From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU

In 1997, the human corneal epithelium was reconstructed in vitro and transplanted on patients. Later, it became a routine treatment, before regulations considered advanced therapy medicinal products and drugs on the same lines. Manufacturing, before and after good manufacturing practice setting, was established in different facilities and the clinical application in several hospitals. Advanced therapy medicinal products, including stem cells, are unique products with different challenges than other drugs: some uncertainties, in addition to benefit, cannot be avoided. This review will focus on all recent developments in the stem cell based corneal therapy

Differential Protein Expression Profiles in Glaucomatous Trabecular Meshwork: An Evaluation Study on a Small Primary Open Angle Glaucoma Population

INTRODUCTION: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. METHODS: TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies. RESULTS: A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFβ1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFβ1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes. CONCLUSION: The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates. FUNDING: This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the “National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation”. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0285-x) contains supplementary material, which is available to authorized users

Epidemiology and economic impact of moderate and severe neurotrophic keratopathy in Italy

Neurotrophic keratopathy is a rare corneal disease caused by impaired corneal innervation. There is a paucity of published evidence on neurotrophic keratopathy with no published studies on the economics of neurotrophic keratopathy in the Italian or international literature. This cost analysis aimed at assessing the economic impact of moderate (persistent epithelial defect) and severe (corneal ulcer without perforation) neurotrophic keratopathy from the perspective of the National Health Service and patients in Italy. Treatment algorithm and health resource use information were collected from a panel of nine experts from Italian centres specialized in ocular/corneal conditions. National ambulatory and inpatient hospital tariffs were applied to units of service, and Agenzia Italiana del Farmaco (AIFA) published prices to pharmaceuticals. Mean annual per patient cost was derived as an average cost weighted by the proportion of patients on each respective treatment and length of the treatment. The National Health Service + patient perspective additionally included patients' out-of-pocket expenses. The mean annual estimated National Health Service cost of treatment was €5167 (persistent epithelial defect) and €10,885 (corneal ulcer without perforation) per patient. Costs were largely driven by ambulatory visits and hospital interventions. The mean annual estimated National Health Service + patient cost was €5731 (persistent epithelial defect) and €11,478 (corneal ulcer without perforation) per patient, including cost of out-of-pocket expenses for pharmaceuticals and therapeutic contact lenses. Mean annual cost of neurotrophic keratopathy in Italy doubles with disease severity. Further research is warranted to provide more insight especially into societal costs

Customized Toric Intraocular Lens Implantation in Eyes with Cataract and Corneal Astigmatism after Deep Anterior Lamellar Keratoplasty: A Prospective Study

Purpose. To investigate the effectiveness of toric intraocular lenses (IOLs) for treating corneal astigmatism in patients with cataract and previous deep anterior lamellar keratoplasty (DALK). Setting. San Giovanni-Addolorata Hospital, Rome, Italy. Design. Prospective interventional case series. Methods. Patients undergoing cataract surgery after DALK for keratoconus were enrolled. Total corneal astigmatism (TCA) was assessed by a rotating Scheimpflug camera combined with Placido-disk corneal topography (Sirius; CSO, Firenze, Italy). A customized toric IOL (FIL 611 T, Soleko, Rome, Italy) was implanted in all eyes. One year postoperatively, refraction was measured, the IOL position was recorded, and vectorial and nonvectorial analyses were performed to evaluate the correction of astigmatism. Results. Ten eyes of 10 patients were analyzed. The mean preoperative TCA magnitude was 4.92 ± 1.99 diopters (D), and the mean cylinder of the IOL was 6.18 ± 2.44. After surgery, the difference between the planned axis of orientation of the IOL and the observed axis was ≤10° in all eyes. The mean surgically induced corneal astigmatism was 0.35 D at 20°. The mean postoperative refractive astigmatism power was 1.13 ± 0.94 D; with respect to preoperative TCA, the reduction was statistically significant (p<0.0001). The mean change in astigmatism power was 3.80 ± 1.60 D, corresponding to a correction of 77% of preoperative TCA power. Nine eyes out of 10 had a postoperative refractive astigmatism power ≤ 2D. Conclusions. Toric IOLs can effectively correct corneal astigmatism in eyes with previous DALK. The predictability of cylinder correction is partially lowered by the variability of the surgically induced changes of TCA. This trial is registered with NCT03398109

Evaluation of a new method for the measurement of corneal thickness in eye bank posterior corneal lenticules using Anterior Segment Optical Coherence Tomography

Background/aimsTo preliminarily evaluate the repeatability of central corneal thickness (CCT) measurements performed with Anterior Segment Optical Coherence Tomography (AS-OCT) on eye bank posterior corneal lenticules.MethodsSix donor lenticules were created with a 350 μm head microkeratome (Moria, Antony, France). All donor tissues were stored at 4°C in Eusol-C solution (Alchimia S.r.l, Ponte S. Nicolò, Italy), without the anterior cornea lamella. The CCT of each lenticule, maintained in the glass phial, was measured using a commercial AS-OCT instrument (Visante, Carl Zeiss Meditec, Dublin, California, USA) and a specially designed adaptor immediately and 4, 24 and 48 hours after dissection. Immediately after AS-OCT, CCT values were measured with the ultrasound pachymetry method used at the Eye Bank.ResultsThe mean donor cornea central thickness was 647±36 μm and 660±38 μm (p=0.001) as measured by AS-OCT and ultrasound, respectively; immediately after dissection, CCT values of posterior lenticules were 235±43 μm and 248±44 μm, respectively (p=0.001). No statistically significant changes in CCT values of donor lenticules were assessed over the 48 h period with both methods. There was a high level of agreement, evidenced by Bland–Altman analysis, between the two methods of pachymetry.ConclusionAS-OCT, with the corneal tissue in the vial, was revealed to be a repeatable and reliable method for measuring posterior donor lenticule central thickness. Lenticule CCT values measured with the investigational AS-OCT method were on average 10 μm thinner than those measured with the established ultrasound method

Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells

Aim: Limbal cultures restore the corneal epithelium in patients with ocular burns. We investigated the biological parameters instrumental for their clinical success. Methods: We report a long-term multicenter prospective study on 152 patients carrying corneal destruction due to severe ocular burns, treated with autologous limbal cells cultured on fibrin and clinical-grade 3T3-J2 feeder cells. Clinical results were statistically evaluated both by parametric and nonparametric methods. Results: Clinical outcomes were scored as full success, partial success and failure in 66.05, 19.14 and 14.81% of eyes, respectively. The total number of clonogenic cells, colony size, growth rate and presence of conjunctival cells could not predict clinical results. Instead, the clinical data provided conclusive evidence that graft quality and likelihood of a successful outcome rely on an accurate evaluation of the number of stem cells detected before transplantation as holoclones expressing high levels of the p63 transcription factor. No adverse effects related to the feeder layer have been observed and the regenerated epithelium was completely devoid of any 3T3-J2 contamination. Conclusion: Cultures of limbal stem cells can be safely used to successfully treat massive destruction of the human cornea. We emphasize the importance of a discipline for defining the suitability and the quality of cultured epithelial grafts, which are relevant to the future clinical use of any cultured cell type

The Management of Dry Eye Disease: Proceedings of Italian Dry Eye Consensus Group Using the Delphi Method

Dry eye disease (DED) is a highly prevalent, chronic and progressive condition that affects 5-33% of the world's adult population [...]