Cell Therapy in Failure Syndromes in Limbal Stem Cells

Study Overview
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Brief Summary
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Transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders in eyes with total limbal deficiency. Prospective non-comparative monocentric study.

Detailed Description
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The limbal stem cell deficiency syndrome is characterized by invasion of the corneal surface by an epithelium with a conjunctival differentiation, and, clinically, by opacification and vascularization of the corneal epithelium with impaired corneal epithelial cicatrisation and corneal ulcers that may lead to corneal perforation. When total, the limbal deficiency syndrome is the cause of major disability. Vision decreases largely under the legal threshold of blindness. Overall, the most frequent etiology is by far the complete loss of limbal stem cells induced by severe ocular burns. Until a rather recent date, no treatment was possible in this pathology. Progress in the comprehension of the physiology of the corneal epithelium renewal made it possible to introduce a therapeutic approach, i.e., transplantation of cultured limbal stem cells retrieved from the healthy contralateral eye (autograft, unilateral diseases) or from a cadaveric donor eye (allograft, bilateral diseases or unique eye). Techniques of cell therapy were first described in Italy, Asia and in the USA with positive clinical results. They have all different processes for preparing the cell product to be transplanted and none answers the safety criteria required by the French legislation. The investigators developed a process for preparing a cell therapy product which was accepted by the French regulation agency (AFSSaPS) for a clinical trial (TC181) which began in 2007. The aims of the study are (1) evaluation of the clinical results of this technique in terms of improvement of visual function, reduction in the handicap, improvement of the anatomical condition of the ocular surface and restitution of the physiological function of the limbal epithelium and (2) evaluation of its possible side effects. It is a biphasic monocentric non-comparative prospective study including, according to the clinical responses observed during the first phase (plane of Gehan, ß = 10%), from 15 to 50 voluntary patients with unilateral or bilateral total limbal deficiency. Patient follow-up is 3 years. The expected minimal success rate is 20% for allografts and 40% for the autografts. Monitoring is ensured by URC-Est. The grafts are prepared by culture of autologous or allogeneic limbal epithelial cells from limbal explants on human amniotic membrane. The medical safety requirements relating to transplantation of tissues and cells are reached and the cell therapy products are secured at each stage of their preparation by conventional bacteriological and fungal tests and viral and bacterial PCR. The graft quality is controlled before transplantation. The main outcome measure is survival of the grafted epithelium (Kaplan-Meier method) defined by absence of recurrence of the clinical signs of limbal deficiency (opacification of the corneal epithelium, irregularity of the corneal epithelium, surface corneal vascularization) in the central cornea. The expected repercussions are (1) restitution of a limbal epithelial function allowing a clear corneal epithelium to be obtained, with no superficial vascularization nor chronic epithelial defects, (2) improvement of vision in blind patients, and (3) obtaining a vision higher than the legal threshold of blindness after cell therapy or after subsequent corneal transplantation. If the clinical trial makes it possible to show the effectiveness of this cell therapy technique, a request for authorization of process will be made at AFSSaPS for routine use.

Official Title
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Thérapie Cellulaire au Cours Des Syndromes d'Insuffisance en Cellules Souches Limbiques

Conditions
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Limbal Deficiency

Intervention / Treatment
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* Biological: epithelial stem cells cultured
* Procedure: transplantation of cultured cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age between 18 and 70 years Informed consent. Unilateral or bilateral limbal deficiency with diffuse opacification of the corneal epithelium, and superficial (or superficial and deep) corneal vascularization, and irregular corneal epithelial surface at slit-lamp examination with fluorescein, either associated with chronic epithelial defects Visual acuity of the eye to be treated < 20/20. Absence de kératinization of the ocular surface. Schirmer test > 0 at 3 minutes. For autografts : sérology HIV -, HCV -, HBs Exclusion Criteria: Age < 18 y or > 70 y. Absence of informed consent or imformed consent not possible. Partial limbal deficiency (healthy corneal epithelium persistant in at least one zone). Previous treatment of limbal deficiency by limbal transplantation or amniotic membrane transplantation during the last 12 months. Conjunctival stem cell deficiency (xerophtalmia, keratinization of the ocular surface). Local anesthesia impossible. Immune keratitis not controlled by medical treatment. Ocular burn during the last 2 weeks. Corneal anesthesia. Pregnancy, breast-feeding. Allergy to steroid eyedrops. Active fungal keratitis. For autografts : risk factor for rabbies or Creutzfeldt-Jacob disease, serology HIV +, VHC +, HBs+. Follow-up not possible

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective Phase II Interventional Clinical Trial (Transplantation of Allogeneic or Autologous Limbal Epithelial Stem Cells Cultured on Human Amniotic Membrane with no Feeders)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranplantation of cultured LSC in stage 3 limbal deficiency<br>Transplantation of Allogeneic or Autologous Limbal Epithelial Stem Cells Cultured on Human Amniotic Membrane with no Feeders in stage 3 unilateral or bilateral limbal stem cell deficiency. | Biological: epithelial stem cells cultured<br>* transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders<br>Procedure: transplantation of cultured cells<br>* transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival of the transplanted epithelium | survival of the transplanted epithelium defined by absence of recurrence of the clinical signs of limbal deficiency (opacification of the corneal epithelium, irregularity of the corneal epithelium, surface corneal vascularization) in the central cornea. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| visual acuity | far best spectacle-corrected LogMAR visual acuity | 3 years | 
| re-epithelialization time after keratoplasty | The healing time of corneal epithelium will be collectively assed by investigators form the CRF and the pictures taken during the study. | 3 years | 
| Symptoms | Symptoms recorded at each visit: redness : absent (0) - present (1) pain : absent (0) - present (1) burning : absent (0) - present (1) foreign body sensation : absent (0) - present (1) photophobia : absent (0) - present (1) blurred vision : absent (0) - present (1) Grading of symptoms : sum of all symptoms (0-6) | 3 years | 
| morphometric analysis of the ocular surface | the morphometric analysis of the corneal epithelial ulcerations will be assed by the CRA from the pictures of the corneal surface. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cell therapy, Limbal deficiency, Limbal stem cell, Transplantation