Identification of Cellular Biomarkers of Rare Eye Diseases in Adults
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 110
- 试验地点
- 2
- 主要终点
- The expression levels of the genes and proteins
研究概览
简要总结
The cornea is the outermost transparent 'window' of the eye allowing light to enter and serving as the first-line immune and mechanical barrier. It is a complex avascular tissue composed of cells, stem cells, nerves, and collagen layers organized in an exquisite manner to maintain its transparency and self-healing capacity. This delicately balanced interplay of corneal elements is disrupted in rare diseases of the cornea, resulting in non-healing wounds, corneal ulceration, inflammation, new vessel ingrowth (neovascularization), defective innervation, scarring, oedema and loss of transparency. For many Rare Eye Diseases (REDs), drug development has been relatively unsuccessful, delivering few to no new therapies. Current management is often prohibitively expensive, has low efficacy and leads to debilitating side effects. The RESTORE VISION project (https://restorevision-project.eu/) aims to improve eye health by using cutting-edge models for each rare disease to test novel and repurposed compounds (9 in total) and determine drug mechanisms of action, formulating compounds as safe eye drop suspensions, and performing several first-in-human trials of novel therapies. Thes drugs have solid preliminary data showing beneficial effects in restoring the cell physiology, immune, avascular, neural and signaling environment in the cornea.
The current clinical study is part of Work package 2 within the RESTORE VISION EU grant agreement (''Validation of human drug targets of repurposed drugs and novel therapies'') and aims to ascertain the expression levels of genes and proteins and investigate pathways of interest in human tissue and fluid samples of REDs, that are targeted by the proposed experimental/repurposed substances. Therapeutic target gene and/or protein expression will be verified in human blood, tears and conjunctival cells collected from 7 RED patient groups. The RESTORE VISION Consortium know multiple putative genes and proteins involved in the REDs and/or affected by the drugs to be tested in RED models. These will be analyzed in patient samples from the 7 REDs to see if they are 1) expressed at all; 2) differ in expression between patient and control group and 3) are correlated with clinical endpoints and/or symptoms of REDs.
The 7 REDs under investigation are briefly explained as follows:
- AAK: genetic progressive limbal stem cell degeneration leading to corneal neovascularization, inflammation, recurrent erosions, chronic pain and vision loss.
- OCP: autoimmune scarring of the conjunctiva leads to deficient wound healing, inflammation, scarring, blindness and pain.
- EEC Syndrome: Ectodermal Dysplasia causes pathological corneal scarring and blindness.
- NK: involves a corneal nerve deficit leading to reduction or loss of corneal sensitivity, impaired wound healing, corneal ulceration and loss of vision.
- LSCD: acquired or hereditary stem cell deficiency inducing epithelial breakdown, neovascularization, scarring and inflammation leading to decreased vision, tearing and pain.
- oGvHD: a severe side-effect of successful bone-marrow transplantation leads to painful and blinding ocular surface inflammation, neovascularization and delayed wound healing.
- CN: in high-risk transplantation, pathologic inflammation, corneal blood and lymphatic vessels are key risk factors for high-risk corneal graft failure, leading to graft rejection and blindness.
详细描述
The expression levels of the genes/proteins that are investigated in this study will be differentially expressed (up/down regulated) between patient and control groups and furthermore there will be associations between the expression levels of these genes/proteins* and clinical endpoints/symptoms in patients with the 7 REDs. The analysis that will be performed in this study will provide key insights into mechanisms of disease in the 7 REDs and the pathways targeted by the RESTORE VISION drugs.
*Restore Vision REDs and gene/protein targets :
Impression cytology :
- For AAK : PAX6, IRS-1, MR, GR, HSD1, HSD2
- For OCP : IRS-1,MR, GR
- For EEC : IRS-1, MR, GR, HSD1, HSD2
- For NK : IRS-1, MR, GR, HSD1, HSD2
- For LSCD : IRS-1, MR, GR, HSD1, HSD2, DCN/LRG-1
- For oGvHD : IRS-1, MR, GR, HSD1, HSD2
- For CN : IRS-1, MR, GR, HSD1, HSD2, DCN/LRG-1
Tear fluid :
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Patient group:
- •Women and men with age equal or higher than 18 years (patients planning to conceive may be included in the study)
- •Willingness and ability to read and understand the informed consent.
