin mutations into seven discrete classes; with defects ranging from misfolding and disruption of proteostasis, through mislocalisation and disrupted intracellular traffic to instability and altered function."
      explanation: >
        The seven-class mutation framework links diverse RP4-causing rhodopsin
        defects to shared downstream rod photoreceptor dysfunction and death.
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
    explanation: >
      This review supports the breadth of RHO missense variation underlying
      the RP4 pathophysiology trunk.
- name: Rod Photoreceptor Apoptosis
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  description: >
    Proteotoxic or homeostatic failure in rod photoreceptors, driven by
    misfolded or mistrafficked rhodopsin, leads to rod-selective apoptotic
    cell death. This node is the shared convergence point for all RP4-causing
    RHO variants regardless of upstream mechanism class.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0051402
      label: neuron apoptotic process
  - preferred_term: photoreceptor cell maintenance
    modifier: DECREASED
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
  downstream:
  - target: Night blindness
    description: >
      Primary rod photoreceptor loss from apoptosis produces nyctalopia, the
      earliest and most consistent presenting symptom of RP4, reflecting direct
      rod-mediated scotopic dysfunction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29042326
      reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
      explanation: >
        Retinitis pigmentosa is classically defined by rod-photoreceptor
        dysfunction presenting as nyctalopia; this review establishes RHO
        mutations as the cause of RP and thereby directly supports night
        blindness as the cardinal early symptom of primary rod loss.
  - target: Secondary Cone Degeneration and Progressive Vision Loss
    description: >
      Primary rod loss deprives cones of rod-derived trophic support and
      disrupts the retinal environment, driving secondary cone degeneration
      and loss of central vision.
    evidence:
    - reference: PMID:32301896
      reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life."
      explanation: >
        Natural-history data showing late central visual field loss support
        secondary cone involvement downstream of primary rod degeneration.
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
    explanation: >
      This natural-history cohort supports progressive rod-driven degeneration
      as the central RP4 pathological process.
- name: Secondary Cone Degeneration and Progressive Vision Loss
  description: >
    Following primary rod loss, photoreceptor degeneration extends to involve
    cones, producing progressive central visual field constriction and eventual
    loss of visual acuity. Retinal remodeling with pigment migration produces
    characteristic bone-spicule pigmentation on fundus examination.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    modifier: DECREASED
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
  downstream:
  - target: Progressive peripheral visual field loss
    description: >
      Advancing rod-cone degeneration constricts peripheral visual fields
      progressively, with median age for low vision (central visual field <20°)
      of 52 years in the generalized phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32301896
      reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
      explanation: Faster field loss in the generalized phenotype supports progressive peripheral degeneration as the primary visual morbidity driver.
  - target: Reduced visual acuity
    description: >
      Late cone involvement and macular degeneration produce central visual
      acuity loss. Median age to mild visual acuity impairment is 72 years.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32301896
      reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "whereas this could not be computed for lower acuities."
      explanation: Natural-history data place late central acuity loss downstream of primary peripheral rod-cone degeneration.
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005)."
    explanation: >
      Structural OCT data link photoreceptor-RPE complex thinning to visual
      acuity loss, supporting progressive cone involvement in the late stage.
- name: Constitutive Rhodopsin Activation in Darkness
  description: >
    Gain-of-function RHO variants (G90D, T94I) shift the receptor toward an
    active conformation in the absence of photon absorption. This generates dark
    continuous phototransduction noise that saturates the rod signaling cascade,
    mimicking constant low-level illumination and abolishing the rod's capacity
    for dark-adapted detection of dim light. Unlike RP4, this branch does not
    cause photoreceptor degeneration.
  gene:
    preferred_term: RHO gain-of-function variant
    modifier: DYSREGULATED
    term:
      id: hgnc:10012
      label: RHO
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: G protein-coupled opsin signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0016056
      label: G protein-coupled opsin signaling pathway
  - preferred_term: phototransduction
    modifier: DYSREGULATED
    term:
      id: GO:0007602
      label: phototransduction
  downstream:
  - target: Congenital night blindness
    description: >
      Persistent constitutive rhodopsin activation desensitizes rods in
      darkness, causing non-progressive congenital night blindness without
      retinal structural degeneration.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38743626
      reference_title: "Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization."
      explanation: Knock-in mouse data directly link gain-of-function G90D rhodopsin activity to the rod-desensitization mechanism of CSNB.
  evidence:
  - reference: PMID:38743626
    reference_title: "Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho."
    explanation: >
      Quantitative mouse data establish that the extraordinary magnitude of
      constitutive G90D noise explains profound rod desensitization in CSNB.
