A Clinical Study on Co-transplantation of Autologous Limbal Stem Cells and Corneal Stromal Stem Cells to Repair Corneal Injury

Phase 1

Not yet recruiting

• Conditions: Limbal Stem Cells Deficiency
• Interventions: Biological: Cornea limbal stem cell transplantation group; Biological: Cornea limbal stem cell transplantation combined corneal stromal stem cell group; Procedure: Corneal transplantation

• Registration Number: NCT06700655
• Lead Sponsor: Zhongshan Ophthalmic Center, Sun Yat-sen University

Brief Summary

This study aims to: 1) verify the feasibility of treating limbal stem cell deficiency (LSCD) caused by chemical injury with autologous limbal stem cell transplantation combined with corneal stromal stem cell transplantation; 2) evaluate the corneal healing patterns following autologous stem cell transplantation; and 3) establish a clinical intervention protocol based on autologous corneal stem cell transplantation. Sixty cases of single-eye LSCD were included.

Detailed Description

Limbal Stem Cells (LSCs) are the sole source of corneal epithelial self-renewal and play a critical role in maintaining corneal transparency. Chemical or physical injury to the eye and inflammation can lead to limbal stem cell deficiency (LSCD), accompanied by a series of pathological changes, such as irreversible fibrosis of corneal stromal cells and neovascularization, ultimately resulting in blindness. The fundamental solution for such diseases is the replenishment of LSCs to reconstruct a functional cornea. However, traditional treatment methods, such as corneal transplantation, face bottlenecks, including a severe shortage of corneal donors and the risk of immune rejection. Additionally, donor corneas do not contain LSCs, making it impossible to reconstruct the patient's limbal region, resulting in poor long-term efficacy.

In 2015, autologous LSCs were approved by the European Union as a commercial stem cell product for treating patients with chemically induced LSCD. However, LSCD patients are often accompanied by damage to the corneal stroma; while LSC transplantation can restore the limbal region and corneal epithelium, it cannot repair stromal opacities. Research indicates that transplantation of corneal stromal stem cells can reconstruct organized collagen structures and restore stromal transparency. Over the past decade, clinical studies using LSCs and corneal stromal stem cells to treat LSCD patients have been conducted in multiple countries, demonstrating the safety and efficacy of these stem cell therapies for corneal blindness.

Based on these findings above, the investigators have established a serum-free, carrier-free culture system that enables efficient and uniform in vitro expansion of functional LSCs and corneal stromal stem cells. By obtaining a 2 x 5 mm limbal tissue sample from the healthy eye of the patient, the investigators can acquire a sufficient number of cells for transplantation. Preclinical studies have confirmed that the expanded cells are effective and safe for treating LSCD animal models. This study aims to use autologous LSCs combined with corneal stromal stem cell transplantation to treat patients with unilateral LSCD, restoring their corneal transparency and visual function. This approach provides a novel treatment method for patients and promotes the application of stem cell regenerative medicine for the treatment of corneal blindness in China.

Study Timeline

• Status Verified: 2024-11
• Study First Submitted: 2024-11-17
• Study First Submitted QC: 2024-11-20
• Last Update Submitted: 2024-11-20
• Study First Posted: 2024-11-22
• Last Update Posted: 2024-11-22
• Study Start: 2024-12-01
• Primary Completion: 2028-12-01
• Study Completion: 2029-03-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Chemical injury from acid or alkali exposure
• Extensive limbal stem cell deficiency (greater than 180 degrees), with corneal stromal opacity not exceeding a depth of 250 μm
• Corneal epithelial conjunctivalization and fibrosis, with neovascularization extending into more than half of the quadrants
• Unilateral ocular involvement, with normal limbal stem cell function in the contralateral healthy eye
• No significant improvement in ocular surface signs and symptoms after pharmacological or surgical interventions, stable for over three months

