Identification of Cellular Biomarkers of Rare Eye Diseases in Adults (REVIBIO)

Institut National de la Santé Et de la Recherche Médicale, France

Status: Begins enrollment in 1 month

Conditions: Ophthalmology; Rare Diseases

Treatments: Other: Tear fluid; Other: Ophthalmological visit; Other: Blood sample collection; Other: Questionnaires; Other: Impression cytology

Study type: Interventional

Funder types: Other

Identifiers

NCT07063719

C24-15

Details and patient eligibility

About

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:

1. AAK: genetic progressive limbal stem cell degeneration leading to corneal neovascularization, inflammation, recurrent erosions, chronic pain and vision loss.
2. OCP: autoimmune scarring of the conjunctiva leads to deficient wound healing, inflammation, scarring, blindness and pain.
3. EEC Syndrome: Ectodermal Dysplasia causes pathological corneal scarring and blindness.
4. NK: involves a corneal nerve deficit leading to reduction or loss of corneal sensitivity, impaired wound healing, corneal ulceration and loss of vision.
5. LSCD: acquired or hereditary stem cell deficiency inducing epithelial breakdown, neovascularization, scarring and inflammation leading to decreased vision, tearing and pain.
6. oGvHD: a severe side-effect of successful bone-marrow transplantation leads to painful and blinding ocular surface inflammation, neovascularization and delayed wound healing.
7. 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.

Full description

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 :

• For AKK : PAX6
• For EEC : SPRR1A
• For LSCD :DCN/LRG

Enrollment: 110 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

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.

Exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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110 participants in 2 patient groups

Control group

Other group

Description:

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.

Treatment:

Other: Impression cytology

Other: Blood sample collection

Other: Questionnaires

Other: Ophthalmological visit

Other: Tear fluid

Patient group

Other group

Description:

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)

Treatment:

Other: Impression cytology

Other: Blood sample collection

Other: Questionnaires

Other: Ophthalmological visit

Other: Tear fluid