- •Diagnosis (including genotype, if needed) of REDs.
- •Affiliation with a social security scheme or beneficiary of such a scheme.
- •RED 1 - AAK Diagnosis criteria
- •Compatible slit lamp examination (iris/pupillary abnormalities, with or without corneal opacification, vascularization, cataract, glaucoma). with or without:
- •Foveal hypoplasia and optic disc malformations as detected through fundus examination or OCT tomography
- •Compatible anterior segment OCT or high-frequency ultrasound biomicroscopy (UBM)
- •Positive genetic testing
- •RED 2 - NK Diagnosis criteria
- •Compatible history and slit lamp findings of one of the three stages of the Mackie classification (I - punctate keratopathy; II - persistent epithelial defect; III - stromal involvement)
- •Reduced/absent corneal sensitivity
- •Exclusion of infectious or toxic etiologies with or without:
- •confocal microscopy findings
- •RED 3 - LSCD Diagnosis criteria
- •Compatible history and slit lamp examination (e.g. corneal conjunctivalization with persistent epithelial defects, loss of limbal anatomy or irregular staining with fluorescein) with or without:
- •confocal microscopy findings
- •RED 4 - OCP Diagnosis criteria
- •Compatible slit lamp examination
- •Exclusion of infectious or toxic etiologies with or without:
- •conjunctival /oral biopsy with characteristic mucous pemphigoid findings
- •RED 5 - OC GVHD Diagnosis criteria • Compatible history and slit lamp examination consistent with one of 4 grades of ocular GVHD (1 - conjunctival hyperemia, 2 - fibrovascular changes <25% of palpebral conjunctiva, 3 - fibrovascular changes >25%, 4 - >75% or cicatricial entropion)
- •RED 6 - EEC Diagnosis criteria
- •Compatible slit lamp examination
- •Compatible systemic findings with or without:
- •Positive genetic testing
- •RED 7- CNV Diagnosis criteria
- •Compatible slit lamp examination of corneal stromal neovascularization (1-4 quadrants)
- •Exclusion of infectious or toxic etiologies with or without:
- •confocal microscopy findings
- •Control group:
- •Women and men with age equal or higher than 18 years (patients planning to conceive may be included in the study).
- •Willingness and ability to read and understand the informed consent.
- •Non-diagnosis of REDs.
- •Affiliation with a social security scheme of beneficiary of such a scheme.
排除标准
- •Patient group:
- •Pregnancy, breastfeeding (in case any stress was caused to the woman by the biological sampling).
- •Descemetocele/impending corneal perforation.
- •Recent (less than 3 months) ocular surgery.
- •Recent (less than 1 month) change in topical medications type and frequency of the ocular pathology.
- •Persons subject to a legal protection measure (under guardianship, curatorship or safeguard of justice)
- •Control group:
- •Pregnancy, breastfeeding.
- •Active ocular infection.
- •Descemetocele/impending corneal perforation.
- •Recent (less than 3 months) ocular surgery.
- •Recent (less than 1 month) change in topical medications type and frequency of the ocular pathology.
- •Persons subject to a legal protection measure. (under guardianship, curatorship or safeguard of justice)
研究组 & 干预措施
Control group
In France, two groups of participants will be recruited (110 participants). 55 of subjects in a control group, will be selected to match the two groups with regard to possible confounding variables, such as gender and age (±5). Patients in the control group will be recruited from the ophthalmology clinics of the Cochin and Necker hospitals, as these patients are already being treated in these hospitals for other pathologies unrelated to rare diseases.
干预措施: Ophthalmological visit (Other)
Control group
In France, two groups of participants will be recruited (110 participants). 55 of subjects in a control group, will be selected to match the two groups with regard to possible confounding variables, such as gender and age (±5). Patients in the control group will be recruited from the ophthalmology clinics of the Cochin and Necker hospitals, as these patients are already being treated in these hospitals for other pathologies unrelated to rare diseases.