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in rhodopsin are also associated with dominant congenital stationary night blindness (adCSNB) and, less frequently, recessive RP (arRP). Recessive RP is usually associated with loss of rhodopsin function, whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
    explanation: >
      This review places gain-of-function constitutive activation as the
      mechanistic basis distinguishing CSNBAD1 from the RP4 branch.
phenotypes:
- category: Ophthalmic
  name: Night blindness
  subtype: RP4
  frequency: VERY_FREQUENT
  description: >
    Rod photoreceptor dysfunction produces nyctalopia, the earliest and most
    consistent presenting symptom in the RP4 branch.
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
    explanation: >
      Retinitis pigmentosa is defined by rod photoreceptor dysfunction presenting
      as nyctalopia; this comprehensive review establishes RHO mutations as the
      most common adRP cause, directly supporting night blindness as the
      cardinal early phenotype of primary rod dysfunction.
- category: Ophthalmic
  name: Progressive peripheral visual field loss
  subtype: RP4
  frequency: VERY_FREQUENT
  description: >
    Advancing rod-cone degeneration progressively constricts the visual field,
    more rapidly in the generalized phenotype than in sector RP.
  phenotype_term:
    preferred_term: Peripheral visual field constriction
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%)"
    explanation: >
      The multicenter cohort confirms progressive peripheral field loss as the
      dominant early functional deficit in RP4, with rate varying by phenotype class.
- category: Ophthalmic
  name: Rod-cone dystrophy
  subtype: RP4
  frequency: VERY_FREQUENT
  description: >
    RP4 is clinically classified as a rod-cone dystrophy: rod dysfunction and
    loss predominate first, followed by secondary cone involvement.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
    explanation: This review directly ties RHO mutations to the rod-first degenerative clinical pattern of retinitis pigmentosa.
- category: Ophthalmic
  name: Reduced visual acuity
  subtype: RP4
  frequency: FREQUENT
  description: >
    Central visual acuity is preserved for several decades before cone and
    macular involvement produces visual acuity loss; median age to mild
    impairment is approximately 72 years.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities."
    explanation: >
      Natural-history data directly quantify the late onset of central acuity
      loss (median 72 years to mild impairment), supporting a predominantly
      rod-first degenerative trajectory with late cone and macular involvement.
- category: Ophthalmic
  name: Spicular retinal pigmentation
  subtype: RP4
  frequency: FREQUENT
  description: >
    Bone-spicule-like pigment deposits in the mid-peripheral fundus are a
    classic hallmark of RP4-type retinal remodeling as rod photoreceptors
    degenerate and retinal pigment epithelium migrates.
  phenotype_term:
    preferred_term: Spicular pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP)."
    explanation: >
      Pigmentary retinopathy (including bone-spicule pigmentation) is a
      defining fundus feature of the RP4 clinical entity caused by RHO mutations.
- category: Ophthalmic
  name: Reduced rod electroretinogram
  subtype: RP4
  frequency: VERY_FREQUENT
  description: >
    In RP4, the dark-adapted (scotopic) rod ERG is severely reduced or
    extinguished proportional to rod photoreceptor loss; cone responses decline
    later as secondary cone degeneration progresses.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005)."
    explanation: >
      Structural-functional correlation tracking BCVA and visual field loss
      in this natural-history cohort supports ERG decline as a readout of
      progressive rod-cone photoreceptor loss in RP4.
- category: Ophthalmic
  name: Negative electroretinogram waveform
  subtype: CSNBAD1
  frequency: VERY_FREQUENT
  description: >
    In CSNBAD1, constitutive rhodopsin activation produces a characteristic
    negative ERG waveform — preserved a-wave with reduced b-wave — reflecting
    inner-retinal signal disruption secondary to rod desensitization rather
    than photoreceptor structural loss.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:38743626
    reference_title: "Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration."
    explanation: >
      This mechanistic study of G90D-rhodopsin CSNB establishes that the
      ERG abnormality reflects rod desensitization without structural
      degeneration, consistent with the negative ERG pattern (preserved
      photoreceptor a-wave, impaired bipolar b-wave) of CSNBAD1.
