RARE DISEASE
Choroideremia
Choroideremia
Choroideremia
Synonyms: CHM, Tapetochoroidal dystrophy
Synonyms: CHM, Tapetochoroidal dystrophy
Synonyms: CHM, Tapetochoroidal dystrophy
Drug discovery
6
drugs
With orphan designations
Overview
Choroideremia is an X-linked recessive retinal dystrophy caused by mutations in the CHM gene, leading to progressive degeneration of the choroid, retinal pigment epithelium, and photoreceptors. Initial symptoms include night blindness in childhood, followed by peripheral vision loss and eventual central vision impairment by mid-adulthood. No approved therapies exist, but investigational gene therapies aim to slow progression by delivering functional CHM via viral vectors [1][5][7][15].
Therapies
Gene therapy trials (e.g., AAV2-REP1 subretinal injection) target macular preservation [1][6][18].
Translational read-through therapies for nonsense mutations (e.g., ataluren) in preclinical stages [2][10].
Supportive care: Low-vision aids, cataract management, and monitoring for complications (e.g., cystoid macular edema) [7][10][13].
Categories: rare genetic diseases, rare ophthalmic disorders
Research Papers
202 drug discovery papers about Choroideremia, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
202 drug discovery papers about Choroideremia, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-23 | mRNA delivery to the retina restores REP1 function in choroideremia.
Inherited retinal diseases (IRDs) represent a major cause of blindness, yet current viral vector-based gene therapies are limited by high cost, restricted cargo capacity, and safety concerns related to immunogenicity. We explore here retinal delivery of non-viral, in-vitro-transcribed mRNA using lipid nanoparticles (LNPs) as a safe, cost-effective gene augmentation strategy for choroideremia (CHM). CHM is an X-linked IRD caused by loss-of-function mutations in CHM that encodes Rab escort protein-1 (REP1), which is essential for Rab GTPases prenylation and intracellular trafficking. We demonstrate that subretinal delivery of human CHM-mRNA (hCHM-mRNA) efficiently targets the retinal pigment epithelium (RPE) and choroid, achieving expression that is detectable up to 15 days post-injection, with lower and transient inflammatory response compared to AAV2 vectors. Furthermore, hCHM-mRNA delivery in vitro to human induced pluripotent stem cell (hiPSC)-derived RPE cells from a CHM patient and in vivo via subretinal injection in the Chm ± mouse model successfully restored REP1 levels and reversed Rab prenylation defect. Concordantly, Chm ± treated with hCHM-mRNA showed functional rescue of retinal activity measured by electroretinography 24 h post-injection. Overall, these results provide a strong proof-of-concept for LNP-mediated mRNA technology in the retina, supporting the development of scalable, non-viral gene approaches for IRDs, including CHM.
2026-05-06 | Independent Degeneration of Photoreceptors and Retinal Pigment Epithelium: Multimodal Imaging Evidence From Choroideremia Carriers.
To characterize retinal structural alterations and elucidate underlying pathogenesis in female carriers of choroideremia (CHM) using multimodal imaging. This single-center retrospective study analyzed 100 eyes of 50 genetically confirmed female CHM carriers. Clinical evaluation comprised genotype, age, visual acuity, color fundus photography, fundus autofluorescence (FAF), infrared reflectance, and optical coherence tomography (OCT). Retinal lesions were identified and classified using point-to-point co-localization analysis across modalities. The mean age of carriers was 39.6 ± 17.8 years (range 3.2-80.3 years). All eyes exhibited varying degrees of retinal abnormalities. Most common findings included yellowish changes on color photographs, mottled areas of hyper- and hypo-autofluorescence on FAF, and isolated interdigitation zone (IZ) loss on OCT. Chorioretinal atrophy beyond the peripapillary region, indicating a severe phenotype, was observed in 18% of eyes. Five characteristic degenerative lesions were identified: Type A, isolated IZ loss; Type B, hyper-autofluorescent spots corresponding to presumed photoreceptor loss; Type C, drusen-like deposits; Type D, degeneration of the retinal pigment epithelium (RPE) and RPE-photoreceptor interface; and Type E, outer retinal degeneration. Type B lesions suggest that photoreceptor loss may precede RPE loss at specific loci. Type A lesions were the earliest abnormality, significantly associated with milder phenotypes, indicating the RPE-photoreceptor interface is the initial site of pathology. In contrast, Type D and E lesions were associated with severe phenotypes. Identified hyper-autofluorescence lesions corresponding to presumed photoreceptor loss indicate independent degeneration of photoreceptors and RPE. These findings suggest that future therapeutic approaches should concurrently target both cellular components.
2026-03-31 | REP-1 deficiency induces aberrant mitochondrial metabolic rewiring from glycolysis to lipid oxidation in CHM disease.
Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose-lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.
2026-02-05 | Anticodon-edited transfer RNAs (ACE-tRNAs) encoded as therapeutic nonviral minimal DNA vectors.
