Abstract:Analysis of these widely available clinical data defines the natural disease characteristics of a relevant patient population eligible for gene therapeutic intervention. In the wake of preliminary reports on safety and efficacy of CHM gene therapy (NCT01461213), this multi-modal assessment of a cohort of CHM patients provides important evidence of the natural rate of disease progression and degree of symmetry between eyes.
“…Selection of older patients and/or later disease stages, however, may limit the use of interocular comparisons as the disease may become more asymmetric and less predictable as suggested by our study and previous reports. 10,13 Careful consideration of each of the factors discussed above will have to take place during the preparation and enrollment phases of the growing number of clinical trials planned for CHM.…”
Purpose
To describe in detail the central retinal structure of a large group of patients with Choroideremia (CHM).
Design
prospective, cross-sectional, descriptive study.
Subjects
Patients (n=97, age 6-71 years) with CHM and subjects with normal vision (n=44; ages 10-50 years) were included.
Methods
Subjects were examined with spectral domain optical coherence tomography (SD-OCT) and near infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n=24) with automated static perimetry within the central regions (±15°) examined with SD-OCT.
Main outcome measures
VA and visual thresholds, total, inner and outer nuclear layer (ONL) thicknesses, and the horizontal extent of the ONL and of the photoreceptor outer segment (POS) interdigitation zone.
Results
Earliest abnormalities in regions with normally appearing RPE were the loss of the POS and EZ zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, non-atrophic retina in the majority (69%) of patients. In general, retinal pigment epithelium (RPE) abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning.
Conclusions
Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until late disease. TZ migration to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.
“…Selection of older patients and/or later disease stages, however, may limit the use of interocular comparisons as the disease may become more asymmetric and less predictable as suggested by our study and previous reports. 10,13 Careful consideration of each of the factors discussed above will have to take place during the preparation and enrollment phases of the growing number of clinical trials planned for CHM.…”
Purpose
To describe in detail the central retinal structure of a large group of patients with Choroideremia (CHM).
Design
prospective, cross-sectional, descriptive study.
Subjects
Patients (n=97, age 6-71 years) with CHM and subjects with normal vision (n=44; ages 10-50 years) were included.
Methods
Subjects were examined with spectral domain optical coherence tomography (SD-OCT) and near infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n=24) with automated static perimetry within the central regions (±15°) examined with SD-OCT.
Main outcome measures
VA and visual thresholds, total, inner and outer nuclear layer (ONL) thicknesses, and the horizontal extent of the ONL and of the photoreceptor outer segment (POS) interdigitation zone.
Results
Earliest abnormalities in regions with normally appearing RPE were the loss of the POS and EZ zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, non-atrophic retina in the majority (69%) of patients. In general, retinal pigment epithelium (RPE) abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning.
Conclusions
Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until late disease. TZ migration to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.
“…Beginning in adolescence, male carriers experience night blindness and visual field constrictions due to centripetal atrophy of the choroid, RPE, and photoreceptor layer, though the macula is spared [154]. …”
Section: Choroideremiamentioning
confidence: 99%
“…Recent work on gene therapy for choroideremia has shown promising preclinical results and is currently undergoing clinical trials, with the first treatment administered in 2011 [157, 158]. FAF is an accurate structural marker that correlates with visual acuity and age, and may help identify candidates for gene therapy [154]. Fig.…”
Fundus autofluorescence (FAF) is a non-invasive retinal imaging modality used in clinical practice to provide a density map of lipofuscin, the predominant ocular fluorophore, in the retinal pigment epithelium. Multiple commercially available imaging systems, including the fundus camera, the confocal scanning laser ophthalmoscope, and the ultra-widefield imaging device, are available to the clinician. Each offers unique advantages for evaluating various retinal diseases. The clinical applications of FAF continue to expand. It is now an essential tool for evaluating age related macular degeneration, macular dystrophies, retinitis pigmentosa, white dot syndromes, retinal drug toxicities, and various other retinal disorders. FAF may detect abnormalities beyond those detected on funduscopic exam, fluorescein angiography, or optical coherence tomography, and can be used to elucidate disease pathogenesis, form genotype-phenotype correlations, diagnose and monitor disease, and evaluate novel therapies. Given its ease of use, non-invasive nature, and value in characterizing retinal disease, FAF enjoys increasing clinical relevance. This review summarizes common ocular fluorophores, imaging modalities, and FAF findings for a wide spectrum of retinal disorders.
“…Así, la primera descripción de pigmentación en espícula ósea (un distintivo clínico de las EHR) la proporcionó Donders [4] en Graefe's Archives ya en 1857. Hoy en día, una amplia gama de herramientas diagnósticas ayuda a describir con detalle los cambios morfológicos y funcionales de las enfermedades de la retina [5][6][7] . No obstante, la baja incidencia de las EHR a menudo complica la realización de ensayos observacionales prospectivos útiles por parte de centros individuales al intentar definir los criterios de valoración y diseños de estudio más adecuados para un ensayo intervencional.…”
Section: Avances En El Campo Del Diagnósticounclassified
Las mutaciones en un gran número de genes provocan degeneración de la retina y ceguera sin que exista actualmente cura alguna. En las últimas décadas, la terapia génica para enfermedades de la retina ha evolucionado y se ha convertido en un nuevo y prometedor paradigma terapéutico para estas enfermedades poco comunes. Este artículo refleja las ideas y los conceptos que parten de la ciencia básica hacia la aplicabilidad de la terapia génica en el ámbito clínico. Se describen los avances y las reflexiones actuales sobre la eficacia de los ensayos clínicos en la actualidad y se discuten los posibles obstáculos y soluciones de cara al futuro de la terapia génica para enfermedades de la retina.
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