Exclusion Criteria

• Bilateral corneal stem cell deficiency, such as in Stevens-Johnson syndrome, ocular cicatricial pemphigoid, or congenital aniridia
• Subclinical limbal stem cell deficiency in the contralateral eye
• Signs of corneal endothelial decompensation, such as corneal bullae or corneal edema
• Presence of infectious inflammation on the ocular surface
• Severe dry eye
• Eyelid abnormalities requiring corrective surgery to restore normal anatomical structure
• Presence of chronic dacryocystitis, cataracts, uveitis, diabetic retinopathy, retinal detachment, or other ocular diseases
• Patients who have undergone cataract surgery or other intraocular procedures
• Glaucoma patients requiring long-term topical ocular medications
• History of corneal perforation in the affected eye
• Severe primary cardiovascular, hepatic, renal, endocrine, or hematologic disorders, diabetes, or immune deficiency in the medical history
• Pregnant or lactating women
• Positive screening for infectious diseases (HIV, HBV, HTLV, EBV, CMV, or syphilis)
• Other vision-impairing diseases present
• Allergy to bovine serum products
• History of multiple drug allergies or hypersensitive constitution
• Concurrent participation in other drug clinical trials
• History of mental health disorders affecting the ability to comply with study requirements
• Judged unsuitable for participation by the investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cornea limbal stem cell transplantation group	Cornea limbal stem cell transplantation group	The corneal limbal tissue (2mm x 5mm) was harvested from the patient's healthy eye, and ex vivo amplification was performed to obtain an adequate quantity of transplantable corneal limbal stem cells The patient was followed up and re-examined for 2 years postoperatively.
Cornea limbal stem cell transplantation combined corneal stromal stem cell group	Cornea limbal stem cell transplantation combined corneal stromal stem cell group	The corneal limbal tissue (2mm x 5mm) was harvested from the patient's healthy eye, and ex vivo amplification was performed to obtain an adequate quantity of transplantable corneal limbal stem cells and corneal stromal stem cells. The patient was followed up and re-examined for 2 years postoperatively.
Corneal transplantation group	Corneal transplantation	The patient awaited allogeneic corneal donation and underwent corneal transplantation surgery. Postoperatively, the patient was followed up and re-examined for 2 years.

Primary Outcome Measures

Name	Time	Method
Vision	[set the tissue sampling date at the begin] Enrollment, before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	The patient should initially be positioned 5 meters from the visual acuity chart in a well-lit environment. Each eye is tested separately (the non-tested eye should be completely covered with an eye patch without applying pressure on the eyeball). During the test, the patient first views the largest line on the chart. If they can identify it, they proceed from top to bottom, viewing progressively smaller lines until the smallest identifiable line is determined. The patient should not spend more than 5 seconds reading each character.

Secondary Outcome Measures

Name	Time	Method
Efficacy Scoring	[set the corneal limbal tissue sampling date at the begin] First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	The efficacy of cell transplantation will be evaluated based on corneal epithelial defect, area of leukoplakia, transparency, neovascularization, and corneal edema.
Ocular adverse event evaluation	[set the corneal limbal tissue sampling date at the begin] before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	The transplantation area for the cells is the ocular surface, so the primary measure of safety will focus on post-transplant ocular symptoms. These include eye irritation symptoms, conjunctival hyperemia, corneal surface edema, and anterior chamber flare. Adverse events are defined as follows: eye irritation symptoms scoring ≥1, conjunctival hyperemia scoring ≥2, corneal surface edema scoring ≥2, anterior chamber flare scoring ≥2, or a total score of 7 or above.; The healthy eye requires postoperative observation, and if infection or delayed healing occurs after tissue sampling, treatment will be necessary.
ophthalmic examination（slit-lamp）	[set the tissue sampling date at the begin] Enrollment, before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	including cornea, conjunctiva, lens, vitreous body and retina. Score each indicator from 0 to 3 based on the standards in the table, and then calculate the final score.
cornea confocal	[set the tissue sampling date at the begin] Enrollment, before the transplantation, Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	Corneal microscopic structure examination. Observe whether the morphology of each layer of the cornea is normal.
corneal topography	[set the tissue sampling date at the begin] Enrollment, before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	Analyze the morphology and curvature characteristics of the entire corneal surface.
Optical Coherence Tomography	[set the tissue sampling date at the begin] Enrollment, before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	Observe the depth of corneal lesions to assess the condition and treatment efficacy.
anterior segment photography	[set the tissue sampling date at the begin] Enrollment, before the transplantation, First follow-up (Day 32), Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	record the statement of ocular surface
VFQ-25 questionnaire	[set the tissue sampling date at the begin] Enrollment, before the transplantation, Second follow-up (Day 48), Third follow-up (Day 108), Fourth follow-up (6 months), Fifth follow-up (1 year), Sixth follow-up (2 years)	The VFQ-25 (Visual Function Questionnaire-25) is a widely used tool to assess the health-related quality of life related to visual function. It consists of 25 questions to evaluate how vision affects daily activities, emotional well-being, and social interactions. The questionnaire covers several domains: general vision, near and distance vision, social functioning, role difficulties, mental health, and driving. It is often used in clinical settings to track the progression of eye diseases, evaluate treatment outcomes, or compare the quality of life between different patient groups. A higher score indicates better visual function and quality of life, meaning the patient experiences fewer difficulties and less impairment in daily activities due to vision problems. Therefore, higher scores are better in this context.