Nonsense mutations, resulting from a premature termination codon (PTC), make up ∼11% of all genetic lesions causing disease, affecting millions of people worldwide. Nonsense suppressor anticodon-edited transfer RNAs (ACE-tRNAs) have emerged as a therapeutic modality for the rescue of PTCs. Delivery of ACE-tRNAs in vivo has been achieved by adeno-associated viral vector and RNA-lipid nanoparticle; however, due to drawbacks associated with these approaches, DNA delivery remains an attractive approach. DNA-based approaches afford ease of manufacturing at a relatively low cost and exhibit improved therapeutic durability and safety as compared to viral vector- or RNA-based approaches. Due to the small size of human tRNA genes employed as ACE-tRNAs, in principle, DNA vectors <200 base pairs (bp) in size (minivectors) could be utilized for delivery of actively transcribed ACE-tRNAs. Here, we demonstrate that linear DNA ACE-tRNA vectors as small as 200 bp effectively suppress several nonsense mutations in CFTR and REP1, and that ACE-tRNA minivectors, when tested in cell or ex vivo models, display significantly improved bioavailability, reduced innate immune burden, and superior biostability as compared to conventional plasmid DNA vectors.
2025-10-07 | One down but many more to go: the state of gene therapy for inherited retinal disease.
Gene therapy has ushered in a new era for the treatment of inherited retinal diseases (IRDs). The approval of voretigene neparvovec-rzyl (Luxturna) for RPE65-associated retinal dystrophy marked a pivotal milestone, establishing proof-of-concept that gene addition can restore visual function in IRDs. However, the success of Luxturna is tempered by the reality that it applies to a narrow subset of IRDs, and that no other IRD gene therapy has thus far received regulatory approval. This review outlines the current landscape of IRD gene therapy, including trials for several forms of IRD including achromatopsia, choroideremia, Leber congenital amaurosis, X-linked retinitis pigmentosa, and X-linked retinoschisis. We highlight the central challenges facing the field: narrow gene- or variant-specific indications, vector limitations, and reliance on suboptimal clinical trial endpoints. The review also discusses emerging strategies - including dual AAV and split-intein vectors, non-viral delivery platforms, and precision gene editing technologies such as CRISPR, base editing, and prime editing. These innovations promise to expand therapeutic reach. Finally, we emphasize the need for improved regulatory frameworks and ethical considerations for gene-based therapies for IRD. The field now stands at a critical juncture, where the lessons of Luxturna can inform a more scalable, inclusive, and transformative future.
2026-07-23 | mRNA delivery to the retina restores REP1 function in choroideremia.
Inherited retinal diseases (IRDs) represent a major cause of blindness, yet current viral vector-based gene therapies are limited by high cost, restricted cargo capacity, and safety concerns related to immunogenicity. We explore here retinal delivery of non-viral, in-vitro-transcribed mRNA using lipid nanoparticles (LNPs) as a safe, cost-effective gene augmentation strategy for choroideremia (CHM). CHM is an X-linked IRD caused by loss-of-function mutations in CHM that encodes Rab escort protein-1 (REP1), which is essential for Rab GTPases prenylation and intracellular trafficking. We demonstrate that subretinal delivery of human CHM-mRNA (hCHM-mRNA) efficiently targets the retinal pigment epithelium (RPE) and choroid, achieving expression that is detectable up to 15 days post-injection, with lower and transient inflammatory response compared to AAV2 vectors. Furthermore, hCHM-mRNA delivery in vitro to human induced pluripotent stem cell (hiPSC)-derived RPE cells from a CHM patient and in vivo via subretinal injection in the Chm ± mouse model successfully restored REP1 levels and reversed Rab prenylation defect. Concordantly, Chm ± treated with hCHM-mRNA showed functional rescue of retinal activity measured by electroretinography 24 h post-injection. Overall, these results provide a strong proof-of-concept for LNP-mediated mRNA technology in the retina, supporting the development of scalable, non-viral gene approaches for IRDs, including CHM.
2026-05-06 | Independent Degeneration of Photoreceptors and Retinal Pigment Epithelium: Multimodal Imaging Evidence From Choroideremia Carriers.
