6 · Emerging therapies — cellular, gene & innovative
Cultivated limbal stem cells (CLET) — HOLOCLAR®
Review — modulators of corneal healing › 6 · Emerging therapies — cellular, gene & innovative › Cultivated limbal stem cells (CLET) — HOLOCLAR®
Cultivated limbal stem cells (CLET) — HOLOCLAR®
Autologous corneal epithelial cells expanded ex vivo · Holostem/Chiesi · first stem-cell-based advanced therapy medicinal product (ATMP) approved in the EU
Oxford II
Moderate–Strong
Present (EU) · MA
Mechanism of actionLimbal biopsy (1–2 mm²) expanded ex vivo on fibrin; the graft must contain an adequate fraction of p63-bright stem cells (release criterion ≥3%), a validated predictor of success. Reconstitutes the limbal niche → self-renewing epithelial phenotype, arrest of conjunctivalisation/neovascularisation.
IndicationsModerate to severe limbal stem cell deficiency (LSCD), uni-/bilateral, secondary to ocular burn (physical/chemical), with superficial neovascularisation ≥2 quadrants and central involvement. Restores the surface before/for subsequent keratoplasty.
Route & dosageSurgical implantation of a single graft (~3.8 cm², ≥79,000 cells/cm²) on a debrided cornea. Single ATMP procedure; re-grafting possible.
Level of evidenceOxford II (prospective/registration cohort; no large RCT — surgical ATMP) · Scale: Moderate–Strong (the strongest evidence base in this section). Success ~66–76%.
| FDA | Not approved (separate BLA required) — not marketed in the USA. |
|---|---|
| EU MA | Approved: conditional MA 17 Feb 2015 (1st stem cell therapy in the EU) → standard/full MA on 22 Feb 2024. Orphan designation 2008. |
| France | Available via reference centres (European MA). |
| USA | Not available. |
| Asia | Analogous CLET protocols (non-Holoclar): Japan, India… |
Key studies: Rama et al., NEJM 2010 (n=112, ~76.6% permanent success, p63 predictor) — PMID 20573916 ; Holostem pivotal cohort; Rama et al., Transplantation 2001 — PMID 11707733.