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American Journal of Ophthalmology Sep 2023To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). (Clinical Trial)
Clinical Trial
PURPOSE
To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM).
DESIGN
Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial.
METHODS
The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months.
RESULTS
AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23).
CONCLUSIONS
AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.
Topics: Humans; Adult; Child; Child, Preschool; Color Vision Defects; Prospective Studies; Cyclic Nucleotide-Gated Cation Channels; Genetic Therapy; Inflammation
PubMed: 37172884
DOI: 10.1016/j.ajo.2023.05.009 -
American Journal of Ophthalmology Oct 2020To characterize the progression of optical gaps and expand the known etiologies of this phenotype.
PURPOSE
To characterize the progression of optical gaps and expand the known etiologies of this phenotype.
DESIGN
Retrospective cohort study.
METHODS
Thirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions.
RESULTS
Longitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 μm/year) and cone dystrophies (31.9 μm/year) compared with patients with achromatopsia (16.2 μm/year) and occult macular dystrophy (15.4 μm/year). Gap height decreased in patients with Stargardt disease (6.5 μm/year; P = .02) but increased in patients with achromatopsia (3.3 μm/year) and occult macular dystrophy (1.2 μm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized.
CONCLUSION
The optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.
Topics: Adolescent; Adult; Aged; Biomarkers; Calcium-Binding Proteins; Child; Color Vision Defects; Cone-Rod Dystrophies; Disease Progression; Electroretinography; Female; Humans; Macular Degeneration; Male; Membrane Proteins; Middle Aged; Phenotype; Retina; Retinitis Pigmentosa; Retrospective Studies; Stargardt Disease; Tomography, Optical Coherence; Visual Acuity; rab GTP-Binding Proteins
PubMed: 32445700
DOI: 10.1016/j.ajo.2020.05.016 -
American Journal of Industrial Medicine Nov 2017Styrene is a chemical used in the manufacture of plastic-based products worldwide. We systematically reviewed eligible studies of occupational styrene-induced... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Styrene is a chemical used in the manufacture of plastic-based products worldwide. We systematically reviewed eligible studies of occupational styrene-induced dyschromatopsia, qualitatively synthesizing their findings and estimating the exposure effect through meta-analysis.
METHODS
PubMed, EMBASE, and Web of Science databases were queried for eligible studies. Using a random effects model, we compared measures of dyschromatopsia between exposed and non-exposed workers to calculate the standardized mean difference (Hedges'g). We also assessed between-study heterogeneity and publication bias.
RESULTS
Styrene-exposed subjects demonstrated poorer color vision than did the non-exposed (Hedges' g = 0.56; 95%CI: 0.37, 0.76; P < 0.0001). A non-significant Cochran's Q test result (Q = 23.2; P = 0.171) and an I of 32.2% (0.0%, 69.9%) indicated low-to-moderate between-study heterogeneity. Funnel plot and trim-and-fill analyses suggested publication bias.
CONCLUSIONS
This review confirms the hypothesis of occupational styrene-induced dyschromatopsia, suggesting a modest effect size with mild heterogeneity between studies.
Topics: Color Vision Defects; Humans; Occupational Diseases; Occupational Exposure; Styrene
PubMed: 28836685
DOI: 10.1002/ajim.22766 -
Cold Spring Harbor Perspectives in... Aug 2014It has been possible to use viral-mediated gene therapy to transform dichromatic (red-green color-blind) primates to trichromatic. Even though the third cone type was... (Review)
Review
It has been possible to use viral-mediated gene therapy to transform dichromatic (red-green color-blind) primates to trichromatic. Even though the third cone type was added after the end of developmental critical periods, treated animals acquired red-green color vision. What happened in the treated animals may represent a recapitulation of the evolution of trichromacy, which seems to have evolved with the acquisition of a third cone type without the need for subsequent modification to the circuitry. Some transgenic mice in which a third cone type was added also acquired trichromacy. However, compared with treated primates, red-green color vision in mice is poor, indicating large differences between mice and monkeys in their ability to take advantage of the new input. These results have implications for understanding the limits and opportunities for using gene therapy to treat vision disorders caused by defects in cone function.
Topics: Animals; Color Vision Defects; Genetic Therapy; Mice; Nerve Net; Neuronal Plasticity; Opsins; Saimiri
PubMed: 25147187
DOI: 10.1101/cshperspect.a017418 -
Proceedings of the National Academy of... Sep 2021Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR...