To characterize retinal structural alterations and elucidate underlying pathogenesis in female carriers of choroideremia (CHM) using multimodal imaging. This single-center retrospective study analyzed 100 eyes of 50 genetically confirmed female CHM carriers. Clinical evaluation comprised genotype, age, visual acuity, color fundus photography, fundus autofluorescence (FAF), infrared reflectance, and optical coherence tomography (OCT). Retinal lesions were identified and classified using point-to-point co-localization analysis across modalities. The mean age of carriers was 39.6 ± 17.8 years (range 3.2-80.3 years). All eyes exhibited varying degrees of retinal abnormalities. Most common findings included yellowish changes on color photographs, mottled areas of hyper- and hypo-autofluorescence on FAF, and isolated interdigitation zone (IZ) loss on OCT. Chorioretinal atrophy beyond the peripapillary region, indicating a severe phenotype, was observed in 18% of eyes. Five characteristic degenerative lesions were identified: Type A, isolated IZ loss; Type B, hyper-autofluorescent spots corresponding to presumed photoreceptor loss; Type C, drusen-like deposits; Type D, degeneration of the retinal pigment epithelium (RPE) and RPE-photoreceptor interface; and Type E, outer retinal degeneration. Type B lesions suggest that photoreceptor loss may precede RPE loss at specific loci. Type A lesions were the earliest abnormality, significantly associated with milder phenotypes, indicating the RPE-photoreceptor interface is the initial site of pathology. In contrast, Type D and E lesions were associated with severe phenotypes. Identified hyper-autofluorescence lesions corresponding to presumed photoreceptor loss indicate independent degeneration of photoreceptors and RPE. These findings suggest that future therapeutic approaches should concurrently target both cellular components.
2026-03-31 | REP-1 deficiency induces aberrant mitochondrial metabolic rewiring from glycolysis to lipid oxidation in CHM disease.
Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose-lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.
2026-02-05 | Anticodon-edited transfer RNAs (ACE-tRNAs) encoded as therapeutic nonviral minimal DNA vectors.
Nonsense mutations, resulting from a premature termination codon (PTC), make up ∼11% of all genetic lesions causing disease, affecting millions of people worldwide. Nonsense suppressor anticodon-edited transfer RNAs (ACE-tRNAs) have emerged as a therapeutic modality for the rescue of PTCs. Delivery of ACE-tRNAs in vivo has been achieved by adeno-associated viral vector and RNA-lipid nanoparticle; however, due to drawbacks associated with these approaches, DNA delivery remains an attractive approach. DNA-based approaches afford ease of manufacturing at a relatively low cost and exhibit improved therapeutic durability and safety as compared to viral vector- or RNA-based approaches. Due to the small size of human tRNA genes employed as ACE-tRNAs, in principle, DNA vectors <200 base pairs (bp) in size (minivectors) could be utilized for delivery of actively transcribed ACE-tRNAs. Here, we demonstrate that linear DNA ACE-tRNA vectors as small as 200 bp effectively suppress several nonsense mutations in CFTR and REP1, and that ACE-tRNA minivectors, when tested in cell or ex vivo models, display significantly improved bioavailability, reduced innate immune burden, and superior biostability as compared to conventional plasmid DNA vectors.
2025-10-07 | One down but many more to go: the state of gene therapy for inherited retinal disease.
Gene therapy has ushered in a new era for the treatment of inherited retinal diseases (IRDs). The approval of voretigene neparvovec-rzyl (Luxturna) for RPE65-associated retinal dystrophy marked a pivotal milestone, establishing proof-of-concept that gene addition can restore visual function in IRDs. However, the success of Luxturna is tempered by the reality that it applies to a narrow subset of IRDs, and that no other IRD gene therapy has thus far received regulatory approval. This review outlines the current landscape of IRD gene therapy, including trials for several forms of IRD including achromatopsia, choroideremia, Leber congenital amaurosis, X-linked retinitis pigmentosa, and X-linked retinoschisis. We highlight the central challenges facing the field: narrow gene- or variant-specific indications, vector limitations, and reliance on suboptimal clinical trial endpoints. The review also discusses emerging strategies - including dual AAV and split-intein vectors, non-viral delivery platforms, and precision gene editing technologies such as CRISPR, base editing, and prime editing. These innovations promise to expand therapeutic reach. Finally, we emphasize the need for improved regulatory frameworks and ethical considerations for gene-based therapies for IRD. The field now stands at a critical juncture, where the lessons of Luxturna can inform a more scalable, inclusive, and transformative future.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Choroideremia.
6 orphan drug designations for Choroideremia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated virus (AAV2) capsid variant carrying a transgene encoding a codon-optimized human choroideremia (CHM) gene | gene therapies | FDA | 2017-10-12 | — | 4D Molecular Therapeutics, Inc. |
Adeno-associated viral vector serotype 5 containing the human CHM gene | gene therapies | EMA | 2015-04-24 | — | Inserm-Transfert SA |
adeno-associated viral vector serotype 2 containing the human Rab escort protein 1 gene | gene therapies | FDA | 2014-11-05 | — | Biogen |
Adeno-associated viral vector serotype 2 containing the human REP1 gene | gene therapies | EMA | 2014-07-04 | — | Biogen Netherlands B.V. |
Adeno-associated viral vector serotype 2 containing the human CHM gene encoding human Rab escort protein 1 | gene therapies | EMA | 2014-06-04 | — | France Choroideremie |
aadeno-associated viral vector, serotype 2, containing the human choroideremia gene encoding human Rab escort protein 1 | gene therapies | FDA | 2013-09-12 | — | Choroideremia Research Foundation, Inc. |
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