干预措施: Questionnaires (Other)
Control group
In France, two groups of participants will be recruited (110 participants). 55 of subjects in a control group, will be selected to match the two groups with regard to possible confounding variables, such as gender and age (±5). Patients in the control group will be recruited from the ophthalmology clinics of the Cochin and Necker hospitals, as these patients are already being treated in these hospitals for other pathologies unrelated to rare diseases.
干预措施: Blood sample collection (Other)
Control group
In France, two groups of participants will be recruited (110 participants). 55 of subjects in a control group, will be selected to match the two groups with regard to possible confounding variables, such as gender and age (±5). Patients in the control group will be recruited from the ophthalmology clinics of the Cochin and Necker hospitals, as these patients are already being treated in these hospitals for other pathologies unrelated to rare diseases.
干预措施: Impression cytology (Other)
Control group
In France, two groups of participants will be recruited (110 participants). 55 of subjects in a control group, will be selected to match the two groups with regard to possible confounding variables, such as gender and age (±5). Patients in the control group will be recruited from the ophthalmology clinics of the Cochin and Necker hospitals, as these patients are already being treated in these hospitals for other pathologies unrelated to rare diseases.
干预措施: Tear fluid (Other)
Patient group
In France, two groups of participants will be recruited (110 participants). 55 subjects with REDs in an experimental group. This group is divided into subgroups. Indeed, 15 patients will be affected by AAK, 5 by NK, 5 by LSCD, 10 by OCP, 5 by Oc GvHD, 10 by EEC and 5 by CNV (the 7 different rare eye diseases)
干预措施: Ophthalmological visit (Other)
Patient group
In France, two groups of participants will be recruited (110 participants). 55 subjects with REDs in an experimental group. This group is divided into subgroups. Indeed, 15 patients will be affected by AAK, 5 by NK, 5 by LSCD, 10 by OCP, 5 by Oc GvHD, 10 by EEC and 5 by CNV (the 7 different rare eye diseases)
干预措施: Questionnaires (Other)
Patient group
In France, two groups of participants will be recruited (110 participants). 55 subjects with REDs in an experimental group. This group is divided into subgroups. Indeed, 15 patients will be affected by AAK, 5 by NK, 5 by LSCD, 10 by OCP, 5 by Oc GvHD, 10 by EEC and 5 by CNV (the 7 different rare eye diseases)
干预措施: Blood sample collection (Other)
Patient group
In France, two groups of participants will be recruited (110 participants). 55 subjects with REDs in an experimental group. This group is divided into subgroups. Indeed, 15 patients will be affected by AAK, 5 by NK, 5 by LSCD, 10 by OCP, 5 by Oc GvHD, 10 by EEC and 5 by CNV (the 7 different rare eye diseases)
干预措施: Impression cytology (Other)
Patient group
In France, two groups of participants will be recruited (110 participants). 55 subjects with REDs in an experimental group. This group is divided into subgroups. Indeed, 15 patients will be affected by AAK, 5 by NK, 5 by LSCD, 10 by OCP, 5 by Oc GvHD, 10 by EEC and 5 by CNV (the 7 different rare eye diseases)
干预措施: Tear fluid (Other)
结局指标
主要结局
The expression levels of the genes and proteins
时间窗: At the inclusion visit
The primary endpoint will be the expression levels of the genes and proteins listed in the Study description. These genes and proteins are expected to be differentially expressed (upregulated or down regulated) compared to the control group. The investigators will arbitrarily set at 1 the target level in the control group and the RED group will be expressed in relation to the control group. While sample collection occurs in 4 Clinical centers (2 in Inserm, France, 1 in Klinikum der Universitaet zu Koeln (UKK, Germany) and 1 in San Raffaele Hospital OSR, Italy), following any initial required processing all samples will be shipped to OSR in Italy who will perform the qPCR, Elisa and/or Mass Spectrometry analysis. Laboratory tests (qPCR, Elisa and/or Mass Spectrometry) will be performed at the Eye Repair lab of the Department of Neuroscience at IRCCS at OSR.
次要结局
- The expression levels of the genes and proteins(At the inclusion visit)