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying disease variants and from gene-edited null hESCs. We found that achromatopsia patient and null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
Topics: Activating Transcription Factor 6; Color Vision Defects; Cone Opsins; Gene Expression; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Organoids; Retina; Retinal Cone Photoreceptor Cells; Vision, Ocular
PubMed: 34561305
DOI: 10.1073/pnas.2103196118 -
The National Medical Journal of India 2018Colour vision deficiency (CVD) is a common problem and persons with CVD experience difficulties in daily life, early learning and development, education, choice of... (Review)
Review
Colour vision deficiency (CVD) is a common problem and persons with CVD experience difficulties in daily life, early learning and development, education, choice of careers and work performance. Medical professionals with CVD also report difficulties in everyday tasks, training in medicine and performance of medical duties. However, because of limited evidence, the real impact of CVD on the lives of medical professionals is unclear, especially regarding the practice of medicine by doctors. The nature and severity of CVD, awareness of its impact, personal circumstances and the ability to cope with the deficiency are the major factors that determine the impact of CVD. However, there is a paucity of methodologically sound research on social and psychological aspects of CVD. Currently, early detection, enhancing awareness and offering support are the only proven ways of helping medical professionals with CVD. With the growing emphasis on equality and inclusivity of those with deficiencies, it is desirable to strike a balance between concerns about patient care and the rights of medical professionals with CVD to pursue their careers. Therefore, any future research also needs to focus on psychological aspects of CVD while exploring its impact on a career in medicine.
Topics: Adaptation, Psychological; Career Choice; Color Vision Defects; Humans; Patient Safety; Physicians; Quality of Life; Severity of Illness Index
PubMed: 30829224
DOI: 10.4103/0970-258X.253167 -
Indian Journal of Ophthalmology Jul 2022Inherited retinal diseases (IRD) are genotypically and phenotypically varied disorders that lead to progressive degeneration of the outer retina and the retinal pigment... (Review)
Review
Inherited retinal diseases (IRD) are genotypically and phenotypically varied disorders that lead to progressive degeneration of the outer retina and the retinal pigment epithelium (RPE) eventually resulting in severe vision loss. Recent research and developments in gene therapy and cell therapy have shown therapeutic promise in these hitherto incurable diseases. In gene therapy, copies of a healthy gene are introduced into the host cells via a viral vector. Clinical trials for several genes are underway while treatment for RPE65 called voretigene neparvovec, is already approved and commercially available. Cell therapy involves the introduction of stem cells that can replace degenerated cells. These therapies are delivered to the target tissues, namely the photoreceptors (PR) and RPE via subretinal, intravitreal, or suprachoroidal delivery systems. Although there are several limitations to these therapies, they are expected to slow the disease progression and restore some visual functions. Further advances such as gene editing technologies are likely to result in more precise and personalized treatments. Currently, several IRDs such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, choroideremia, achromatopsia, and Usher syndrome are being evaluated for possible gene therapy or cell therapy. It is important to encourage patients to undergo gene testing and maintain a nationwide registry of IRDs. This article provides an overview of the basics of these therapies and their current status.
Topics: Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Retina; Retinal Diseases; Retinitis Pigmentosa
PubMed: 35791112
DOI: 10.4103/ijo.IJO_82_22 -
Cold Spring Harbor Perspectives in... Oct 2014Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2... (Review)
Review
Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
Topics: Animals; Bardet-Biedl Syndrome; Choroideremia; Clinical Trials as Topic; Color Vision Defects; Disease Models, Animal; Eye Diseases, Hereditary; Genetic Diseases, X-Linked; Genetic Heterogeneity; Genetic Therapy; Humans; Leber Congenital Amaurosis; Macular Degeneration; Myopia; Night Blindness; Optogenetics; Retinal Degeneration
PubMed: 25324231
DOI: 10.1101/cshperspect.a017111 -
Cells Apr 2020Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches,... (Review)
Review
Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.
Topics: Animals; Disease Models, Animal; Inheritance Patterns; Light Signal Transduction; Mutation; Photoreceptor Cells, Vertebrate; Retinal Degeneration
PubMed: 32260251
DOI: 10.3390/cells9040882 -
Proceedings (Baylor University. Medical... Oct 2014Binasal hemianopia is a rarely encountered visual field defect. We examined two asymptomatic female patients, aged 17 and 83, with complete binasal hemianopia. Both...
Binasal hemianopia is a rarely encountered visual field defect. We examined two asymptomatic female patients, aged 17 and 83, with complete binasal hemianopia. Both patients had unremarkable eye exams except for the visual field deficits and minimally reduced visual acuity and color vision. Both patients had normal neuroimaging. These are the first reported cases of complete binasal visual field defects without an identifiable ocular or neurologic cause.
PubMed: 25484511
DOI: 10.1080/08998280.2014.11929158