- category: Ophthalmic
  name: Congenital night blindness
  subtype: CSNBAD1
  frequency: VERY_FREQUENT
  description: >
    In the CSNBAD1 branch, night blindness is congenital, non-progressive,
    and unaccompanied by retinal degeneration. Rod sensitivity is profoundly
    reduced by constitutive signaling noise from the gain-of-function rhodopsin
    variant.
  phenotype_term:
    preferred_term: Congenital night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:38743626
    reference_title: "Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration."
    explanation: >
      This CSNB mechanistic study defines the stationary and non-degenerative
      nature of the gain-of-function RHO phenotype.
genetic:
- name: RHO pathogenic variants
  gene_term:
    preferred_term: RHO
    term:
      id: hgnc:10012
      label: RHO
  association: Causative
  notes: >
    Over 150 pathogenic RHO variants have been identified. They are classified
    into mechanistic classes ranging from misfolding (class II, e.g., P23H) and
    trafficking failure (class I, e.g., P347L) to gain-of-function constitutive
    activation (class III, e.g., G90D, T94I). The P23H variant (c.68C>A) is the
    most common single cause of adRP in North America.
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:29042326
      reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity."
      explanation: This review identifies gain-of-function and dominant negative mechanisms as the basis for autosomal dominant RHO disease.
  evidence:
  - reference: PMID:29042326
    reference_title: "The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP)."
    explanation: >
      This review is the primary reference establishing RHO as the most
      common single adRP gene with a large pathogenic variant spectrum.
  - reference: CGGV:assertion_29542633-051c-4b06-af52-d2c5a2a8ee90-2025-02-20T170000.000Z
    reference_title: "RHO / inherited retinal dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RHO | HGNC:10012 | inherited retinal dystrophy | MONDO:0019118 | SD | Definitive"
    explanation: >
      ClinGen classifies the RHO–inherited retinal dystrophy gene-disease
      relationship as Definitive with semidominant inheritance, reflecting
      the predominance of AD disease alongside rare AR null-allele cases.
treatments:
- name: QR-1123
  description: >
    QR-1123 is an investigational allele-selective RNase H-mediated gapmer ASO
    that targets and degrades the P23H mutant RHO mRNA while sparing wild-type
    RHO transcripts. It was administered as a single intravitreal injection.
    ProQR suspended the development program in April 2022 following a strategic
    restructuring after the ILLUMINATE trial failure for sepofarsen.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: RHO
      term:
        id: hgnc:10012
        label: RHO
    target_transcript: P23H mutant RHO mRNA (allele-selective)
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: clinicaltrials:NCT04123626
    reference_title: "A Prospective First-In-Human Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa (adRP) Due to the P23H Mutation in the RHO Gene"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study evaluates the safety, tolerability and efficacy of QR-1123 injection in the eye (intravitreal; IVT) injections (one eye/unilateral) in subjects receiving a single dose or repeat doses."
    explanation: >
      AURORA Phase 1/2 first-in-human study confirms QR-1123 was clinically
      evaluated as an intravitreal ASO for adRP due to the P23H RHO mutation.
- name: Low vision rehabilitation and supportive care
  description: >
    Low vision aids, orientation and mobility training, and genetic counseling
    form the current standard of care for RP4. No approved pharmacotherapy exists.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:32301896
    reference_title: "CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life."
    explanation: >
      Natural-history data highlighting the optimal intervention window
      underscore the role of supportive care in managing this progressive
      disease pending disease-modifying therapies.
clinical_trials:
- name: NCT04123626
  phase: PHASE_I
  status: SUSPENDED
  notes: >-
    NCT04123626 is registered on ClinicalTrials.gov as a Phase 1/2 study.
    Mapped to PHASE_I per schema granularity; the Phase 2 component consisted
    of dose-escalation cohorts with primary safety and tolerability endpoints,
    consistent with PHASE_I scope as used in other entries (e.g.,
    Angelman_Syndrome, Canavan_Disease).
  description: >
    AURORA: first-in-human Phase 1/2 study of intravitreal QR-1123 (single and
    repeat doses) in adults with adRP due to the P23H RHO mutation. Open-label
    single-dose cohorts and double-masked repeat-dose cohorts. Program suspended
    by ProQR in April 2022.
  target_phenotypes:
  - preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  - preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: clinicaltrials:NCT04123626
    reference_title: "A Prospective First-In-Human Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa (adRP) Due to the P23H Mutation in the RHO Gene"
    supports: SUPPORT
    snippet: "This study evaluates the safety, tolerability and efficacy of QR-1123 injection in the eye (intravitreal; IVT) injections (one eye/unilateral) in subjects receiving a single dose or repeat doses."
    explanation: >-
      AURORA (NCT04123626) was the sole clinical trial of QR-1123 and the
      most advanced ASO program for RHO-related RP to date.